Open access peer-reviewed chapter

Bactericidal and Bacteriostatic Antibiotics

Written By

Sachin M. Patil and Parag Patel

Submitted: March 9th, 2021 Published: August 31st, 2021

DOI: 10.5772/intechopen.99546

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Of all the medications available to physicians worldwide, antibiotics play an essential role in inpatient and outpatient settings. Discovered in the early nineteenth century by Alexander Fleming, penicillin was the first antibiotic isolated from a mold. Dr. Gerhard Domagk developed synthetic sulfa drugs by altering the red dye used in chemical industries. Since then, multiple antibiotic classes have been discovered with varying antimicrobial effects enabling their use empirically or in specific clinical scenarios. Antibiotics with different mechanisms of action could be either bactericidal or bacteriostatic. However, no clinical significance has been observed between cidal and static antibiotics in multiple trials. Their presence has led to safer deep invasive surgeries, advanced chemotherapy in cancer, and organ transplantation. Indiscriminate usage of antibiotics has resulted in severe hospital-acquired infections, including nosocomial pneumonia, Clostridioides difficile infection, multidrug-resistant invasive bacterial infections, allergic reactions, and other significant side effects. Antibiotic stewardship is an essential process in the modern era to advocate judicial use of antibiotics for an appropriate duration. They play a vital role in medical and surgical intensive care units to address the various complications seen in these patients. Antibiotics are crucial in severe acute infections to improve overall mortality and morbidity.


  • Sepsis
  • antibiotics
  • bactericidal
  • bacteriostatic
  • stewardship

1. Introduction

Antibiotic is a term used to define a chemical substance produced by one microorganism that stunts the metabolism and development of other organisms [1]. The antibiotic term was used initially for naturally acquired substances; however, now the term encompasses both natural and synthetic antimicrobial substances. Although penicillin was the first antibiotic isolated from the mold, it was superseded by sulfa drugs used by physicians to treat infections successfully [2]. Due to antibiotic use, the infectious disease death rate has declined from 280 per 100,000 to 60 per 100,000 in the 1950s [3]. A common belief is that cidal antibiotics are efficient than static antibiotics with no clinical evidence supporting it. Both cidal and static are invitro terms which, refer to the effect of antibiotic concentrations affecting bacterial growth at a predefined threshold. They cannot predict the infection outcome in vivo. Antibiotics targeting the organism’s cell wall are mostly bactericidal, whereas those targeting protein syntheses are bacteriostatic. MIC (minimum inhibitory concentration) is the lowest antibiotic concentration, which prevents visible growth at 24 hours. MBC (minimum bactericidal concentration) is the minimal concentration of antibiotics that causes bacterial death. Breakpoints for antibiotic MIC’s are set by the the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and National Committee for Clinical and Laboratory Standards Institute (CLSI). A bactericidal antibiotic MBC is less than or equal to four folds above the MIC, accounting for a 1000-fold decline in bacterial density [4]. A bacteriostatic antibiotic achieves a > 1000-fold reduction at eight-fold above MIC or a 500-fold reduction in bacterial density at 4-fold above its MIC. They are still labeled as static despite the clear demonstration of bacterial killing. An antibiotic becomes more bactericidal as the MIC moves closer to the MBC. Bacteriostatic agents have an MBC to MIC ratio > than that for bactericidal antibiotics.

A systematic literature review revealed no confirmation that cidal agents are better than static agents [5]. In addition, there was no substantial difference in efficiency, including critically ill patients with severe infections and sepsis. Six trials demonstrated the superiority of static agent linezolid over cidal agents such as vancomycin [5]. A single trial showed the efficiency of cidal agent imipenem over tigecycline; however, the dose of tigecycline was small, and with increased appropriate dosing, the efficacy disappeared [6, 7]. A rapidly bactericidal agent such as daptomycin does not perform better than a slowly cidal agent such as vancomycin to treat right-sided infective endocarditis (IE) and staphylococcal bacteremia [8] . A synergistic combination of beta-lactam with aminoglycosides enhances the bactericidal effect with rapid blood clearance [9]. However, this synergistic combination has not improved clinical outcomes or mortality [10]. In the initial studies, static agents such as tetracyclines and macrolides were inferior to cidal agents in IE therapy [11]. This assumption can be erroneous as the static agents do not achieve adequate low blood concentrations to treat infective endocarditis effectively. A bacteriostatic antibiotic such as linezolid can attain sufficient bloodstream concentrations resulting in higher cure rates for IE [12]. Daptomycin, a rapidly bactericidal agent, is inferior to vancomycin in left-sided IE [13]. For an individual antibiotic to be effective, the importance of its pharmacokinetic-pharmacodynamic properties and attaining adequate drug levels at the infection site is substantial than static versus cidal properties used in predicting clinical efficacy. An intact immune system is critical for the efficacy of bacteriostatic agents, and bactericidal agents are preferred in immunosuppressed patients. Broad-spectrum agents cover many susceptible pathogens, whereas narrow-spectrum agents cover a limited number of pathogens. Broad-spectrum agents are used empirically in the therapy of lung and abdominal infections. Narrow-spectrum agents are used in a limited number of indications.


2. Bacteriostatic antibiotics

These include folate inhibitors (sulfonamides and trimethoprim) in Table 1 (2A I), tetracyclines in Table 2 (2A II), glycylcyclines in Table 3 (2A III), macrolides in Table 4 (2A IV), lincosamides in Table 5 (2A V), oxazolidinones in Table 6 (2A VI) and fusidic acid in Table 7 (2A VII).

OriginSulfonamides are sulfanilamide derivatives identical to para-aminobenzoic acid (PABA) required for folic acid synthesis in most bacteria.
Trimethoprim is a synthetic derivative from trimethoxybenzyl-pyrimidine [14].
Mechanism of actionSulfonamides antagonize PABA inclusion into dihydropteroate by its greater affinity for tetrahydropteroic acid synthetase in microorganisms resulting in decreased dihydrofolic acid, a substrate for dihydrofolate reductase (DHFR) [15, 16].
Trimethoprim is a potent bacterial inhibitor of DFR, preventing the formation of tetrahyrofolic acid needed for purine and deoxyribonucleic acid [14].
Thus, sulfonamides and trimethoprim together stop two consecutive steps essential in the folic acid synthesis. A combination of both is synergistic and bactericidal in trimethoprim and the sulfa ratio of 1:20 [17].
RoutesSulfonamides are available in oral, intravenous (IV), topical, and ophthalmic formulations.
Trimethoprim is available in oral and intravenous formulations.
IndicationSulfonamides: Nocardiosis, Toxoplasmosis, Plasmodium falciparum malaria, Nongonococcal urethritis,
Trimethoprim: Acute urinary tract infection (UTI), Recurrent UTI
Trimethoprim and sulfamethoxazole (TMP-SMX): Above indications plus UTI, Skin and soft tissue infections (SSTI) due to Staphylococcus aureus, Pneumocystis jiroveci (PCJ) pneumonia, and prophylaxis, Melioidosis, Whipple disease, Alternative in Listeria meningitis
ResistanceSulfonamides: Point mutations in folP gene modifying dihydropteroate synthetase resulting in decreased affinity for sulfonamide [18]. PABA binding site alteration due to F28L/T and P64S mutations [19]. Integrons sul1, sul2, and sul3 coding drug resistance enzymes [20].
Trimethoprim: Plasmid-mediated resistant DHFR enzyme
Pharmaco-kineticsSulfonamides: Well distributed throughout the body, and protein binding predicts the blood and tissue levels. It is metabolized in the liver (CYP2C9 & CYP3A4 hepatic enzyme system) and excreted via renal excretion. Chronic kidney disease results in decreased renal clearance [21]. It can interact with multiple other drugs resulting in increased serum levels and toxicity especially antiseizure medications.
ToxicitySkin: Rashes, Steven-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN) [22, 23].
Blood: Anemia, agranulocytosis, thrombocytopenia, methemoglobinemia [24].
Renal: Hyperkalemia, Acute renal failure, Interstitial nephritis,
Lactic acidosis [24, 25, 26].
Gastrointestinal (GI): Pseudomembranous colitis, Pancreatitis, and Fulminant liver failure [27, 28, 29].
Others: aseptic meningitis

Table 1.

2AI folate inhibitors: Sulfonamides & trimethoprim.

OriginTetracycline is derived from catalytic dehalogenation of chlortetracycline obtained from Streptomyces rimosus [30].
Doxycycline and Minocycline are semisynthetic derivatives of oxytetracycline.
Mechanism of actionReversibly binds 30S ribosomal subunit of the bacteria and inhibits protein synthesis. In protozoa, it additionally binds to 70S ribosome and stops protein synthesis [30, 31].
RoutesOrally via capsules, tablets, syrups, and IV formulations.
IndicationCommunity-acquired bacterial pneumonia (CABP), MSSA &MRSA SSTI, Stenotrophomonas infections, Helicobacter pylori infection, Nongonococcal urethritis, Lyme disease, Rickettsial infections, Nocardiosis, Falciparum malaria, Cholera, Anaplasmosis, and Ehrlichiosis. Q fever, Brucellosis, Melioidosis, Acne vulgarism, the second line in syphilis, and a part of the combination regimen in pelvic inflammatory disease (PID).
ResistanceIt is mediated mainly by active efflux pumps and ribosomal protection proteins. Other minor mechanisms include antibiotic enzymatic lysis, a decline in-wall permeability, and binding site alterations [32].
Pharmac-okineticsUnlike tetracycline, food does not substantially alter doxycycline and minocycline absorption, and both have excellent bioavailability [33]. Lipid solubility determines the tissue and fluid levels of which minocycline > doxycycline > tetracycline. At higher doses, doxycycline reaches adequate levels in the cerebrospinal fluid (CSF) [34]. The clearance mechanism is via both renal (tetracycline) and hepatic (doxycycline and minocycline).
Toxicity/ Adverse effectsGI: pill-induced esophagitis, heartburn, epigastric pain, nausea, vomiting, acid reflux disorder [35]. Hepatotoxicity from IV tetracycline [36]. Skin: photosensitive rash and hyperpigmentation of body parts [37]. Nephrogenic diabetes insipidus: by demeclocycline [38]. Central Nervous System(CNS): Vestibular symptoms, Pseudotumor cerebri Teeth, and Bone: tooth staining, enamel hypoplasia, and diminished bone growth in premature infants exposed to tetracycline [39]. Hypersensitivity reactions: facial swelling, drug-induced lupus, anaphylaxis, urticaria [40]. Tetracyclines are teratogenic and reach the fetus via the placenta.

Table 2.

2A II tetracyclines.

OriginTigecycline is a semisynthetic derivative of minocycline developed against resistant organisms [41].
Mechanism of actionIts reversal binding to 30S ribosomes is stronger by five times, and ribosomal protection proteins do not affect it [42, 43].
RoutesDue to poor oral absorption, it is available in IV formulations.
IndicationComplicated SSTI, Complicated intraabdominal infections (cIAIs), CABP, Used as salvage therapy in critically ill patients when no other alternatives exist for multidrug-resistant infections (MDR).
ResistanceIt is due to increased efflux pumps such as AcrAB and MexAB-OprM after detecting the drug [44]. Pseudomonas is intrinsically resistant due to MexXY efflux pump presence [45].
Pharmac-okineticsAdequate tissue distribution was observed with a half-life of 37 to 67 hours and a plasma protein binding of about 80% [46]. No dose adjustment is required in renal impairment and mild to moderate hepatic impairment. Dose adjustment is needed for severe hepatic impairment. It is not removed by hemodialysis [47]. It is excreted by the liver and minimally by the kidney.
Toxicity/Adverse effectsGI: nausea, vomiting, transaminase elevation, acute pancreatitis. Others: infection, phlebitis, headache, dizziness, skin rash [47]. It is associated with increased mortality compared to other antibiotics used for the same indication. 13 clinical trials have validated this pooled analysis [48].

Table 3.

2A III glycylcyclines.

OriginErythromycin was obtained from Streptomyces erythreus present in the soil. Azithromycin and Clarithromycin are semisynthetic derivatives from erythromycin, which improve stability in gastric acid [49].
Mechanism of actionMacrolides bind to 23S ribosomal ribonucleic acid (rRNA), a subunit of the 50S subunit of the bacterial ribosome, and stop the RNA-based synthesis of proteins [50]. Bactericidal activity is seen against , Hemophilus influenzae, and Streptococcus pneumoniae.
RoutesIt is available as oral liquid, tablet, capsule, IV, ophthalmic and topical preparations.
IndicationErythromycin: used as an alternative to penicillin (PCN) in allergic patients. Treatment and preexposure prophylaxis in pertussis. Azithromycin: CABP, Pertussis, Trachoma, Chancroid, Babesiosis, Mycobacterium avium complex (MAC) infections, alternative for Lyme disease, sinusitis, pharyngitis, and acute otitis media. Clarithromycin: Helicobacter pylori infection, Nontubercular mycobacterial infection, Campylobacter enteritis, MAC infections
Resistance50S ribosomal protein mutations or 23S rRNA receptor alterations confer resistance to macrolides (M), lincosamides (L), and streptogramin B (SB) (MLSB phenotype). Erm (erythromycin ribosome methylation) genes present on transposons or plasmids mediate this effect [51, 52].
Pharmac-okineticsErythromycin is metabolized by hepatic CYP3A cytochrome subclass of cytochrome 450 system. It is incompatible with other IV preparations [53, 54]. It follows total body water distribution [55] and persists in tissues longer than in blood. Oral azithromycin bioavailability is around 37% [56]. It is well distributed in tissues with levels > than in blood by 10 to 100 fold. It is excreted primarily unchanged via hepatic clearance into the feces. No dose adjustments are required for renal and hepatic impairment. Clarithromycin oral bioavailability is 55%, has excellent tissue distribution, and undergoes mainly hepatic clearance with 30% clearance vis the kidneys [50]. Dose adjustment is needed for renal failure only [57].
Toxicity/Adverse effectsErythromycin: GI side effects (nausea, vomiting, and abdominal pain), Thrombophlebitis, Allergic reactions, Ototoxicity, Torsades de pointes. Clarithromycin and Azithromycin: GI side effects as above, Acute mania, Torsades de pointes, reversible cholestatic hepatitis [58, 59, 60].

Table 4.

2A IV macrolides.

OriginLincomycin is derived from Streptomyces lincolnensis present in the soil. Clindamycin is semisynthetically by chemically modifying lincomycin resulting in increased potency and bioavailability [61].
Mechanism of actionIt binds to 50S ribosomal sites and inhibits protein synthesis, and competes with macrolides for the same site.
RoutesAvailable in IV, oral capsules and liquid solution, topical gel, foam or solution, and vaginal cream or suppository.
IndicationGram-positive or anaerobic SSTI, acne vulgaris, part of the combination regimen against toxoplasmosis, falciparum malaria, and Pneumocystis jiroveci pneumonia.
ResistanceMLSB phenotype regulated by the ermA or ermC genes [62]. rRNA mutations, including the receptor site, 23S rRNA nucleotide methylation, and adenylation of clindamycin [51, 63, 64, 65].
Pharmac-okinetics90% oral bioavailability with good tissue levels except in CSF [61, 66]. It is metabolized by the liver, and excretion occurs via feces and urine [67]. Dosing adjustment is needed in severe renal and hepatic impairment
Toxicity/Adverse effectsCutaneous drug reactions in patients with (human leukocyte antigen)HLA-B*51:01 genotype including maculopapular eruptions, erythema multiforme, urticaria, drug rash with eosinophilia, and systemic symptoms (DRESS), SJS, TEN [68]. GI: diarrhea, pseudomembranous colitis by Clostridioides difficile, reversible transaminitis [69]. Others: agranulocytosis, thrombocytopenia, and neutropenia which are transient.

Table 5.

2A V lincosamides.

OriginLinezolid and Tedizolid are derived from 5-(halomethyl)-3-aryl-2-oxazolidinones (organic synthesis) by chemical modification. Unique structure with no cross-resistance seen.
Mechanism of actionHalts bacterial protein synthesis by binding to the V-domain of 23S RNA, a part of the 50S ribosomal unit [70]. Efficacy is proportional to the drug level area under the curve AUC/MIC ratio.
RoutesAvailable as oral tablets and IV formulations.
IndicationLinezolid: MSSA/MRSA nosocomial pneumonia, CABP, Gram-positive complicated and uncomplicated SSTI, Vancomycin-resistant Enterococcus (VRE) infections, Nocardiosis. Tedizolid: Gram-positive SSTI.
ResistanceIt is <1% and due to 23S rRNA domain V region receptor site mutation, cfr (chloramphenicol-florfenicol resistance) ribosomal RNA methyltransferase, and optrA causing adenylation [71, 72, 73].
Linezolid: oral bioavailability is 100%, excellent tissue distribution, and 31% plasma protein-bound [74]. It is oxidized and renally excreted. No dosage adjustment is needed. Tedizolid: oral bioavailability is 91% with adequate tissue distribution and 80% plasma protein-bound. It undergoes hepatic clearance with 20% excreted renally. No dosage adjustment is needed [75, 76].
Toxicity/Adverse effectsBlood: Thrombocytopenia, pancytopenia, pure red cell aplasia, and reversible myelosuppression [77]. Mitochondrial toxicity: lactic acidosis, peripheral and optic neuropathy [78, 79, 80]. Others: Serotonin syndrome with serotonergic medications, tooth and tongue discoloration, and hypoglycemia [78, 81, 82].

Table 6.

2A VI oxazolidinones.

OriginIt was derived from the fungus Fusidium coccineum.
Mechanism of actionIt inhibits protein synthesis by preventing the translocation, elongation phase, and blocking the elongation factor G (EF-G) effect on the ribosome, making the bacteria susceptible to phagocytosis due to reduced surface proteins [83, 84]. It is active against MSSA, MRSA, Coagulase-negative staphylococci, Clostridium spp, Peptostreptococcus, and most anaerobes except for Fusoabcterium spp.
RoutesAvailable in oral, eye, topical, and IV formulations.
IndicationAs a part of a combination regimen against staphylococcal SSTI and bone infections, especially with rifampin or beta-lactams.
ResistanceChromosomal or plasmid-mediated mutations in the gene encoding the EF-G (fusA, fusB, fusC, and fusE).
Pharmac-okineticsNewer film-coated tablets have better oral bioavailability, highly plasma protein-bound with adequate intracellular and tissue penetration [85, 86]. It undergoes hepatic metabolism and needs dose adjustment with hepatic impairment [87].
Toxicity/Adverse effectsNausea, diarrhea, vomiting, and elevated bilirubin due to bile transport blockade. When used along with statin, the risk of rhabdomyolysis is observed after 20 to 30 days after therapy initiation [88].

Table 7.

2A VII fusidane (fusidic acid).

Dapsone can substitute sulfamethoxazole in the TMP-SMX combination for PCJ pneumonia in patients with allergies to sulfonamide antibiotics [89]. TMP-SMX is the drug of choice for Q-fever in pregnancy. An essential fact to remember is that TMP-SMX does not cover pseudomonas and should be avoided in streptococcal infections due to a higher incidence of resistance [90]. Iclaprim is a DHFR inhibitor with bactericidal activity against methicillin-sensitive Staphylococcus aureus (MSSA), Methicillin-resistant (MRSA), beta-hemolytic Streptococcal spp, and Enterococcus faecalis. It undergoes hepatic clearance, and dose adjustment is needed in hepatic impairment. Tissue penetration is excellent in the lungs. It is effective without a sulfa moiety so that it can be used in patients with sulfa allergy. The side effects include nausea, headache, fatigue, and QT interval prolongation. Currently, it is under trials for SSTI and nosocomial pneumonia [91, 92].

Doxycycline is the drug of choice in bioterrorism caused by Bacillus anthracis, Yersinia pestis, Francisella tularensis, Coxiella burnetti, and Brucella spp [93]. In the medical intensive care unit (MICU), tetracyclines are the drug of choice in acute sepsis due to cholera, ehrlichiosis, stenotrophomonas infections, rickettsial disease, anaplasmosis, and PID.

In sepsis, tigecycline is used in MDR infections as a last resort, and the federal drug authority (FDA) has placed a boxed warning about this death risk. It can also be used effectively at a higher dosage in MDR hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).

Two other newer tetracycline derivatives have been released Eravacycline, a fluorocycline, and Omadacycline, an aminomethylcycline., while omadacycline has been approved for SSTI and CABP. In contrast, Eravacycline has been approved for cIAI [94, 95]. Similar to tigecycline, neither of these agents cover pseudomonas. No dosing modification is needed for renal or hepatic impairment. They are teratogenic, and the anticoagulant dose needs adjustment when used concomitantly. A slightly increased mortality was observed in the CABP trial of omadacycline [94].

Azithromycin is an excellent choice for treating CABP caused by atypical organisms such as Mycoplasma pneumoniae, Legionella spp., Chlamydia pneumoniae, and Coxiella burnetti. An important fact is to remember the numerous interactions this class has with other medications, and also, it can prolong the QT interval resulting in ventricular tachyarrythmias.

When used in the therapy for staphylococcal infections, it is prudent always to perform a “D” test to identify any chance of inducible resistance. It is recommended not to use clindamycin as an empirical regimen against streptococcal infections due to a higher risk of resistance. Clindamycin can suppress the cyclosporine effect and can cause neuromuscular blockade.

Linezolid is an alternative for vancomycin in MRSA/MSSA pneumonia and is used in combination regimens for nosocomial pneumonia. It is an alternative in Nocardiosis and a part of combination regimens in the therapy of Mycobacterium tuberculosis, Mycobacterium avium complex, and Mycobacterium abscessus complex.


3. Bactericidal antibiotics

These include glycopeptides in Table 8 (3A I), lipoglycopeptides in Table 9 (3A II), lipopeptides in Table 10 (3A III), aminoglycosides in Table 11 (3A IV), quinolones in Table 12 (3A V), penicillin in Table 13 (3A VI), cephalosporins in Table 14 (3A VII), beta-lactamase and beta-lactamase inhibitor combinations in Table 15 (3A VIII), monobactams in Table 16 (3A IX), carbapenems in Table 17 (3A X), polymixins in Table 18 (3A XI), epoxide in Table 19 (3A XII), pleuromutilin in Table 20 (3A XIII), rifamycins in Table 21 (3A XIV) and metronidazole in Table 22 (3A XV).

OriginVancomycin was derived from Amycolatopsis orientalis. Teicoplannin was isolated from Actinoplanes teichomyceticus. Teicoplanin has not been approved in the United States as it did not offer any advantage over vancomycin.
Mechanism of actionCell wall synthesis is stopped by inhibition of transpeptidation and disaccharide subunits incorporation into peptidoglycan.
RoutesVancomycin is available in oral, IV, intrathecal, intraventricular, intraperitoneal, and intraocular formulations. Teicoplanin is available in oral, intramuscular, and IV formulations.
IndicationVancomycin: Gram-positive and MRSA SSTI, MRSA bacteremia, MRSA native and prosthetic valve IE, Vancomycin sensitive Enterococcal IE, Corynebacterium jeikeium and striatum infections, MRSA meningitis, and ventriculitis, MRSA pneumonia, joint infections, and osteomyelitis. Pseudomembranous colitis by Clostridioides difficile, Febrile neutropenia, Pre-procedure surgical prophylaxis.
Teicoplanin: MRSA bacteremia, Gram-positive and MRSA SSTI, Alternative for IE due to Streptococci viridans and Enterococci, Pseudomembranous colitis by Clostridioides difficile, Pre-procedure surgical prophylaxis.
ResistanceVancomycin: mecA and mecC encode for a low-affinity penicillin-binding protein PBP2a and PBP2c. Some MRSA strains acquire the VanA gene from enterococci species. Enterococci with VanA, VanB, VanC, VanD, VanE, VanG, VanL, VanM and VanN genes encode a ligase assembling the last two amino acids or peptidoglycan precursors, resulting in a peptidoglycan precursor with less affinity for glycopeptides. Teicoplanin: All Vancomycin intermediate Staphylococcus aureus (VISA) strains are cross-resistant [96]. Enterococci containing the above Van genes render them resistant to it.
Pharmac-okineticsVancomycin: Oral intake results in minimal absorption. When given IV, efficacy is best indicated by 24 hour AUC/MIC ratio ≥ 400 associated with lower clinical failure [97]. Adequate CSF levels are seen in infection [98]. It is renally excreted with no tubular secretion or absorption, and creatinine clearance inversely affects its serum level. In obese patients, the dosing should be based on actual body weight instead of ideal weight due to increased distribution volume [99]. Therapy needs to be monitored with trough levels (correlate with AUC/MIC ratio) to prevent toxicity. Dose adjustment is needed with renal failure.
Teicoplanin: Poor oral absorption, 90% bound to plasma protein, and highly bound in tissues. It reaches adequate concentrations in all tissues except for vitreous and CSF, even with infection. It undergoes renal clearance, and dosing adjustments are needed in renal failure. Trough levels ≥28 μg/mL are associated with hepatotoxicity. Monitoring not needed if dose used is <12 mg/kg/day. It has a long half-life of 83 to 168 hours [100].
Toxicity/Adverse effectsFrequently seen when the trough levels are ≥15 μg/mL with a treatment duration of >7 days [101].
Infusion-related reactions: red man syndrome, hypotension, and cardiac arrest. Others: Nephrotoxicity, Ototoxicity, Neutropenia, Thrombocytopenia, and DRESS [102, 103, 104].
Teicoplanin: Nephrotoxicity, fever, maculopapular rash, red man syndrome.

Table 8.

3A I glycopeptides.

OriginTelavancin is a vancomycin derivative post alkylation [105]. Dalbavancin is a semisynthetic derivation from teicoplanin like glycopeptide, a fermentation product of Nonomuraea spp. Oritavancin is a semisynthetic derivation from lipoglycopeptide chloroeremomycin.
Mechanism of actionTelavancin: binds to peptidoglycan precursors, inhibits transglycosylation, and inhibits cell wall synthesis. It also disrupts cell wall homeostasis [106]. Dalbavancin: binds to peptidoglycan precursors with higher affinity and inhibits cell wall synthesis. Oritavancin: Binds to peptidoglycan precursors, stops transglycosylation, transpeptidation and inhibits cell wall synthesis. It disrupts the cell wall membrane [107].
RoutesTelavancin: available in IV formulations Dalbavancin: available in IV formulations Oritavancin: available in IV formulations
IndicationTelavancin: Acute gram-positive bacterial SSTI Dalbavancin: Acute gram-positive bacterial SSTI Oritavancin: Acute gram-positive bacterial SSTI in adults only
ResistanceTelavancin: VRE containing VanA gene are resistant to it [108]. Dalbavancin: is bacteriostatic against VISA strains, no activity against VanA but is active against VanB and VanC possessing bacterial strains. Oritavancin: VanZ gene and mutations in vanSB sensor gene ofthevanBcluster confer cross-resistance to teicoplanin and oritavancin [109].
Pharmac-okineticsTelavancin: Tissue distribution is similar to vancomycin, 90% plasma protein bound, undergoes renal clearance and dose adjustment needed in renal failure [105]. It is recommended to avoid use in severe acute renal failure. Dalbavancin: High volume tissue distribution, plasma protein binding of 93%, and a half-life of 8 to 9 days. It undergoes primarily renal clearance with the remaining via feces. It requires dose modification in renal failure [110]. The best predictor of its activity is the 24-hour AUC/MIC. Oritavancin: High volume tissue distribution, plasma protein binding of 85–90%, and a half-life of 10 days. It gets intracellularly retained in the liver, kidneys, lungs, and lymphoid tissue, from where it is released slowly. No dosage adjustment is done for mild to moderate liver or renal impairment.
Toxicity/Adverse effectsTelavancin: prolongs the QTc interval, nephrotoxicity, nausea, vomiting, chills, and creatinine rise. It is teratogenic. Dalbavancin: pruritis, vomiting, nausea, infusion reactions, skin, and hypersensitive reactions. Oritavancin: nausea, headache, vomiting, diarrhea, mild transaminitis, hypersensitive reactions. Drug interactions can be seen as it inhibits cytochrome P450 enzymes.

Table 9.

3A II lipoglycopeptides.

OriginDaptomycin is a lipopeptide antibiotic isolated from Streptomyces roseosporus.
Mechanism of actionIt is an antimicrobial peptide of cation origin attaching to the cell wall in the presence of calcium, disrupting the cell wall structure by displacing the cell wall proteins and formation of an oligomer in the cell wall. This action is unalterable, causing impaired cell wall function and leakage of ions leading to cell death [111, 112, 113].
RoutesAvailable in only IV formulations
IndicationAcute SSTI by MSSA, MRSA, Enterococcus faecalis, streptococcal species (as an alternative in glycopeptide therapy failure or intolerance or higher MRSA vancomycin MIC. Acute MSSA, MRSA bacteremia, and right-sided endocarditis [114].
ResistanceCell wall changes with increased fluidity, net positive charge, and lack of depolarization or permeability decreased phosphatidylglycerol, leading to daptomycin resistance. Multiple genes are involved in this, including mprF, yycFG, vraSR, dlt, rpoB, rpoC, pgsA, and cls [115, 116, 117, 118].
Pharmac-okineticsIt has a long half of 7.3 to 9.6 hrs with a small distribution volume and is highly bound to plasma proteins (90% - 93%) [119, 120]. It gets excreted via the renal system unchanged. Dose adjustment is needed in acute renal failure and dialysis patients. It has poor penetration into CSF [121]. It is inactivated by the pulmonary surfactant leading to ineffectiveness against bronchioalveolar pneumonia. It exerts a dose-dependent postantibiotic effect longer than vancomycin [122].
Toxicity/Adverse effectsHigher doses (>8 mg/kg/day) results in elevation of serum creatinine phosphokinase (CPK) levels with no muscle cell lysis or fibrosis [123]. CPK level monitoring during therapy is a must. Peripheral neuropathy with paraesthesia and dysesthesia. Acute eosinophilic pneumonia (after ten days of therapy)

Table 10.

3A III lipopeptides.

OriginAminoglycoside with the name ending in mycin is derived from Streptomyces [124]. Aminoglycoside with the name ending in micin is derived from Micromonospora spp. Fermentation products: Neomycin, Gentamicin, Kanamycin Semisynthetic derivatives: Amikacin, Netilmicin
Mechanism of actionCationic aminoglycosides bind to the anionic lipopolysaccharides and disrupt their structure resulting in cell wall leaks and altered permeability. Once in the cytosol, it binds reversibly to ribosomal decoder acceptance site on 16S reverse transfer RNA portion of messenger RNA (mRNA), a 30S subunit of prokaryotic ribosomes. This decreases the mRNA translocation and translation stopping protein synthesis [125, 126, 127, 128]. They demonstrate the postantibiotic effect, synergistic behavior with other antibiotics, and concentration-dependent effect.
RoutesAvailable in IV and oral formulations.
IndicationEmpirical therapy of aerobic gram-negative bacilli (GNB) including Pseudomonas spp. As a part of a combination therapy for HAP, Enterococcal bacteremia, and IE due to enterococcus and streptococcus spp. Acute urinary tract infection and cystic fibrosis exacerbations. Preoperative prophylaxis in gastrointestinal and genitourinary procedures.
ResistanceAltered cell wall membrane with diminished interaction, active efflux pumps resulting in lesser concentration in the cytosol [129, 130]. Decreased ribosomal binding due to mutation or methylation of the binding site [131]. Inactivation of the aminoglycosides by phosphorylation, adenylation, and nucleotidation [132]. Induce biofilm formation [133].
Pharmac-okineticsPlasma protein binding is low, highly soluble in water, with distribution resembling extracellular fluid compartments [134, 135]. Appropriate concentrations are attained in all body fluids except for CSF and vitreous humor [136, 137, 138]. They undergo renal clearance unchanged with minimal excretion via feces [139]. Dose adjustment is needed in renal failure.
Toxicity/Adverse effectsNephrotoxicity Ototoxicity includes both cochlear and vestibular Neuromuscular blockade

Table 11.

3A IV aminoglycosides.

OriginInitially derived as a byproduct of chloroquine synthesis, the newer quinolones are semisynthetic with chemical modifications to increase their efficacy and absorption.
Mechanism of actionInhibit deoxyribonucleic acid (DNA) synthesis by inhibiting DNA gyrase and topoisomerase IV. It also leads to hydroxy radicals, damaging the bacterial cellular molecules causing bacterial cell death [140, 141].
RoutesAvailable as oral, IV, and eye drop formulations
IndicationAcute cystitis, Acute uncomplicated, and cUTI. Acute Bacterial prostatitis, Sexually transmitted disease, PID, Chlamydiae trachomatis, Hemophilus ducreyi. Acute bacterial gastroenteritis due to Shigella spp, Campylobacter jejuni, Cholera, Typhoid, Nontyphoidal Salmonellae gastroenteritis in specific patients.
Acute intraabdominal infections, Spontaneous bacterial peritonitis (SBP). Acute CABP, Acute bronchitis, Aspiration pneumonia, Lung abscess, HAP, stenotrophomonas infections. Acute osteomyelitis, Acute native and prosthetic joint infections, SSTI. MDR pulmonary tuberculosis, Nontuberculous mycobacterial infections, GNB susceptible organisms causing meningitis, Prophylaxis in neutropenic patients.
ResistanceChromosomal gene mutations alter DNA gyrase, and topoisomerase IV decreases cell membrane permeability. Plasmid-mediated genes enabling acetylation and efflux pumps decreasing efficacy.
Pharmac-okineticsExcellent oral bioavailability and food can alter absorption [142]. Plasma protein binding is low except for delafloxacin and gemifloxacin. Tissue distribution is excellent, with above serum levels seen in bile, prostate, kidney, lung, and stool [143]. Levofloxacin and moxifloxacin attain adequate CSF penetration [144]. Levofloxacin, ofloxacin, ciprofloxacin undergo renal clearance, whereas moxifloxacin undergoes hepatic metabolism. Dose adjustment is needed in renal insufficiency [145].
Toxicity/Adverse effectsGI: vomiting, nausea, abdominal discomfort, diarrhea, Clostridioides difficile associated diarrhea [146]. CNS: headache, dizziness, mood changes, peripheral neuropathy [147, 148]. Skin: allergy and skin reactions such as maculopapular rash, phototoxicity [149, 150]. Others: hypoglycemia, prolongs QT interval, increased risk of aortic aneurysm and dissection, retinal detachment, tendinitis with arthropathy [151, 152, 153, 154, 155].

Table 12.

3A V quinolones.

OriginPCN was isolated from Penicillium chrysogenum in 1928 by Alexander Fleming [156]. Chemical modifications created numerous semisynthetic PCNs. Natural PCNs: PCN V, PCN G. Penicillinase resistant PCN: Methicillin. Nafcillin, Oxacillin. Aminopenicillins: Amoxicillin, Ampicillin. Carboxypenicillins: Ticarcillin and Carbenicillin. Ureidopenicillins: Piperacillin, Azlocillin and Mezlocillin.
Mechanism of actionPCNs bind to multiple PBP simultaneously, stopping the cell wall synthesis and creating hydroxy radicals that permanently damage the cell. PCNs do not affect dormant bacteria [141, 157].
RoutesOral, IV, and intramuscular (IM) formulations are available.
IndicationIV PCN G is the antibiotic of choice for PCN susceptible strains causing pneumococcal and meningococcal meningitis, streptococcal IE, and neurosyphilis. Benzathine PCN is used in syphilis treatment and for rheumatic fever prophylaxis. Oral PCN V or G or Benzathine PCN are used to stop outbreaks of streptococcal infection. Intrapartum prophylaxis with PCN is used at membrane rupture or at labor to prevent Streptococcal agalactiae infections in colonized patients. PCNase resistant PCNs are the agent of choice for MSSA infections and an alternative to treat streptococcal infections. AminoPCNs treat UTI, Upper and lower airway infections, Gastroenteritis, IE, Meningitis by susceptible non-beta- lactamase organisms. IV ampicillin is the treatment of choice for Enterococcus faecalis IE and other infections. Amoxicillin is a part of the combination regimen against Helicobacter pylori. Oral amoxicillin or ampicillin are used as prophylaxis in asplenic or agammaglobulinemia patients to prevent infections by capsulated organisms. Ampicillin-sulbactam is the drug of choice for aspiration pneumonia. Piperacillin-tazobactam is an antipseudomonal and is also used for necrotizing fasciitis, susceptible GNB infections.
ResistancePresence of beta-lactamase [158]. Alteration of cell membrane permeability with a decreased intracellular entry (absence of porin) [159]. Presence of efflux pumps [159]. Synthesis of PBP with decreased affinity for the beta-lactam [160].
Pharmac-okineticsPCNs vary in their oral absorption and plasma protein binding. The tissue distribution is more than adequate in most tissues. The primary route of excretion is via the renal system, whereas some undergo biliary excretion too.
Toxicity/Adverse effectsHypersensitivity reactions: rash, anaphylaxis, exfoliative dermatitis, allergic vasculitis, SJS, and TEN [161]. GI: nausea, vomiting, diarrhea, Clostridioides difficile associated diarrhea, liver function test abnormality with oxacillin in patients with HLA-B 5701 [162, 163]. Hematological: neutropenia [164]. Renal: Nephrotoxicity, allergic interstitial nephritis [165]. CNS: Myoclonic seizures.

Table 13.

3A VI penicillin (beta-lactams).

OriginSemisynthetic derivatives of Cephalosporin C isolated from Acremonium chrysogenum [166]. First-generation: cefazolin, cephalexin, and cefadroxil. Second generation: cefprozil and cefuroxime, cephamycin: cefoxitin Third generation: cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftriaxone. Fourth generation: Cefepime, Cefpirome. Fifth-generation: Ceftaroline, ceftobiprole. Siderophore cephalosporins: Cefiderocol.
Mechanism of actionThey bind to PBPs and stop transpeptidation and block the cell wall synthesis resulting in a bactericidal effect with a postantibiotic effect [167]. MRSA active cephalosporins bind to PBP2A, whereas the other cephalosporins bind to PBP1A&B in gram negatives [168]. Cephalosporins active against gram-positive organisms bind to PBP 2&3 (186). Cefiderocol binds to iron and enters the bacteria via siderophores into the periplasmic space and binds to PBP in addition to being a poor substrate for efflux pumps [169].
RoutesFirst, second and third generations are available in oral and parenteral (IV/IM) formulations. The fourth and fifth-generation are available in IV formulations. Fifth-generation are available in IV formulations. Siderophore cephalosporins: available in IV formulations.
IndicationFirst-generation: oral therapy for MSSA and Streptococcal SSTI outpatient, susceptible Streptococcal SSTI, MSSA IE, the prophylactic antibiotic of choice for prosthesis implantation and surgical procedures with a high risk of infection except for intraabdominal procedures. Second generation: as a part of a combination regimen for PID (cefoxitin), nontuberculous mycobacterial infection (cefoxitin), cefuroxime for acute otitis media, pharyngitis, maxillary sinusitis, and an alternative for Lyme disease [170, 171]. Third generation: treatment of susceptible GNB bacilli induced SSTI, Prosthetic joint infection (PJI), CABP, cUTI, and peritonitis [172]. Empirical therapy for CABP, acute bronchitis, and meningitis. IM single dose for Neisseria gonorrhea and chancroid [173]. Lyme disease and an alternative for PCN allergic patients with syphilis, typhoid fever, and shigellosis [174, 175]. Monotherapy for Streptococcal IE [176]. Ceftazidime is the drug of choice for susceptible Pseudomonas spp infections, including CNS [177]. Fourth generation: antibiotic of choice for infections caused by AmpC (Class C beta-lactamases) inducible resistant organisms [178]. Febrile neutropenia monotherapy or a part of a combination regimen [179]. Empirical therapy in severe CABP, HAP by Pseudomonas spp or resistant Enterobacteriaceae [180]. It is an alternative for susceptible GNB meningitis, bacteremia, SSTI, PJI and cUTI. Fifth-generation: Ceftaroline used for MRSA pneumonia, CABP, SSTI, HAP, and in combination with daptomycin for daptomycin resistant MRSA infections [181, 182, 183]. Ceftobiprole also is an alternative for Pseduomonal spp infections. Siderophore cephalosporins: approved for use in cUTI by Enterobacterales & P. aeruginosa, HAP, and VAP by the Enterobacterales, P. aeruginosa, and Acinetobacter baumannii complex [169].
ResistanceBeta-lactamase hydrolyzes the antibiotic. Cell wall membrane changes alter the entry of antibiotics through the lipopolysaccharide layer. Efflux pumps removing the antibiotic from the periplasmic space. PBP changes to alter antibiotic binding.
Pharmac-okineticsThe first three generations are water-soluble and come in oral and parenteral formulations, whereas the fourth and fifth-generation are parenteral only. Distribution is dependent on their lipid solubility and plasma protein binding. They reveal higher serum concentrations and lower tissue levels. The third and fourth generations attain adequate CNS concentrations. Most of them undergo renal clearance except for ceftriaxone and cefoperazone, which undergo biliary excretion. Probenecid inhibits tubular secretion of cephalosporins and increases their half-life. Renal failure will need a dose adjustment. Ceftriaxone dose is adjusted with simultaneous renal and hepatic impairment [184]. Cefiderocol is excreted renally and needs renal dose adjustment [185].
Toxicity/Adverse effectsHypersensitivity reactions: immunoglobulin E (IgE)-mediated reactions occur in <1 in 100,000 patients; fever, rash, eosinophilia, serum sickness, and anaphylaxis are seen. Cross-reaction frequency is ≤1%. Hematology: eosinophilia, neutropenia (prolonged use), anemia, thrombocytopenia, hypoprothrombinemia, impaired platelet aggregation, hemolytic anemia (ceftriaxone). Nephrology: allergic interstitial nephritis GI: nausea, vomiting, diarrhea, Clostridioides difficile infection, biliary pseudolithiasis (ceftriaxone), transaminitis. CNS: seizures, encephalopathy Others: fever, disulfiram-like reaction, phlebitis.

Table 14.

3A VII cephalosporins.

CombinationsAugmentin = Amoxicillin + Clauvulinic acid in an 2:1, 4:1,7:1 ratio (isolated from Streptomyces clavuligerus [186]. Unasyn = Ampicillin + Sulbactam in an 2:1 ratio Sulperazone = Cefoperazone + Sulbactam in an 1:1 ratio Zosyn = Piperacillin + Tazobactam in an 8:1 ratio Zerbaxa = Ceftolazone + Tazobactam in a 2:1 ratio Avycaz, Zavicefta = Ceftazidime + Avibactam in a 4:1 ratio Vabomere = Meropenem + Vaborbactam in a 1:1 ratio
Mechanism of actionClavulanic acid: is potent and inhibits class A beta-lactamase and some extended-spectrum beta-lactamases (ESBL). Sulbactam: is a broad-spectrum inhibitor than clavulanic acid but less potent (inhibits class A beta-lactamases). Tazobactam: spectrum is similar to sulbactam but is more potent. Avibactam: inhibits class A beta-lactamases, including ESBL, Klebsiella pneumoniae carbapenemase (KPC), class C, and some class D beta-lactamases. It does not stop Metall0beta-lactamases (MBL). Vaborbactam: inhibits class A beta-lactamases including ESBL, KPC, class C beta-lactamases with no effect on MBL and class D beta-lactamases.
RoutesAugmentin: available orally and IV formulations. Unasyn: available in IV formulations Sulperazone: available in IV formulations Zosyn: available in IV formulations Zerbaxa: available in IV formulations Avycaz, Zavicefta: available in IV formulations Vabomere: available in IV formulations
IndicationAugmentin: acute otitis media, acute sinusitis, outpatient CABP by susceptible organisms with a higher dose, diabetic foot infection, SSTI, human or animal bites. Unasyn: as a part of a combination regimen against MDR Acinetobacter baumannii infection, SSTI, cIAIs, and obstetric and gynecological infections. Sulperazone: treatment of A. baumannii infection Zosyn: treatment of pneumonia, SSTI, cIAIs, febrile neutropenia, and polymicrobial infections [187]. Zerbaxa: indicated in cUTI, cIAIs, and Carbapenemase resistant Pseudomonas aeruginosa infections. Avycaz, Zavicefta: indicated in cUTI, cIAIs, HAP, and KPC Enterobacteriaceae infections. Vabomere: indicated in KPC Enterobacteriaceae infections and cUTI.
ResistanceAugmentin: plasmid-mediated beta-lactamase TEM-1 and OXA-1 (Oxacillin beta-lactamases) [188]. Unasyn: cephalosporinase, ESBL, and carbapenemase production by resistant strains. Sulperazone: cephalosporinase, ESBL, and carbapenemase production by resistant strains. Zosyn: ESBL and carbapenemase production by resistant strains. Zerbaxa: carbapenemase production KPC, OXA, ESBL, and MBL by resistant strains. Avycaz, Zavicefta: porin mutations, efflux pumps, and MBL. Vabomere: coproduction of KPC and class B or D beta-lactamases, porin mutations, and efflux pumps [189].
Pharmac-okineticsAugmentin: well absorbed orally and undergoes renal clearance with dosing adjustment needed in renal impairment. It does not penetrate CSF but reaches therapeutic levels in the peritoneum, bile, tonsils, and middle ear. Unasyn: renally cleared and dose adjustment needed in renal insufficiency. Levels in peritoneal and intestinal fluids are the same as in serum with minimal CSF penetration. Sulperazone: available in IV formulations Zosyn: renally cleared and will need a dose adjustment and minimal CSF penetration. Zerbaxa: renally cleared and will need a dose adjustment. Avycaz, Zavicefta: gets excreted renally unchanged, and dosage adjustment is a must when creat clearance is <50 mL/min. Vabomere: the majority of the drug undergoes renal clearance so that it will need dose adjustment with renal insufficiency.
Toxicity/Adverse effectsAugmentin: skin reactions, delayed hypersensitivity, diarrhea, and nausea. Unasyn: occasional transaminitis and similar reactions as seen with ampicillin Sulperazone: occasional transaminitis and similar reactions as seen with ampicillin. Zosyn: platelet dysfunction, immune thrombocytopenia, allergic reactions, renal failure, Clostridioides difficile infection [190, 191]. Zerbaxa: headache, nausea, diarrhea, Clostridioides difficile infection Avycaz, Zavicefta: anxiety, nausea, vomiting, and constipation. Vabomere: phlebitis, headache, diarrhea, and infusion site reactions.

Table 15.

3A VIII beta-lactamase inhibitors and beta-lactam combinations.

OriginIt is a semisynthetic derivation of a biochemical substance isolated from Chromobacterium violaceum.
Mechanism of actionIt avidly binds to PBP3 of aerobic GNB, inhibiting cell wall synthesis resulting in death [192]. It remains active against all class B beta-lactamases and the majority of class A and D beta-lactamases. It is destroyed by KPC, ESBLs, and AmpC beta-lactamases if present in a larger quantity.
RoutesAvailable in IV formulations.
IndicationAs an alternative in susceptible aerobic GNB infections in patients with beta-lactam allergy. As a part of a combination regimen against MBL producing GNB infections.
ResistanceIt is via efflux pumps and alterations to the PBP3 binding site [193].
Pharmac-okineticsOrally it is absorbed poorly with 56% plasma protein binding after IV administration. Excellent tissue distribution with CSF penetration. Excretion is renally, and dose adjustment is needed in renal impairment and severe hepatic impairment.
Toxicity/Adverse effectsNausea, vomiting, diarrhea, rash, phlebitis [194]. Crossreaction with other beta-lactams is rare even in patients with anaphylaxis to other beta-lactams.

Table 16.

3A IX monobactams.

OriginThey are semisynthetic derivatives from thienamycin, an antibiotic isolated from Streptomyces cattleya. The human renal enzyme dehydropeptidase breaks down imipenem and is combined with cilastatin which inhibits this enzyme.
Mechanism of actionThey gain entry into the periplasmic space via porins located on the cell wall and avidly bind to the PBPs 1a, 1b, 2, 4, and also to PBP3 minimally. This stops the cell wall synthesis and leads to the death of the bacteria. They are inactive against organisms producing MBL or class B beta-lactamases such as Stenotrophomonas maltophilia and Elizabethkingia meningoseptica. Ertapenem has minimal activity against Pseudomonas and Acinetobacter spp. Imipenem is partially active against Enerococcus faecalis [195].
RoutesIV formulations: Imipenem. Meropenem, Ertapenem, Doripenem. Oral formulations: Tebipenem in Japan.
IndicationTreatment of bacterial meningitis, Pseudomonas spp, and ESBL bacterial infections. An alternative choice for infections caused by AmpC organisms. Treatment of infections such as bacteremia, cUTI, cIAI, HAP, SSTI, nocardiosis, and actinomycosis.
ResistanceBeta-lactamase synthesis breaks down carbapenem such as KPC, OXA, and MBL. Decreased cell wall entry due to porin mutations or lack of porins. Efflux pumps. Alterations in PBPs site resulting in less avid binding of the carbapenem.
Pharmac-okineticsPoor oral absorption except for Tebipenem. Plasma protein binding, if higher, leads to a longer half-life (Ertapenem) and once-daily dosing. Tissue distribution and penetration are excellent, including CSF [195]. Excretion is via the renal route, and dose adjustments are needed in renal impairment. Only imipenem undergoes destruction by dehydropeptidase.
Toxicity/Adverse effectsPhlebitis, nausea, vomiting, headache, diarrhea, rash, and Clostridioides difficile infection. Seizures, especially with imipenem. Interact with valproic acid and lead to subtherapeutic valproate levels [196]. Potential crossreactivity exists between PCN and cephalosporins; a negative PCN skin test makes it safer to administer a carbapenem [197].

Table 17.

3A X carbapenems.

OriginPolymixin B is semisynthetically derived from a biochemical product from Bacillus polymyxa. Polymixin E (Colistin) is semisynthetically derived from a biochemical product from Bacillus colistinus. It is commercially available in an inactive prodrug methanesulfonate (CMS) which is converted to colistin invivo.
Mechanism of actionIt is a surface-active agent with both lipophilic and lipophobic subunits which infiltrate the outer cell membrane of GNB. Then they interact with the phospholipids electrostatically, resulting in cell membrane destruction. They bind avidly to lipid A portion of lipopolysaccharide and stop its endotoxin effect [198].
RoutesPolymixin B: available in oral, IV/IM, and topical formulations. Polymixin E: available in oral, IV/IM, inhalation, and topical formulations.
IndicationPolymixin B favored over CMS in all infections except in UTI. Oral preparations are used for intestinal decontamination. Administered intraventricularly for GNB meningitis. Inhaled CMS for infections in Cystic fibrosis. Parenteral administration for severe systemic infections caused by MDR GNB, including VAP.
ResistanceResistance is mediated via the plasmid-mediated MCR-1, MCR-2, and MCR-3, which alter the lipopolysaccharide structure and prevent polymixin binding [199]. Cross-resistance between the polymyxins is complete [200].
Pharmac- okineticsThey are poorly absorbed, and post IV administration, the distribution to the biliary tract, CSF, joint and pleural fluid is low. CMS undergoes renal clearance, so the dose needs to be adjusted in renal impairment. Both colistin and polymyxin undergo nonrenal clearance (Unknown exact mechanism) after extensive tubular reabsorption with no need for renal dose adjustment [201].
Toxicity/Adverse effectsDose-related nephrotoxicity is frequent with colistin than polymyxin B seen as renal impairment often reversible on stopping the medication. Dose-related neurotoxicity manifesting as neuromuscular blockade resulting in muscular weakness, apnea, and respiratory failure. This effect can be augmented on concurrent administration with aminoglycosides. Peripheral neuropathy of extremities and perioral paraesthesia [202].

Table 18.

3A XI polymixins.

OriginIt was isolated from the soil bacteria Streptomyces fradiae.
Mechanism of actionIt inhibits phosphoenolpyruvate synthetase, an enzyme needed to synthesize N-acetylmuramic acid, an essential component of cell wall formation, thus inhibiting cell wall formation. Its bactericidal effect is broad, covering resistant gram-negative and gram-positive microorganisms [203, 204].
RoutesAvailable in IV and oral formulations. Only oral formulation is currently approved.
IndicationThe oral form has been approved for uncomplicated UTI due to susceptible strains of Escherichia coli and Enterococcus faecalis. IV formulation has been used in a combination regimen against deep-seated infections due to MDR organisms.
ResistanceModification of phosphoenolpyruvate synthetase enzyme, porin mutations, and some carbapenemases such as OXA. No cross-resistance to other antimicrobial classes.
Pharmac- okineticsIt undergoes renal clearance with dose adjustment needed in renal impairment. Higher doses are associated with bradycardia [205].
Toxicity/Adverse effectsHypernatremia, hypokalemia, hypocalcemia, and phlebitis.

Table 19.

3A XII epoxide (fosfomycin).

OriginIt is isolated from the fungus Pleurotus mutilus.
Mechanism of actionIt inhibits protein synthesis by binding to 23SrRNA part of the 50S ribosome subunit. Its activity against gram-positive organisms is potent invitro (MSSA/MRSA/Streptococcal spp). Its spectrum of bactericidal effects is broad, covering both gram-positive and negative respiratory pathogens.
RoutesAvailable in both oral and IV formulations.
IndicationIt is approved for CABP therapy in patients >18 years old by both IV and oral formulations.
ResistanceMutations in the 23S rRNA and methylation of the target site preventing Lefamulin from 23S rRNA binding [206].
Pharmac- okineticsIt undergoes hepatic clearance by cytochrome CYP3A and can lead to interactions. Dose adjustment is needed in hepatic impairment and none in renal failure.
Toxicity/Adverse effectsInfusion site reactions, phlebitis, headache, nausea, diarrhea, and QT prolongation [207].

Table 20.

3A XIII pleuromutilin (lefamulin).

OriginRifampin was semisynthetically obtained from rifamycin SV isolated from Amycolatopsis mediterranei. Similarly, Rifabutin, Rifapentine, and Rifaximin are semisynthetic modifications.
Mechanism of actionRifamycins bind avidly to DNA-dependent RNA polymerase and block RNA synthesis.
RoutesRifampin: available in oral and IV formulations. Rifabutin, Rifapentine, Rifaximin: available in oral formulations.
IndicationRifampin: Antitubercular therapy for active tuberculosis. Treatment of Nontubercular mycobacterial infections due to Mycobacterium leprae (M. leprae), Mycobacterium avium-intracellulare (MAC), Mycobacterium kansasii.
Combination therapy for synergistic antistaphylococcal effect and antibiofilm effect in PJI, chronic osteomyelitis, and SSTI. Therapy for resistant Streptococcus pneumoniae strains causing CNS infections and Enterococcal hip and knee PJI. Therapy for severe legionella infection along with a macrolide. As a part of combination therapy of Rhodococcus equi infections in immunosuppressed patients. As a part of combination therapy of MDR GNB infections. Brucellosis and complicated Bartonella infection antimicrobial therapy. Chemoprophylaxis in Meningococcal meningitis and Active Hemophilus influenzae infection close contacts.
Rifabutin: As an alternative to rifampin in the treatment of tuberculosis and MAC infection.
Rifapentine: As a part of the short regimen for latent tuberculosis therapy,
Rifaximin: Hepatic encephalopathy treatment, Alternative for travelers diarrhea and recurrent Clostridioides difficile infection. It is an alternative for GI invasive pathogens Salmonella, Shigella, Campylobacter, and Escherichia coli.
ResistancerpoB gene mutations result in decreased binding of rifamycins to RNA polymerase [208]. Decreased cellular uptake of rifampin. Mutations in the arr gene lead to ribosylation of rifamycins and decreased binding [209].
Pharmac- okineticsRifampin: excellent oral bioavailability with broad tissue and fluid distribution, including brain [210]. It undergoes hepatic clearance, enterohepatic circulation with biliary excretion, and minimal renal excretion. Dosage adjustment is needed in hepatic impairment. It induces hepatic enzyme CYP3A resulting in drug interactions, especially with protease inhibitors. Rifabutin: is more lipid-soluble with a long half-life and extensive tissue distribution, including CSF. Its metabolites post hepatic metabolism undergo renal clearance, so dose adjustment is needed with hepatic and renal impairment. Hepatic enzyme induction is minimum. Protease inhibitors increase their levels. Rifapentine: Food increases its bioavailability, and it is more potent with a longer half-life. Intracellular concentrations are higher than rifampin with minimal CSF penetration. It undergoes hepatic clearance with induction of hepatic enzymes CYP3A4 and protease inhibitors decrease its absorption [211]. Rifaximin: Oral absorption is minimal, and 97% of the drug gets excreted in stools. It can induce cytochrome P450 3A4, but it is not seen as the systemic levels are minimal [212]. No dosage adjustment is required.
Toxicity/Adverse effectsRifampin: type 1 hypersensitivity reactions, flu-like syndrome, hemolysis, thrombocytopenia, acute interstitial nephritis with tubular necrosis, mild transaminitis with increased risk of hepatotoxicity with isoniazid [213], and red-orange discoloration of body fluids. Rifabutin: polyarthralgia, leukopenia, and uveitis [214]. Rifapentine:flu-like syndrome, hyperuricemia, hemolysis, and renal failure. Rifaximin: neutropenia.

Table 21.

3A XIV rifamycins.

OriginIt is a semisynthetic derivative of azomycin isolated from a streptomyces bacterium. Tinidazole, Secnidazole and Ornidazole are the other semisynthetic derivatives.
Mechanism of actionIt enters the cell passively and then gets an electron transferred to its nitro group, creating a free radical which is cytotoxic and interacts with DNA (prodrug to an active drug). This change enhances the drug gradient in the cell by increased uptake. The active drug oxidizes DNA damaging it and block DNA synthesis [215].
RoutesAvailable in oral capsules, tablets, topical gels, creams, lotion, vaginal gel, suspension, and IV formulations.
IndicationTreatment of parasitic infections such as trichomoniasis, symptomatic GI Dientamoeba fragilis infection, Giardiasis, mild to moderate Clostridioides difficile infection, anaerobic infections of CNS, lung, abdomen, Skin, gynecologic, oral, dental, bone, and joint. As a part of a combination regimen against Helicobacter pylori. As an alternative agent recommended for surgical prophylaxis in intraabdominal, head, and neck cancer, urology surgery for patients intolerant or allergic to beta-lactams [216]. Prophylaxis perioperatively in obstetric and gynecologic procedures [217].
ResistanceDecreased uptake of the antibiotic. Active drug efflux pumps. Reduced activation of the prodrug (↓nitroreductase enzymes). Inactivation of the antibiotic (nim-encoded nitroimidazole reductase). Altered DNA repair [215].
Pharmac- okineticsOral bioavailability is close to 100%, with a more considerable volume of distribution attaining excellent concentrations in tissue, body fluids, abscess, and CSF [10]. It undergoes hepatic clearance and enterohepatic circulation with some amount being excreted renally with no change. Dosage adjustment is needed in hepatic impairment.
Toxicity/Adverse effectsCommon ones include nausea, metallic taste, dry mouth, diarrhea, vaginal candida infection, CNS side effects on prolonged therapy (aseptic meningitis, encephalopathy, ataxia, seizure). Rare serious events include ototoxicity, Stevens-Johnson syndrome, pancreatitis [10].

Table 22.

3A XV metronidazole.

An increased risk of renal failure is observed when vancomycin is administered along with aminoglycosides and piperacillin-tazobactam [218, 219]. If a VRE strain susceptibility reveals sensitivity to teicoplanin, it should be avoided due to resistance emergence during therapy. When teicoplanin is used for IE, bone, and joint infections as a monotherapy, the recommendation is to keep serum levels close to 20 μg/mL and, if needed >30 μg/mL [220]. A higher AUC/MIC ratio is related to better clinical outcomes and decreased mortality with vancomycin therapy [221].

The lipoglycopeptides have a longer half-life and are currently undergoing trials for bacteremia, joint infections, osteomyelitis.

Retrospective data indicate higher cure rates and lower mortality when a higher dose (> 8 mg/kg/day) of daptomycin is used [222]. In the therapeutic failure of vancomycin therapy, a suggestion is to use a higher dose of daptomycin or combine it with a beta-lactam or aminoglycoside or TMP-SMX to increase its bactericidal activity. In VRE endocarditis with bacteremia, daptomycin with beta-lactam is an ideal combination to prevent the emergence of resistance [223, 224]. Due to lack of CNS penetration, it should not be used in the therapy for meningitis [225]. Daptomycin is inactivated by the pulmonary surfactant and is rendered ineffective in bronchoalveolar pneumonia but is adequate in hematogenous pneumonia [226]. In patients with chronic kidney disease and on dialysis, more frequent monitoring of CPK is ideal. CPK monitoring is a must if the patient is on statins for hyperlipidemia. It needs to be stopped if the CPK levels are >1000 units/L with clinical features of myopathy or > 2000 (ten times the upper limit) with no myopathy features [123].

Streptogramins are another class of lipopeptides rarely used currently. They are made up of two macrocyclic lactone peptolide components. They are labeled as streptogramin A, and streptogramin B. Quinupristin-Dalfopristin is a 30: 70 ratio IV formulation available for therapy. These components are bacteriostatic as dalfopristin ends protein synthesis by binding to 50S ribosomal unit and quinupristin prevents peptide elongation. Dalfopristin binding increases the affinity to quinupristin due to structural change resulting in synergistic bactericidal activity. It is currently used as an alternative for MSSA or streptococcal SSTI. It needs a central line for administration as it is an irritant and can cause thrombophlebitis [227].

Due to the lack of active intrinsic electron transport chain and cell membrane potential difference, the anaerobic bacteria are resistant to aminoglycosides. Enterococci are intrinsically resistant to aminoglycosides [228]. Once-daily dosing is effective as traditional multiple doses, decreases the risk of ototoxicity and nephrotoxicity, is straightforward, and is economical towards resources and time [229]. This dosing pattern does not decline neuromuscular function in sick intubated patients but needs evaluation in cystic fibrosis, meningitis, and osteomyelitis caused by aerobic gram-negative bacilli [230, 231, 232]. The once-daily dose should be used cautiously in IE patients [176]. Inhaled aminoglycosides used in conjunction with a beta-lactam reveal better clinical outcomes [233]. For endophthalmitis and intracranial infections, they need to be administered locally (direct intravitreal injection, intraventricular administration). Aminoglycoside combination regimens diminish the emergence of resistant strains to the companion antibiotic and aminoglycoside. The synergistic antibiotic effect is observed when aminoglycoside is combined with an anti-cell wall antibiotic (beta-lactam). This combination is effective in the therapy of MSSA, enterococci, pseudomonas spp, and Streptococcal viridans infections but not in MRSA infections.

Plazomicin is a semisynthetic aminoglycoside derived from sisomicin. It is potent against MDR GNB, especially the ones with carbapenemase. It has been approved currently for the treatment of complicated UTI (cUTI) by aerobic gram-negative bacilli. It is synergistic with other beta-lactams, especially zosyn cefepime and doripenem [234]. The main side effects are tinnitus, headache, dizziness, and mild to moderate drowsiness.

Delafloxacin, a newer quinolone, has MRSA activity and can be used in native and prosthetic joint infections as an oral pill.

PCN skin tests are inaccurate in predicting skin reactions. In PCN or cephalosporin allergy patients, the clinical decision to use a different cephalosporin is decided by the severity of the reaction and the cephalosporin to be used. In patients with no severe reactions, a cephalosporin with a different side chain can be used. It is recommended not to use a cephalosporin in case of a severe reaction [235]. Cephalosporins are not active against atypical organisms responsible for CABP. An initial study disclosed increased mortality with cefepime than other cephalosporins compared to a beta-lactam plus beta-lactamase inhibitor (BLI), which was not observed in a more extensive meta-analysis [236, 237]. Cefepime is not recommended to be used in ESBL infections [238]. Siderophore cephalosporins Cefiderocol are active against all beta-lactamases and carbapenemase enzymes [239]. It is also active against the GNB lactose-non fermenters by its affinity for the PBP3.

Zosyn should not be used to treat ESBL infections with bacteremia due to higher mortality observed in trials compared to meropenem [240, 241].

Most Burkholderia cepacia, Stenotrophomas maltophilia, Acinetobacter baumannii strains are resistant to aztreonam.

Lactose-non fermenters such as Stenotrophomonas maltophilia, B. cepacia, and Elizabethkingia meningoseptica are intrinsically resistant to all carbapenems due to intrinsic MBL synthesis. Similarly, Enterobacteriaceae containing KPC (Klebsiella pneumoniae), OXA (A. baumannii), or acquired MBL are resistant to carbapenems. They are an ideal choice for polymicrobial infections as they also cover MSSA. Pseudomonas aeruginosa resistance to carbapenems is primarily due to porin mutations and efflux pumps than the carbapenemase. Porin mutations affect the imipenem, whereas the efflux pumps affect the meropenem and doripenem [242, 243]. The duration of therapy for lactose-non fermenters causing VAP is controversial, as a shorter duration of seven days is associated with an increased recurrence rate [244].

Compared to other antimicrobial classes, polymixins have been associated with poorer outcomes, but this appears to be a poor application of prior suboptimal dose adjustments based on the newer pharmacokinetics and pharmacodynamics data [245, 246]. Polymixin combination regimens should be used as a last resort in the absence of any alternative antimicrobial regimen.

Extreme consideration should be given to the possible drug interactions when rifamycins are used clinically due to their ability to induce the hepatic cytochrome system.


4. Antibiotics in ICU

Antimicrobial prescription in the intensive care unit has three essential ideals to be followed: the correct time when to initiate the antimicrobial, what dose to be used, and how long the antimicrobial should be used. Initiate empirical regimen as early as possible once the infection is suspected to prevent poor clinical outcomes [247]. Trials reveal a positive association between earlier antimicrobial use and mortality in sepsis and septic shock [248]. 2016 surviving sepsis guidelines recommend administering appropriate antimicrobial therapy within one hour of sepsis and septic shock recognition based on the moderate quality of evidence [249]. The empirical regimen should be based on the clinical presentation and associated risk factors. The dose used should be based on the antimicrobial pharmacokinetics, and antibiotics are labeled as either time-dependent (beta-lactams), concentration-dependent (aminoglycosides and daptomycin), and concentration-dependent with time dependence (fluoroquinolones, linezolid) [250].

For time-dependent antimicrobials, the best way to achieve efficacy is a continuous infusion to keep the drug levels above the MIC for a longer time [251]. For concentration-dependent antimicrobials, once-daily higher doses are adequate as they demonstrate postantibiotic effect with reduced adverse events [252]. It is prudent to increase the antimicrobial dosage in patients with augmented renal clearance (burns, trauma, febrile neutropenia) to increase the antimicrobial dosage to achieve the target drug levels [253]. De-escalation of antibiotics is done via three different methods. First, once empirical therapy is initiated, follow the pending culture results, and on day three, when the antimicrobials have reached adequate therapeutic levels, the regimen can be de-escalated to a narrower spectrum based on the patient’s culture results and clinical diagnosis. Second, in patients with negative culture results, which is a common finding in ICU patients, the de-escalation process is unclear. For example, in patients treated for HAP who are clinically improving with negative sputum cultures for MRSA and P. aeruginosa, antibiotics covering these organisms can be stopped as per guidelines [254]. The third mechanism uses the empirical regimen for the shortest duration possible for a better clinical outcome [255]. This recommendation is based on expert opinion than clinical data.

Recent guidelines based on multiple trials conducted on the VAP antimicrobial therapy duration suggest using the treatment for seven days than 14 days [256]. However, they also recommend following the improvement in clinical, imaging, and laboratory parameters to decide the duration of therapy judiciously. Seven days of VAP therapy was associated with an increased recurrence of infections among lactose-non fermenter GNB such as Pseudomonas and Acinetobacter spp. [244]. Similarly, in MRSA and MSSA pneumonia, the duration is decided by the clinical picture, and most often, it is more than seven days and closer to 14 days.

Antibiotic use in the intensive care unit (ICU) usually follows two different thought processes. One way is to use a single or limited number of antimicrobials as workhorse agents as empirical therapy for infections which carries an inherent risk of resistance emergence via selective pressure (antibiotic homogeneity). This was initiated to control resistance. Another way is to select the antibiotics based on clinical presentation and comorbid risk factors associated with decreased resistance (antibiotic heterogeneity). This is a newer initiation in managing resistance. It is recommended to use antibiotic heterogeneity as much as possible to prevent antimicrobial resistance emergence [257]. Antibiotic stewardship is a must in this modern era for better clinical outcomes, prevent antibiotic adverse events and resistance using local data, reduce the costs by selecting the correct antibiotic dose duration and route. An ideal stewardship team should include an infectious disease consultant, clinical microbiologist, infectious disease trained clinical pharmacist. The current guidelines recommend two strategies to attain this objective. First, reduce the future antibiotic use by auditing institutional antimicrobial usage with feedback to the prescribers. Second, it is ideal to restrict certain antimicrobials to prevent inappropriate usage and decrease institutions’ economic burden. Measures taken to enhance the ICU staff education boosts the stewardship process and increases its acceptance among health care workers.


5. Conclusion

Antibiotic resources are finite and need to be managed judiciously with principles based on antimicrobial stewardship. Management of sick patients in ICU will need timely appropriate antimicrobial adjustments based on new laboratory results and clinical parameters. It seems reasonable to utilize a stewardship team to support the intensivist in the ICU for better outcomes. It seems appropriate to extend the stewardship program to progressive care units or step-down units where antimicrobial utilization is greater than the floors. Education of the ICU staff and positive feedback to antibiotic prescribers can change prescription behavior from antibiotic homogeneity to antibiotic heterogeneity to prevent the emergence of MDR organisms.



“None, this manuscript preparation did not need external funds.”


Conflict of interest

“We, the authors declare no conflict of interest.”


Notes/thanks/other declarations

“A special thanks to the editor for allowing us to author this manuscript.


Acronyms and abbreviations


Minimum inhibitory concentration


Minimum bactericidal concentration


Clinical and Laboratory Standards Institute


European Committee on Antimicrobial Susceptibility Testing


Infective endocarditis


Para-aminobenzoic acid


Dihydrofolate reductase




Urinary tract infection


Trimethoprim and sulfamethoxazole


Skin and soft tissue infections


Pneumocystis jiroveci


Dihydrofolate reductase encoding gene


Steven-Johnson syndrome


Toxic epidermal necrolysis




Methicillin-sensitive S. aureus


Methicillin-resistant S. aureus


Community-acquired bacterial pneumonia


Pelvic inflammatory disease


Cerebrospinal fluid


Central Nervous System


Medical intensive care unit


Complicated intraabdominal infections




Federal drug authority


Hospital-acquired pneumonia


Ventilator-associated pneumonia


ribosomal ribonucleic acid




M. avium complex


Macrolide Lincosamide and streptogramin B


Erythromycin ribosome methylation


Human leukocyte antigen


Drug rash with eosinophilia and systemic symptoms


Area under the curve


Vancomycin-resistant Enterococcus


Adenylation coding gene


Elongation factor G


Elongation factor G coding gene


Penicillin-binding protein


Methicillin resistance encoding gene


Vancomycin resistance encoding gene


Vancomycin intermediate S. aureus


Creatinine phosphokinase


messenger RNA


Gram-negative bacillus


Complicated UTI


Deoxyribonucleic acid


Spontaneous bacterial peritonitis




Prosthetic joint infection


Immunoglobulin E


Beta-lactamase inhibitor


Extended-spectrum beta-lactamases


K. pneumoniae carbapenemase




Oxacillin beta-lactamases


Class C beta-lactamses




Lipopolysaccharide encoding gene


RNA polymerase rifamycin binding target encoding gene


Methytransferase encoding gene


  1. 1. Waksman SA. What is an antibiotic or an antibiotic substance? Mycologia. 1947;39(5):565-9
  2. 2. Northey EH. The sulfonamides and allied compounds. Journal of the American Pharmaceutical Association. 1948;37(8):338-
  3. 3. Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. JAMA. 1999;281(1):61-6
  4. 4. Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clin Infect Dis. 2004;38(6):864-70
  5. 5. Wald-Dickler N, Holtom P, Spellberg B. Busting the Myth of "Static vs Cidal": A Systemic Literature Review. Clin Infect Dis. 2018;66(9):1470-4
  6. 6. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010;68(2):140-51
  7. 7. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013;57(4):1756-62
  8. 8. Fowler VG, Jr., Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653-65
  9. 9. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: A prospective study. Ann Intern Med. 1982;97(4):496-503
  10. 10. Falagas ME, Matthaiou DK, Bliziotis IA. The role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials. J Antimicrob Chemother. 2006;57(4):639-47
  11. 11. Finland M. Current status of therapy in bacterial endocarditis. J Am Med Assoc. 1958;166(4):364-73
  12. 12. Mancino P, Ucciferri C, Falasca K, Pizzigallo E, Vecchiet J. Methicillin-resistant Staphylococcus epidermidis (MRSE) endocarditis treated with linezolid. Scand J Infect Dis. 2008;40(1):67-73
  13. 13. Kanafani Z, Boucher H, Fowler V, Cabell C, Hoen B, Miro JM, et al. Daptomycin compared to standard therapy for the treatment of native valve endocarditis. Enferm Infecc Microbiol Clin. 2010;28(8):498-503
  14. 14. Bushby SR, Hitchings GH. Trimethoprim, a sulphonamide potentiator. Br J Pharmacol Chemother. 1968;33(1):72-90
  15. 15. Woods DD. The Relation of p-aminobenzoic Acid to the Mechanism of the Action of Sulphanilamide. Br J Exp Pathol. 1940;21(2):74-90
  16. 16. Brown GM. The biosynthesis of pteridines. Adv Enzymol Relat Areas Mol Biol. 1971;35:35-77
  17. 17. Grose WE, Bodey GP, Loo TL. Clinical pharmacology of intravenously administered trimethoprim-sulfamethoxazole. Antimicrob Agents Chemother. 1979;15(3):447-51
  18. 18. Swedberg G, Castensson S, Skold O. Characterization of mutationally altered dihydropteroate synthase and its ability to form a sulfonamide-containing dihydrofolate analog. J Bacteriol. 1979;137(1):129-36
  19. 19. Shin HW, Lim J, Kim S, Kim J, Kwon GC, Koo SH. Characterization of trimethoprim-sulfamethoxazole resistance genes and their relatedness to class 1 integron and insertion sequence common region in gram-negative bacilli. J Microbiol Biotechnol. 2015;25(1):137-42
  20. 20. Watanabe T. Infective heredity of multiple drug resistance in bacteria. Bacteriol Rev. 1963;27:87-115
  21. 21. Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ. Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab Dispos. 2002;30(6):631-5
  22. 22. Chertow GM, Seifter JL, Christiansen CL, O'Donnell WJ. Trimethoprim-sulfamethoxazole and hypouricemia. Clin Nephrol. 1996;46(3):193-8
  23. 23. Mittmann N, Knowles SR, Koo M, Shear NH, Rachlis A, Rourke SB. Incidence of toxic epidermal necrolysis and Stevens-Johnson Syndrome in an HIV cohort: an observational, retrospective case series study. Am J Clin Dermatol. 2012;13(1):49-54
  24. 24. Ho JM, Juurlink DN. Considerations when prescribing trimethoprim-sulfamethoxazole. CMAJ. 2011;183(16):1851-8
  25. 25. Garvey JP, Brown CM, Chotirmall SH, Dorman AM, Conlon PJ, Walshe JJ. Trimethoprim-sulfamethoxazole induced acute interstitial nephritis in renal allografts; clinical course and outcome. Clin Nephrol. 2009;72(5):331-6
  26. 26. Hemstreet BA. Antimicrobial-associated renal tubular acidosis. Ann Pharmacother. 2004;38(6):1031-8
  27. 27. Kouklakis G, Mpoumponaris A, Zezos P, Moschos J, Koulaouzidis A, Nakos A, et al. Cholestatic hepatitis with severe systemic reactions induced by trimethoprim-sulfamethoxazole. Ann Hepatol. 2007;6(1):63-5
  28. 28. Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol. 2005;39(8):709-16
  29. 29. Sembera S, Lammert C, Talwalkar JA, Sanderson SO, Poterucha JJ, Hay JE, et al. Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation. Liver Transpl. 2012;18(7):803-10
  30. 30. Duggar BM. Aureomycin; a product of the continuing search for new antibiotics. Ann N Y Acad Sci. 1948;51(Art. 2):177-81
  31. 31. Dahl EL, Shock JL, Shenai BR, Gut J, DeRisi JL, Rosenthal PJ. Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother. 2006;50(9):3124-31
  32. 32. Thaker M, Spanogiannopoulos P, Wright GD. The tetracycline resistome. Cell Mol Life Sci. 2010;67(3):419-31
  33. 33. Smith C, Woods CG, Woods MJ. Absorption of minocycline. J Antimicrob Chemother. 1984;13(1):93
  34. 34. Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis. Antimicrob Agents Chemother. 1985;28(2):347-8
  35. 35. Hey H, Jorgensen F, Sorensen K, Hasselbalch H, Wamberg T. Oesophageal transit of six commonly used tablets and capsules. Br Med J (Clin Res Ed). 1982;285(6356):1717-9
  36. 36. Schultz JC, Adamson JS, Jr., Workman WW, Norman TD. Fatal Liver Disease after Intravenous Administration of Tetracycline in High Dosage. N Engl J Med. 1963;269:999-1004
  37. 37. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27(9):1329-42
  38. 38. Perks WH, Walters EH, Tams IP, Prowse K. Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone. Thorax. 1979;34(3):324-7
  39. 39. Cohlan SQ. Teratogenic Agents and Congenital Malformations. J Pediatr. 1963;63:650-9
  40. 40. Knowles SR, Shapiro L, Shear NH. Serious adverse reactions induced by minocycline. Report of 13 patients and review of the literature. Arch Dermatol. 1996;132(8):934-9
  41. 41. Sum PE, Lee VJ, Testa RT, Hlavka JJ, Ellestad GA, Bloom JD, et al. Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem. 1994;37(1):184-8
  42. 42. Bauer G, Berens C, Projan SJ, Hillen W. Comparison of tetracycline and tigecycline binding to ribosomes mapped by dimethylsulphate and drug-directed Fe2+ cleavage of 16S rRNA. J Antimicrob Chemother. 2004;53(4):592-9
  43. 43. Bergeron J, Ammirati M, Danley D, James L, Norcia M, Retsema J, et al. Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection. Antimicrob Agents Chemother. 1996;40(9):2226-8
  44. 44. Visalli MA, Murphy E, Projan SJ, Bradford PA. AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob Agents Chemother. 2003;47(2):665-9
  45. 45. Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother. 2003;47(3):972-8
  46. 46. Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother. 2005;49(1):220-9
  47. 47. Frampton JE, Curran MP. Tigecycline. Drugs. 2005;65(18):2623-35; discussion 36-7
  48. 48. McGovern PC, Wible M, El-Tahtawy A, Biswas P, Meyer RD. All-cause mortality imbalance in the tigecycline phase 3 and 4 clinical trials. Int J Antimicrob Agents. 2013;41(5):463-7
  49. 49. Bahal N, Nahata MC. The new macrolide antibiotics: azithromycin, clarithromycin, dirithromycin, and roxithromycin. Ann Pharmacother. 1992;26(1):46-55
  50. 50. Piscitelli SC, Danziger LH, Rodvold KA. Clarithromycin and azithromycin: new macrolide antibiotics. Clin Pharm. 1992;11(2):137-52
  51. 51. Leclercq R, Courvalin P. Resistance to macrolides and related antibiotics in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2002;46(9):2727-34
  52. 52. Edelstein PH. Pneumococcal resistance to macrolides, lincosamides, ketolides, and streptogramin B agents: molecular mechanisms and resistance phenotypes. Clin Infect Dis. 2004;38 Suppl 4:S322-7
  53. 53. Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmacokinet. 1985;10(1):63-79
  54. 54. Amsden GW. Macrolides versus azalides: a drug interaction update. Ann Pharmacother. 1995;29(9):906-17
  55. 55. Osono T, Umezawa H. Pharmaco kinetics of macrolides, lincosamides and streptogramins. J Antimicrob Chemother. 1985;16 Suppl A:151-66
  56. 56. Schentag JJ, Ballow CH. Tissue-directed pharmacokinetics. Am J Med. 1991;91(3A):5S-11S
  57. 57. Hardy DJ, Guay DR, Jones RN. Clarithromycin, a unique macrolide. A pharmacokinetic, microbiological, and clinical overview. Diagn Microbiol Infect Dis. 1992;15(1):39-53
  58. 58. Katapadi K, Kostandy G, Katapadi M, Hussain KM, Schifter D. A review of erythromycin-induced malignant tachyarrhythmia--torsade de pointes. A case report. Angiology. 1997;48(9):821-6
  59. 59. Chandrupatla S, Demetris AJ, Rabinovitz M. Azithromycin-induced intrahepatic cholestasis. Dig Dis Sci. 2002;47(10):2186-8
  60. 60. Shaffer D, Singer S, Korvick J, Honig P. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis. 2002;35(2):197-200
  61. 61. McGehee RF, Jr., Smith CB, Wilcox C, Finland M. Comparative studies of antibacterial activity in vitro and absorption and excretion of lincomycin and clinimycin. Am J Med Sci. 1968;256(5):279-92
  62. 62. Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis. 2003;37(9):1257-60
  63. 63. Matzov D, Eyal Z, Benhamou RI, Shalev-Benami M, Halfon Y, Krupkin M, et al. Structural insights of lincosamides targeting the ribosome of Staphylococcus aureus. Nucleic Acids Res. 2017;45(17):10284-92
  64. 64. Poehlsgaard J, Pfister P, Bottger EC, Douthwaite S. Molecular mechanisms by which rRNA mutations confer resistance to clindamycin. Antimicrob Agents Chemother. 2005;49(4):1553-5
  65. 65. Leclercq R, Brisson-Noel A, Duval J, Courvalin P. Phenotypic expression and genetic heterogeneity of lincosamide inactivation in Staphylococcus spp. Antimicrob Agents Chemother. 1987;31(12):1887-91
  66. 66. Panzer JD, Brown DC, Epstein WL, Lipson RL, Mahaffey HW, Atkinson WH. Clindamycin levels in various body tissues and fluids. J Clin Pharmacol New Drugs. 1972;12(7):259-62
  67. 67. DeHaan RM, Metzler CM, Schellenberg D, Vandenbosch WD. Pharmacokinetic studies of clindamycin phosphate. J Clin Pharmacol. 1973;13(5):190-209
  68. 68. Yang Y, Chen S, Yang F, Zhang L, Alterovitz G, Zhu H, et al. HLA-B*51:01 is strongly associated with clindamycin-related cutaneous adverse drug reactions. Pharmacogenomics J. 2017;17(6):501-5
  69. 69. Bartlett JG. Historical perspectives on studies of Clostridium difficile and C. difficile infection. Clin Infect Dis. 2008;46 Suppl 1:S4-11
  70. 70. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med. 2003;138(2):135-42
  71. 71. Long KS, Vester B. Resistance to linezolid caused by modifications at its binding site on the ribosome. Antimicrob Agents Chemother. 2012;56(2):603-12
  72. 72. Diaz L, Kiratisin P, Mendes RE, Panesso D, Singh KV, Arias CA. Transferable plasmid-mediated resistance to linezolid due to cfr in a human clinical isolate of Enterococcus faecalis. Antimicrob Agents Chemother. 2012;56(7):3917-22
  73. 73. Wang Y, Lv Y, Cai J, Schwarz S, Cui L, Hu Z, et al. A novel gene, optrA, that confers transferable resistance to oxazolidinones and phenicols and its presence in Enterococcus faecalis and Enterococcus faecium of human and animal origin. J Antimicrob Chemother. 2015;70(8):2182-90
  74. 74. Roger C, Roberts JA, Muller L. Clinical Pharmacokinetics and Pharmacodynamics of Oxazolidinones. Clin Pharmacokinet. 2018;57(5):559-75
  75. 75. Zhanel GG, Love R, Adam H, Golden A, Zelenitsky S, Schweizer F, et al. Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens. Drugs. 2015;75(3):253-70
  76. 76. Flanagan S, Minassian SL, Passarell JA, Fiedler-Kelly J, Prokocimer P. Pharmacokinetics of Tedizolid in Obese and Nonobese Subjects. J Clin Pharmacol. 2017;57(10):1290-4
  77. 77. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother. 2002;46(8):2723-6
  78. 78. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy. 2007;27(8):1189-97
  79. 79. De Vriese AS, Coster RV, Smet J, Seneca S, Lovering A, Van Haute LL, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis. 2006;42(8):1111-7
  80. 80. Barnhill AE, Brewer MT, Carlson SA. Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components. Antimicrob Agents Chemother. 2012;56(8):4046-51
  81. 81. Nagel S, Kohrmann M, Huttner HB, Storch-Hagenlocher B, Schwab S. Linezolid-induced posterior reversible leukoencephalopathy syndrome. Arch Neurol. 2007;64(5):746-8
  82. 82. Refaat M, Hyle E, Malhotra R, Seidman D, Dey B. Linezolid-induced lingua villosa nigra. Am J Med. 2008;121(6):e1
  83. 83. Harvey CL, Knight SG, Sih CJ. On the mode of action of fusidic acid. Biochemistry. 1966;5(10):3320-7
  84. 84. Gemmell CG, O'Dowd A. Regulation of protein A biosynthesis in Staphylococcus aureus by certain antibiotics: its effect on phagocytosis by leukocytes. J Antimicrob Chemother. 1983;12(6):587-97
  85. 85. Taburet AM, Guibert J, Kitzis MD, Sorensen H, Acar JF, Singlas E. Pharmacokinetics of sodium fusidate after single and repeated infusions and oral administration of a new formulation. J Antimicrob Chemother. 1990;25 Suppl B:23-31
  86. 86. Wise R, Pippard M, Mitchard M. The disposition of sodium fusidate in man. Br J Clin Pharmacol. 1977;4(5):615-9
  87. 87. Godtfredsen WO, Jahnsen S, Lorck H, Roholt K, Tybring L. Fusidic acid: a new antibiotic. Nature. 1962;193:987
  88. 88. Deljehier T, Pariente A, Miremont-Salame G, Haramburu F, Nguyen L, Rubin S, et al. Rhabdomyolysis after co-administration of a statin and fusidic acid: an analysis of the literature and of the WHO database of adverse drug reactions. Br J Clin Pharmacol. 2018;84(5):1057-63
  89. 89. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, et al. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med. 1996;124(9):792-802
  90. 90. Feikin DR, Dowell SF, Nwanyanwu OC, Klugman KP, Kazembe PN, Barat LM, et al. Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus pneumoniae in Malawian children after treatment for malaria with sulfadoxine/pyrimethamine. J Infect Dis. 2000;181(4):1501-5
  91. 91. Huang DB, O'Riordan W, Overcash JS, Heller B, Amin F, File TM, et al. A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-1. Clin Infect Dis. 2018;66(8):1222-9
  92. 92. Andrews J, Honeybourne D, Ashby J, Jevons G, Fraise A, Fry P, et al. Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men. J Antimicrob Chemother. 2007;60(3):677-80
  93. 93. Brouillard JE, Terriff CM, Tofan A, Garrison MW. Antibiotic selection and resistance issues with fluoroquinolones and doxycycline against bioterrorism agents. Pharmacotherapy. 2006;26(1):3-14
  94. 94. Zhanel GG, Esquivel J, Zelenitsky S, Lawrence CK, Adam HJ, Golden A, et al. Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent. Drugs. 2020;80(3):285-313
  95. 95. Lee YR, Burton CE. Eravacycline, a newly approved fluorocycline. Eur J Clin Microbiol Infect Dis. 2019;38(10):1787-94
  96. 96. Hiramatsu K. Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect Dis. 2001;1(3):147-55
  97. 97. Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925-42
  98. 98. Ricard JD, Wolff M, Lacherade JC, Mourvillier B, Hidri N, Barnaud G, et al. Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study. Clin Infect Dis. 2007;44(2):250-5
  99. 99. Grace E. Altered vancomycin pharmacokinetics in obese and morbidly obese patients: what we have learned over the past 30 years. J Antimicrob Chemother. 2012;67(6):1305-10
  100. 100. Wilson AP. Clinical pharmacokinetics of teicoplanin. Clin Pharmacokinet. 2000;39(3):167-83
  101. 101. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-44
  102. 102. Geraci JE, Heilman FR, Nichols DR, Wellman WE. Antibiotic therapy of bacterial endocarditis. VII. Vancomycin for acute micrococcal endocarditis; preliminary report. Proc Staff Meet Mayo Clin. 1958;33(7):172-81
  103. 103. Elyasi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol. 2012;68(9):1243-55
  104. 104. Von Drygalski A, Curtis BR, Bougie DW, McFarland JG, Ahl S, Limbu I, et al. Vancomycin-induced immune thrombocytopenia. N Engl J Med. 2007;356(9):904-10
  105. 105. Van Bambeke F. Glycopeptides in clinical development: pharmacological profile and clinical perspectives. Curr Opin Pharmacol. 2004;4(5):471-8
  106. 106. Higgins DL, Chang R, Debabov DV, Leung J, Wu T, Krause KM, et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2005;49(3):1127-34
  107. 107. Zhanel GG, Schweizer F, Karlowsky JA. Oritavancin: mechanism of action. Clin Infect Dis. 2012;54 Suppl 3:S214-9
  108. 108. Goldstein EJ, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT. In vitro activities of the new semisynthetic glycopeptide telavancin (TD-6424), vancomycin, daptomycin, linezolid, and four comparator agents against anaerobic gram-positive species and Corynebacterium spp. Antimicrob Agents Chemother. 2004;48(6):2149-52
  109. 109. Zeng D, Debabov D, Hartsell TL, Cano RJ, Adams S, Schuyler JA, et al. Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance. Cold Spring Harb Perspect Med. 2016;6(12)
  110. 110. Marbury T, Dowell JA, Seltzer E, Buckwalter M. Pharmacokinetics of dalbavancin in patients with renal or hepatic impairment. J Clin Pharmacol. 2009;49(4):465-76
  111. 111. Hobbs JK, Miller K, O'Neill AJ, Chopra I. Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus. J Antimicrob Chemother. 2008;62(5):1003-8
  112. 112. Muller A, Wenzel M, Strahl H, Grein F, Saaki TNV, Kohl B, et al. Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proc Natl Acad Sci U S A. 2016;113(45):E7077-E86
  113. 113. Muraih JK, Pearson A, Silverman J, Palmer M. Oligomerization of daptomycin on membranes. Biochim Biophys Acta. 2011;1808(4):1154-60
  114. 114. Sharma M, Riederer K, Chase P, Khatib R. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2008;27(6):433-7
  115. 115. Ernst CM, Staubitz P, Mishra NN, Yang SJ, Hornig G, Kalbacher H, et al. The bacterial defensin resistance protein MprF consists of separable domains for lipid lysinylation and antimicrobial peptide repulsion. PLoS Pathog. 2009;5(11):e1000660
  116. 116. Mehta S, Cuirolo AX, Plata KB, Riosa S, Silverman JA, Rubio A, et al. VraSR two-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin in in vivo-selected clinical strains of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2012;56(1):92-102
  117. 117. Cafiso V, Bertuccio T, Spina D, Purrello S, Campanile F, Di Pietro C, et al. Modulating activity of vancomycin and daptomycin on the expression of autolysis cell-wall turnover and membrane charge genes in hVISA and VISA strains. PLoS One. 2012;7(1):e29573
  118. 118. Bertsche U, Weidenmaier C, Kuehner D, Yang SJ, Baur S, Wanner S, et al. Correlation of daptomycin resistance in a clinical Staphylococcus aureus strain with increased cell wall teichoic acid production and D-alanylation. Antimicrob Agents Chemother. 2011;55(8):3922-8
  119. 119. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother. 2006;50(10):3245-9
  120. 120. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother. 2003;47(4):1318-23
  121. 121. Cottagnoud P, Pfister M, Acosta F, Cottagnoud M, Flatz L, Kuhn F, et al. Daptomycin is highly efficacious against penicillin-resistant and penicillin- and quinolone-resistant pneumococci in experimental meningitis. Antimicrob Agents Chemother. 2004;48(10):3928-33
  122. 122. Hanberger H, Nilsson LE, Maller R, Isaksson B. Pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis and Staphylococcus aureus demonstrated by studies of initial killing and postantibiotic effect and influence of Ca2+ and albumin on these drugs. Antimicrob Agents Chemother. 1991;35(9):1710-6
  123. 123. Figueroa DA, Mangini E, Amodio-Groton M, Vardianos B, Melchert A, Fana C, et al. Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clinical program. Clin Infect Dis. 2009;49(2):177-80
  124. 124. Wright GD, Berghuis AM, Mobashery S. Aminoglycoside antibiotics. Structures, functions, and resistance. Adv Exp Med Biol. 1998;456:27-69
  125. 125. Hurwitz C, Rosano CL, Landau JV. Kinetics of loss of vibility of Escherichia coli exposed to streptomycin. J Bacteriol. 1962;83:1210-6
  126. 126. Martin NL, Beveridge TJ. Gentamicin interaction with Pseudomonas aeruginosa cell envelope. Antimicrob Agents Chemother. 1986;29(6):1079-87
  127. 127. Walter F, Vicens Q, Westhof E. Aminoglycoside-RNA interactions. Curr Opin Chem Biol. 1999;3(6):694-704
  128. 128. Lynch SR, Puglisi JD. Structural origins of aminoglycoside specificity for prokaryotic ribosomes. J Mol Biol. 2001;306(5):1037-58
  129. 129. Hocquet D, Vogne C, El Garch F, Vejux A, Gotoh N, Lee A, et al. MexXY-OprM efflux pump is necessary for a adaptive resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob Agents Chemother. 2003;47(4):1371-5
  130. 130. Mao W, Warren MS, Lee A, Mistry A, Lomovskaya O. MexXY-OprM efflux pump is required for antagonism of aminoglycosides by divalent cations in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2001;45(7):2001-7
  131. 131. Magnet S, Blanchard JS. Molecular insights into aminoglycoside action and resistance. Chem Rev. 2005;105(2):477-98
  132. 132. Bush K, Miller GH. Bacterial enzymatic resistance: beta-lactamases and aminoglycoside-modifying enzymes. Curr Opin Microbiol. 1998;1(5):509-15
  133. 133. Hoffman LR, D'Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller SI. Aminoglycoside antibiotics induce bacterial biofilm formation. Nature. 2005;436(7054):1171-5
  134. 134. Barza M, Brown RB, Shen D, Gibaldi M, Weinstein L. Predictability of blood levels of gentamicin in man. J Infect Dis. 1975;132(2):165-74
  135. 135. Bailey DN, Briggs JR. Gentamicin and tobramycin binding to human serum in vitro. J Anal Toxicol. 2004;28(3):187-9
  136. 136. Rodriguez V, Stewart D, Bodey GP. Gentamicin sulfate distribution in body fluids. Clin Pharmacol Ther. 1970;11(2):275-81
  137. 137. Rahal JJ, Jr., Hyams PJ, Simberkoff MS, Rubinstein E. Combined intrathecal and intramuscular gentamicin for gram-negative meningitis. Pharmacologic study of 21 patients. N Engl J Med. 1974;290(25):1394-8
  138. 138. Baum J. Infections of the eye. Clin Infect Dis. 1995;21(3):479-86; quiz 87-8
  139. 139. Wilson TW, Mahon WA, Inaba T, Johnson GE, Kadar D. Elimination of tritiated gentamicin in normal human subjects and in patients with severely impaired renal function. Clin Pharmacol Ther. 1973;14(5):815-22
  140. 140. Wang JC. DNA topoisomerases. Annu Rev Biochem. 1996;65:635-92
  141. 141. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007;130(5):797-810
  142. 142. Dudley MN. Pharmacokinetics of Fluoroquinolones. Quinolone Antimicrobial Agents2003. p. 113-32
  143. 143. Tamai I, Yamashita J, Kido Y, Ohnari A, Sai Y, Shima Y, et al. Limited distribution of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the blood-brain barrier. J Pharmacol Exp Ther. 2000;295(1):146-52
  144. 144. Alffenaar JW, van Altena R, Bokkerink HJ, Luijckx GJ, van Soolingen D, Aarnoutse RE, et al. Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis. Clin Infect Dis. 2009;49(7):1080-2
  145. 145. Stass H, Buhrmann S, Mitchell A, Kubitza D, Moller JG, Kribben A, et al. The influence of continuous venovenous haemodialysis on the pharmacokinetics of multiple oral moxifloxacin administration to patients with severe renal dysfunction. Br J Clin Pharmacol. 2007;64(6):745-9
  146. 146. Lode H, Rubinstein E. Adverse Effects. Quinolone Antimicrobial Agents2003. p. 405-19
  147. 147. Norrby SR. Central Nervous System Toxicity. Quinolone Antimicrobial Agents2003. p. 461-5
  148. 148. Etminan M, Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: a pharmacoepidemiologic study. Neurology. 2014;83(14):1261-3
  149. 149. Ball P, Mandell L, Patou G, Dankner W, Tillotson G. A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context. Int J Antimicrob Agents. 2004;23(5):421-9
  150. 150. Iannini P, Mandell L, Patou G, Shear N. Cutaneous adverse events and gemifloxacin: observations from the clinical trial program. J Chemother. 2006;18(1):3-11
  151. 151. Hypoglycemia and hyperglycemia with fluroroquinolones. Med Lett Drugs Ther. 2003;45(1162):64
  152. 152. Yap YG, Camm AJ. QT Prolongation with Quinolone Antimicrobial Agents. Quinolone Antimicrobial Agents2003. p. 421-40
  153. 153. Pasternak B, Inghammar M, Svanstrom H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ. 2018;360:k678
  154. 154. Etminan M, Forooghian F, Brophy JM, Bird ST, Maberley D. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307(13):1414-9
  155. 155. Stahlmann R. Effects on Connective Tissue Structures. Quinolone Antimicrobial Agents2003. p. 441-9
  156. 156. Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929. Bull World Health Organ. 2001;79(8):780-90
  157. 157. Giesbrecht P, Kersten T, Maidhof H, Wecke J. Staphylococcal cell wall: morphogenesis and fatal variations in the presence of penicillin. Microbiol Mol Biol Rev. 1998;62(4):1371-414
  158. 158. Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev. 2007;20(3):440-58, table of contents
  159. 159. Tomas M, Doumith M, Warner M, Turton JF, Beceiro A, Bou G, et al. Efflux pumps, OprD porin, AmpC beta-lactamase, and multiresistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother. 2010;54(5):2219-24
  160. 160. Zapun A, Contreras-Martel C, Vernet T. Penicillin-binding proteins and beta-lactam resistance. FEMS Microbiol Rev. 2008;32(2):361-85
  161. 161. Yates AB. Management of patients with a history of allergy to beta-lactam antibiotics. Am J Med. 2008;121(7):572-6
  162. 162. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(4):881-91
  163. 163. Maraqa NF, Gomez MM, Rathore MH, Alvarez AM. Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin and other commonly used antimicrobials. Clin Infect Dis. 2002;34(1):50-4
  164. 164. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007;146(9):657-65
  165. 165. Appel GB, Neu HC. The nephrotoxicity of antimicrobial agents (first of three parts). N Engl J Med. 1977;296(12):663-70
  166. 166. Bo G. Giuseppe Brotzu and the discovery of cephalosporins. Clin Microbiol Infect. 2000;6 Suppl 3:6-9
  167. 167. Waxman DJ, Strominger JL. Penicillin-binding proteins and the mechanism of action of beta-lactam antibiotics. Annu Rev Biochem. 1983;52:825-69
  168. 168. Fontana R, Cornaglia G, Ligozzi M, Mazzariol A. The final goal: penicillin-binding proteins and the target of cephalosporins. Clin Microbiol Infect. 2000;6 Suppl 3:34-40
  169. 169. Simner PJ, Patel R. Cefiderocol Antimicrobial Susceptibility Testing Considerations: the Achilles' Heel of the Trojan Horse? J Clin Microbiol. 2020;59(1)
  170. 170. Peterson HB, Galaid EI, Zenilman JM. Pelvic inflammatory disease: review of treatment options. Rev Infect Dis. 1990;12 Suppl 6:S656-64
  171. 171. Nadelman RB, Luger SW, Frank E, Wisniewski M, Collins JJ, Wormser GP. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med. 1992;117(4):273-80
  172. 172. Trenholme GM, Schmitt BA, Nelson JA, Gvazdinskas LC, Harrison BB, Parkhurst GW. Comparative study of three different dosing regimens of cefotaxime for treatment of gram-negative bacteremia. Diagn Microbiol Infect Dis. 1989;12(1):107-11
  173. 173. Workowski KA, Bolan GA, Centers for Disease C, Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137
  174. 174. Augenbraun M, Workowski K. Ceftriaxone therapy for syphilis: report from the emerging infections network. Clin Infect Dis. 1999;29(5):1337-8
  175. 175. Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017;65(12):1963-73
  176. 176. Baddour LM, Wilson WR, Bayer AS, Fowler VG, Jr., Tleyjeh IM, Rybak MJ, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015;132(15):1435-86
  177. 177. Fong IW, Tomkins KB. Review of Pseudomonas aeruginosa meningitis with special emphasis on treatment with ceftazidime. Rev Infect Dis. 1985;7(5):604-12
  178. 178. Sanders CC. Cefepime: the next generation? Clin Infect Dis. 1993;17(3):369-79
  179. 179. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52(4):e56-93
  180. 180. Bartlett JG, Dowell SF, Mandell LA, File TM, Jr., Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis. 2000;31(2):347-82
  181. 181. Noel GJ, Bush K, Bagchi P, Ianus J, Strauss RS. A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections. Clin Infect Dis. 2008;46(5):647-55
  182. 182. Nicholson SC, Welte T, File TM, Jr., Strauss RS, Michiels B, Kaul P, et al. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int J Antimicrob Agents. 2012;39(3):240-6
  183. 183. Werth BJ, Sakoulas G, Rose WE, Pogliano J, Tewhey R, Rybak MJ. Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2013;57(1):66-73
  184. 184. Bennett WM, Aronoff GR, Morrison G, Golper TA, Pulliam J, Wolfson M, et al. Drug prescribing in renal failure: dosing guidelines for adults. Am J Kidney Dis. 1983;3(3):155-93
  185. 185. Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R. Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function. Antimicrob Agents Chemother. 2017;61(1)
  186. 186. Reading C, Cole M. Clavulanic acid: a beta-lactamase-inhiting beta-lactam from Streptomyces clavuligerus. Antimicrob Agents Chemother. 1977;11(5):852-7
  187. 187. Gin A, Dilay L, Karlowsky JA, Walkty A, Rubinstein E, Zhanel GG. Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination. Expert Rev Anti Infect Ther. 2007;5(3):365-83
  188. 188. Stapleton P, Wu PJ, King A, Shannon K, French G, Phillips I. Incidence and mechanisms of resistance to the combination of amoxicillin and clavulanic acid in Escherichia coli. Antimicrob Agents Chemother. 1995;39(11):2478-83
  189. 189. Dhillon S. Meropenem/Vaborbactam: A Review in Complicated Urinary Tract Infections. Drugs. 2018;78(12):1259-70
  190. 190. Fass RJ, Copelan EA, Brandt JT, Moeschberger ML, Ashton JJ. Platelet-mediated bleeding caused by broad-spectrum penicillins. J Infect Dis. 1987;155(6):1242-8
  191. 191. Arnold DM, Kukaswadia S, Nazi I, Esmail A, Dewar L, Smith JW, et al. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost. 2013;11(1):169-76
  192. 192. Sykes RB, Wells JS, Parker WL, Koster WH, Cimarusti CM. Aztreonam: discovery and development of the monobactams. N J Med. 1986;Spec No:8-15
  193. 193. Jorth P, McLean K, Ratjen A, Secor PR, Bautista GE, Ravishankar S, et al. Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa. mBio. 2017;8(5)
  194. 194. Ramsey C, MacGowan AP. A review of the pharmacokinetics and pharmacodynamics of aztreonam. J Antimicrob Chemother. 2016;71(10):2704-12
  195. 195. Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, et al. Comparative review of the carbapenems. Drugs. 2007;67(7):1027-52
  196. 196. Mori H, Takahashi K, Mizutani T. Interaction between valproic acid and carbapenem antibiotics. Drug Metab Rev. 2007;39(4):647-57
  197. 197. Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Valluzzi R, Gueant JL. Brief communication: tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillins. Ann Intern Med. 2007;146(4):266-9
  198. 198. From AH, Fong JS, Good RA. Polymyxin B sulfate modification of bacterial endotoxin: effects on the development of endotoxin shock in dogs. Infect Immun. 1979;23(3):660-4
  199. 199. Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16(2):161-8
  200. 200. Bergen PJ, Forrest A, Bulitta JB, Tsuji BT, Sidjabat HE, Paterson DL, et al. Clinically relevant plasma concentrations of colistin in combination with imipenem enhance pharmacodynamic activity against multidrug-resistant Pseudomonas aeruginosa at multiple inocula. Antimicrob Agents Chemother. 2011;55(11):5134-42
  201. 201. Sandri AM, Landersdorfer CB, Jacob J, Boniatti MM, Dalarosa MG, Falci DR, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin Infect Dis. 2013;57(4):524-31
  202. 202. Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10(1):R27
  203. 203. Kahan FM, Kahan JS, Cassidy PJ, Kropp H. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci. 1974;235(0):364-86
  204. 204. Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis. 2011;15(11):e732-9
  205. 205. Wenzler E, Ellis-Grosse EJ, Rodvold KA. Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers. Antimicrob Agents Chemother. 2017;61(9)
  206. 206. Paukner S, Riedl R. Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance. Cold Spring Harb Perspect Med. 2017;7(1)
  207. 207. Prince WT, Ivezic-Schoenfeld Z, Lell C, Tack KJ, Novak R, Obermayr F, et al. Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections. Antimicrob Agents Chemother. 2013;57(5):2087-94
  208. 208. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 1998;79(1):3-29
  209. 209. Floss HG, Yu TW. Rifamycin-mode of action, resistance, and biosynthesis. Chem Rev. 2005;105(2):621-32
  210. 210. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb). 2010;90(5):279-92
  211. 211. Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40(5):327-41
  212. 212. Jiang ZD, Ke S, Palazzini E, Riopel L, Dupont H. In vitro activity and fecal concentration of rifaximin after oral administration. Antimicrob Agents Chemother. 2000;44(8):2205-6
  213. 213. Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis. 2000;4(3):256-61
  214. 214. Griffith DE, Brown BA, Girard WM, Wallace RJ, Jr. Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. Clin Infect Dis. 1995;21(3):594-8
  215. 215. Lofmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis. 2010;50 Suppl 1:S16-23
  216. 216. Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283
  217. 217. Norman WV. Metronidazole prophylaxis before surgical abortion: retrospective review of 51 330 cases. J Obstet Gynaecol Can. 2012;34(7):648-52
  218. 218. Cosgrove SE, Vigliani GA, Fowler VG, Jr., Abrutyn E, Corey GR, Levine DP, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis. 2009;48(6):713-21
  219. 219. Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant Vancomycin and Piperacillin/tazobactam. Clin Infect Dis. 2017;64(5):666-74
  220. 220. Wilson AP, Gruneberg RN, Neu H. A critical review of the dosage of teicoplanin in Europe and the USA. Int J Antimicrob Agents. 1994;4 Suppl 1:1-30
  221. 221. Men P, Li HB, Zhai SD, Zhao RS. Association between the AUC0-24/MIC Ratio of Vancomycin and Its Clinical Effectiveness: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(1):e0146224
  222. 222. Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ. Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case-control study. Clin Infect Dis. 2012;54(1):51-8
  223. 223. Britt NS, Potter EM, Patel N, Steed ME. Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients. Clin Infect Dis. 2017;64(5):605-13
  224. 224. Chuang YC, Lin HY, Chen PY, Lin CY, Wang JT, Chen YC, et al. Effect of Daptomycin Dose on the Outcome of Vancomycin-Resistant, Daptomycin-Susceptible Enterococcus faecium Bacteremia. Clin Infect Dis. 2017;64(8):1026-34
  225. 225. Riser MS, Bland CM, Rudisill CN, Bookstaver PB. Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. Ann Pharmacother. 2010;44(11):1832-5
  226. 226. Pertel PE, Bernardo P, Fogarty C, Matthews P, Northland R, Benvenuto M, et al. Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia. Clin Infect Dis. 2008;46(8):1142-51
  227. 227. Delgado G, Jr., Neuhauser MM, Bearden DT, Danziger LH. Quinupristin-dalfopristin: an overview. Pharmacotherapy. 2000;20(12):1469-85
  228. 228. Moellering RC, Jr. The Garrod Lecture. The enterococcus: a classic example of the impact of antimicrobial resistance on therapeutic options. J Antimicrob Chemother. 1991;28(1):1-12
  229. 229. Gilbert DN. Meta-analyses are no longer required for determining the efficacy of single daily dosing of aminoglycosides. Clin Infect Dis. 1997;24(5):816-9
  230. 230. Wong J, Brown G. Does once-daily dosing of aminoglycosides affect neuromuscular function? J Clin Pharm Ther. 1996;21(6):407-11
  231. 231. Zabner R, Quinn JP. Antimicrobials in cystic fibrosis: emergence of resistance and implications for treatment. Semin Respir Infect. 1992;7(3):210-7
  232. 232. de Groot R, Smith AL. Antibiotic pharmacokinetics in cystic fibrosis. Differences and clinical significance. Clin Pharmacokinet. 1987;13(4):228-53
  233. 233. Ghannam DE, Rodriguez GH, Raad, II, Safdar A. Inhaled aminoglycosides in cancer patients with ventilator-associated Gram-negative bacterial pneumonia: safety and feasibility in the era of escalating drug resistance. Eur J Clin Microbiol Infect Dis. 2009;28(3):253-9
  234. 234. Landman D, Kelly P, Backer M, Babu E, Shah N, Bratu S, et al. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob Chemother. 2011;66(2):332-4
  235. 235. Zagursky RJ, Pichichero ME. Cross-reactivity in beta-Lactam Allergy. J Allergy Clin Immunol Pract. 2018;6(1):72-81 e1
  236. 236. Paul M, Yahav D, Fraser A, Leibovici L. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2006;57(2):176-89
  237. 237. Kim PW, Wu YT, Cooper C, Rochester G, Valappil T, Wang Y, et al. Meta-analysis of a possible signal of increased mortality associated with cefepime use. Clin Infect Dis. 2010;51(4):381-9
  238. 238. Tamma PD, Rodriguez-Bano J. The Use of Noncarbapenem beta-Lactams for the Treatment of Extended-Spectrum beta-Lactamase Infections. Clin Infect Dis. 2017;64(7):972-80
  239. 239. Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017;23(10):704-12
  240. 240. Rodriguez-Bano J, Navarro MD, Retamar P, Picon E, Pascual A, Extended-Spectrum Beta-Lactamases-Red Espanola de Investigacion en Patologia Infecciosa/Grupo de Estudio de Infeccion Hospitalaria G. beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012;54(2):167-74
  241. 241. Tamma PD, Han JH, Rock C, Harris AD, Lautenbach E, Hsu AJ, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum beta-lactamase bacteremia. Clin Infect Dis. 2015;60(9):1319-25
  242. 242. Trias J, Nikaido H. Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1990;34(1):52-7
  243. 243. Davies TA, Marie Queenan A, Morrow BJ, Shang W, Amsler K, He W, et al. Longitudinal survey of carbapenem resistance and resistance mechanisms in Enterobacteriaceae and non-fermenters from the USA in 2007-09. J Antimicrob Chemother. 2011;66(10):2298-307
  244. 244. Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-98
  245. 245. Oliveira MS, Prado GV, Costa SF, Grinbaum RS, Levin AS. Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother. 2008;61(6):1369-75
  246. 246. Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother. 2017;61(8)
  247. 247. Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis. 2000;31 Suppl 4:S131-8
  248. 248. Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-55
  249. 249. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552
  250. 250. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014;77:3-11
  251. 251. Beumier M, Casu GS, Hites M, Wolff F, Cotton F, Vincent JL, et al. Elevated beta-lactam concentrations associated with neurological deterioration in ICU septic patients. Minerva Anestesiol. 2015;81(5):497-506
  252. 252. Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediatr. 1986;108(5 Pt 2):835-40
  253. 253. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49(1):1-16
  254. 254. American Thoracic S, Infectious Diseases Society of A. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416
  255. 255. Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin Infect Dis. 2011;52(10):1232-40
  256. 256. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111
  257. 257. Burke JP, Pestotnik SL. Antibiotic use and microbial resistance in intensive care units: impact of computer-assisted decision support. J Chemother. 1999;11(6):530-5

Written By

Sachin M. Patil and Parag Patel

Submitted: March 9th, 2021 Published: August 31st, 2021