Treatment of Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a Priority 1 pathogen under the WHO list for research and discovery of new antibiotics. The epidemiology of the pathogen suggests its relevance as an important “healthcare-associated” pathogen—with the most common clinical syndrome being ventilator-associated pneumonia. Rising rates of carbapenem resistance in this pathogen have necessitated re-purposing of old drugs, use of high-dose regimens, and newer antimicrobial options. Combination therapy for carbapenem-resistant isolates, especially in sicker patients, is now advocated. Here, we describe the traditional treatment options and selection of drugs in multidrug- resistant infections, along with a brief review of the evidence followed by emerging treatment options.

1. Introduction

Acinetobacter baumannii has established itself as an important pathogen over the years, especially in the critical care settings. Often, it has been a pathogen of “intensive care unit (ICU) outbreaks” and a major pathogen for ventilator-associated pneumonia. The varied resistance mechanisms and its potential for environmental persistence have ensured its position as Priority 1 pathogen in the World Health Organization (WHO) list [1]. This necessitates a deeper understanding of the available treatment options, selection of drugs in combination therapy, and emerging treatment options so that we can offer the best chance of survival in the critically ill.

2. Empiric therapy for A. baumannii infections

Choosing an empirical cover that includes A. baumannii infections depends on various factors, such as the local epidemiology and risk factors in patients, such as mechanical ventilation or long-term hospitalization. An appropriate empiric cover can slash down mortality rates, especially in critical care [2, 3, 4]. Addition of antibiotics that cover for carbapenem-resistant Acinetobacter baumannii (CRAB) in areas, where there is a higher incidence is recommended [5].

2.1 Epidemiology and local antibiogram

The incidence of A. baumannii infection outbreaks can be related to the carbapenem resistance rates of the area. Recent data from a global study on A. baumannii has shown around 65% resistance rates to meropenem among clinical isolates [6]. The distribution of CRAB and multidrug-resistant (MDR) Acinetobacter varies between regions in the world, with lower rates in the United States and Central Europe to higher rates in Asia and Africa [7, 8, 9]. Within the European subcontinent, the incidence varies as Central Asian and European surveillance of antimicrobial resistance (CAESAR) and European Center for Disease Prevention and Control (ECDC) surveillance report more than 50% of invasive isolates of A. baumannii to be carbapenem resistant from Southern and Eastern Europe [10, 11].

A delay in initiation of appropriate antimicrobial therapy can affect the clinical outcome in patients with A. baumannii infections, which can be tackled with the help of a hospital-based antibiogram [12, 13, 14]. An antibiogram based on overall susceptibility patterns distributed over location and time can suitably guide a clinician in the timely choice of empiric antibiotic [15].

2.2 Risk factors for infection

In high endemic areas of CRAB, certain risk factors can prompt empirical coverage for the same. The most common risk factors include critically ill, prolonged mechanical ventilation, length of hospital or ICU stay, long-term care facility inmates, and previously colonized patients [16, 17, 18]. The predilection for colonization in healthcare settings can be explained by the ability of the bacteria to survive in dry surfaces and biofilm production on medical devices, particularly endotracheal tubes. Other risk factors, including malignancy, previous antibiotic use, and re-intubation, among which prior use of antimicrobials, including third-generation cephalosporins and fluoroquinolones, are strong predictors [2, 18].

Multidrug-resistant organism (MDRO) screening or surveillance culture reports are seldom performed in regions with higher prevalence and reported to have lower sensitivity with limited sites of sampling [19]. Treatment or decolonization for MDR Gram-negative organisms based on surveillance sampling is disapproved by many organizations and is only implicated as an infection control measure [20, 21].

Even though nosocomial infection is the dominant picture among Acinetobacter infections, community-acquired infections rarely occur more often in tropical climates, presenting commonly as pneumonia [22, 23, 24]. Fulminant infections associated with a high mortality of 64% have also been reported in the Asia-Pacific region [25]. These strains are infrequently resistant to antibiotics but will not be covered by the usual community-acquired pneumonia (CAP) cover, such as ceftriaxone [23, 26].

2.3 Site of infection

Acinetobacter infections can occur in any organ system, with the majority in respiratory tracts causing ventilator-associated pneumonia (VAP) or hospital-acquired pneumonia (HAP). The incidence of VAP varies with the endemicity in a region, comprising an overall incidence rate of 3–7% of VAP/HAP globally, this increases to a maximum of 36% in Asian countries [27, 28, 29]. Secondary infections associated with COVID-19 pneumonia are also being reported worldwide [30, 31, 32]. Bacteremia and urinary tract infection (UTI) follows, associated with indwelling catheters and immunocompromised conditions [29]. In post-neurosurgical patients with or without intraventricular catheters, A. baumannii can cause meningitis, leading to a 70% overall mortality [33, 34]. Skin and soft tissue infections of injuries associated with war and natural disasters reportedly caused by pan-drug isolates and can complicate orthopedic infections [35, 36, 37].

2.4 Resistance patterns

Most strains have intrinsic beta-lactamases, providing resistance to penicillin and older generations of cephalosporins. Extended-spectrum beta-lactamases are predominant in many regions, influencing carbapenem over-use, and subsequently breeding multidrug-resistant isolates.

Carbapenem resistance in CRAB is driven chiefly by carbapenemases of classes B (metallo-beta-lactamases) and D (oxacillinases) for which non-beta-lactam choices, such as polymyxins and tetracycline are recommended. Resistance to tigecycline is less compared to minocycline, with most CRAB isolates remaining susceptible and hence can be a good companion drug. Aminoglycoside and fluoroquinolone resistance are common and involve efflux pumps or target modification, conferring high level of resistance to these agents.

Hetero resistance is when subpopulations within a susceptible isolate are resistant but determined as sensitive by standard antimicrobial susceptibility testing (AST) methods, which can lead to clinical failure. This is often seen in cases with previous therapy using colistin and that can possibly be prevented by combination therapy [38, 39, 40].

2.5 Choice of empiric therapy

Based on above conditions, an assessment for the need for anti-Acinetobacter cover should be determined as the appropriate and timely initiation of antimicrobial therapy in serious infections is crucial. Also, inappropriate or inadequate empirical antimicrobial choice can lead to increased length of stay, as well as hospital costs [12, 41]. In ICU settings with lower prevalence of CRAB, carbapenems are the drugs of choice. Ertapenem should be avoided as it only has weak action against Acinetobacter spp. Combination therapy can be considered in critically ill based on local susceptibility patterns. For mild infections, particularly UTI, monotherapy with cephalosporins or aminoglycosides is a good option with close monitoring of the patient [42].

When there is a higher suspicion of carbapenem resistance, polymyxin-based combination therapy is recommended as empirical therapy. The companion drugs being tetracyclines (tigecycline or minocycline) or sulbactam. Sulbactam in combination with ampicillin and most recently durlobactam has risen as the drug of choice for CRAB infections, but caution is advised for empiric indications due to mounting resistance [5, 43]. The pulmonary endothelial lining fluid (ELF) concentrations are lower for tigecycline with usual dosing for CRAB and are associated with a higher chance for resistance development, hence monotherapy should be avoided [5, 18, 44].

If a second episode of suspected infection occurs when the patient is on an antibiotic for a different infection, it is suggested to choose a different class of antibiotic due to a higher chance of resistance to the ongoing antibiotic [45].

3. Targeted therapy for A. baumannii infections

De-escalation or targeting the therapy based on microbiological culture is the recommended step to be taken when culture reports are available as this move can bring in reduction of drug toxicity, unnecessary cost, and prevent antibiotic-associated diarrhea or Clostridium difficile infections.

3.1 Colonizers vs. pathogenic A. baumannii

Acinetobacter baumannii is acquired through the hospital environment from surfaces and hands of healthcare workers. It commonly colonizes the respiratory tract, skin, and any indwelling catheters of a patient. Hence, sampling can often detect such colonizing organisms, which need to be differentiated from infection. The task becomes more perplexing yet key in immunocompromised or severely ill [46]. This is more relevant in CRAB isolates as differentiating plays a decisive role on need for expensive and restricted antimicrobial agents for treatment.

Clinical, radiological, and laboratory parameters can aid in differentiating colonization from infection. When isolated from sterile sites, such as blood culture or cerebrospinal fluid culture, treatment is mandatory. Treatment includes both the removal of indwelling catheter if present and appropriate antimicrobial. Antibiotics are not recommended when the culture is positive from a non-sterile site from a patient with no signs of infection. Parameters that help in diagnosing infection by A. baumannii are admission to ICU, number of days of hospitalization, absolute neutrophil count (ANC), and C-reactive protein (CRP) according to two prospective cohort studies [47, 48]. Clinical-pulmonary infection score (CPIS) score developed for diagnosing VAP using fever, endotracheal tube (ET) secretions, leukocytosis, PaO2/FiO2, chest radiographic picture, and isolation of pathogenic bacteria in culture is ideally used for determining the need for bronchoalveolar lavage (BAL) but can also confirm the presence of pneumonia and relevance of culture.

3.2 Non-carbapenem-resistant A. baumannii

3.2.1 Beta lactams

Most clinical isolates have intrinsic beta-lactamase production that lyses penicillin and first-generation cephalosporins. If susceptible to penicillin, these agents are the drugs of choice for Acinetobacter infections, including third-generation cephalosporins. In the presence of extended-spectrum Beta-lactamase (ESBLs) and Acinetobacter-derived cephalosporins (ADCs), carbapenems become the agent of choice, with ertapenem having a weak activity against Acinetobacter spp [49]. These agents are ideal for its bactericidal action and good pharmacotherapeutic properties.

3.2.2 Beta-lactamase inhibitors

All beta-lactamase inhibitors, such as clavulanate and tazobactam, have intrinsic activity against Acinetobacter, but sulbactam has the better activity among them [50]. For sensitive isolates with MIC <4 mg/L, sulbactam at a lower dose of 4 grams per day is sufficient to be infused in 350 ml normal saline over 4 hours. Most commonly, this is available as the formulation of ampicillin sulbactam or cefoperazone sulbactam. There is a rising MIC trend for sulbactam that impedes its use as empiric therapy or monotherapy for severe infections [43].

3.2.3 Aminoglycosides

Amikacin and tobramycin are the most active agents in the group. These agents have low lung and CSF penetration with high toxicity profiles. With higher chances of bacteriological failures and dosing concerns in critically ill, aminoglycosides are not recommended as monotherapy except for urinary tract infections, where they reach in very high concentrations [51, 52]. Amikacin and gentamicin can be administered intrathecally or intraventricular for CRAB meningitis or ventriculitis.

3.2.4 Quinolones

Susceptibility to these agents is lower, and thus is less commonly used in the treatment of these infections. Due to its good pharmacotherapeutic properties and oral bioavailability, quinolones are a good option if susceptible. Resistance to these agents arises along with other antimicrobials with multiple mechanisms mainly arising with mutations in gyrA and parC genes.

3.3 Carbapenem-resistant A. baumannii

Most A. baumannii infections are caused by carbapenem-resistant strains in nosocomial settings due to the capacity of the organism to acquire resistance genes and its resilience in the hospital environment. Mortality associated with MDR A. baumanii strains is higher than in susceptible organisms [53].

3.3.1 Sulbactam

A penicillanic acid derivative that has intrinsic activity against Acinetobacter by saturating PBPs 1, 2, and 3, especially with higher doses [54]. The beta-lactamases produced by CRAB can lyse sulbactam, which is observed in vitro and reflected in the international surveillance systems, such as The Clinical and Laboratory Standards Institute (CLSI) [55]. But this was not observed in clinical trials, where sulbactam activity is intact even for MIC>16 mg/L, when given as 9 gram/day dosing over 4 hours infusion [56]. At this dose, sulbactam overcomes resistance by Oxa-23 beta-lactamases and has shown effectiveness more with meropenem [42, 57, 58]. At lower MICs of sulbactam, lower doses of 1 g sulbactam every fourth to sixth hourly should be enough. Ampicillin sulbactam is the commonest formulation available for sulbactam with 2:1 ratio of ampicillin to sulbactam that is recommended by Infectious diseases society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines [59, 60]. For mild invasive CRAB infections, monotherapy with ampicillin sulbactam is the treatment of choice and is given as 27 g per day dosing over 4 hours [59].

When compared to colistin, previously, the first choice for CRAB infections, sulbactam has better kinetics and lesser nephrotoxicity, thus showing improved clinical outcomes in research [61, 62, 63]. This brought sulbactam to the limelight, even with conflicting issues on standardized susceptibility testing for CRAB isolates and studies showing lower mortality with colistin therapy [64]. High doses of sulbactam can be associated with hepatotoxicity, and it is suggested to monitor LFT while on therapy. The resistance to sulbactam arises through reduced expression of PBP 2 and increased TEM-1 expression [65, 66]. Hence, it warrants monitoring for resistance development and the use of combination therapy for severe and complicated infections.

3.3.2 Polymyxins

Polymyxins are polypeptide cationic antibiotics comprised of polymyxin B and E (colistin). Colistin is the most widely used form worldwide, which is available in its prodrug form as colistimethate (CMS). Polymyxins were once considered the main backbone for CRAB infections but were replaced by sulbactam in the recent IDSA and ESCMID guidance documents. Current recommendations by IDSA recommend polymyxin B as the preferred form except in UTI and to be given in combination with other agents according to susceptibility patterns [59]. Due to a high risk of nephrotoxicity with colistin [63] and the poor ELF concentrations in critically ill, polymyxin B is the preferred choice except in UTI, where colistin achieves better concentrations.

Dosing of polymyxin B is body weight based with a loading dose and given when MIC is less than 2 mg/L for CRAB isolates. A loading dose of colistin, which is needed to achieve target plasma concentration, has been shown to increase mortality when administered to critically ill patients with CRAB infections [67, 68]. Resistance develops by modification of LPS, the target site of polymyxin action, through plasmid acquired resistance genes. Intrathecal colistin and polymyxin B can be administered for CRAB meningitis or ventriculitis with systemic antimicrobial. The dosing varies for both polymyxins ranging from 20,000 IU to 250,000 IU per day for polymyxin B to 5–20 mg per day for colistin [34, 69, 70].

3.3.3 Tetracyclines

Minocycline and tigecycline are active against CRAB even when other tetracyclines are found resistant, with tigecycline having a more than 90% susceptibility among CRAB isolates based on a countrywide surveillance in Europe [43]. Due to its bactericidal nature and unclear pharmacokinetics, both are suggested to be given in combination therapy for CRAB treatment. Minocycline is available both orally and parentally, whereas tigecycline is available only as IV formulation.

The breakpoint for tigecycline in CRAB is not recommended by CLSI or EUCAST and a (food and drug administration) FDA approved clinical breakpoint of 2 mg/l for Enterobacterales is adopted. With MIC <2 mg/l, combination therapy has shown benefit, even though earlier studies have shown higher all-cause mortality in the critically ill [71, 72, 73, 74]. These studies have focused mostly on bacteremia and pneumonia, where tigecycline concentrations are very low, that is. plasma and ELF concentrations, respectively. A higher dose of tigecycline with 200 mg of loading dose followed by 100 mg twice daily doses depicts a better outcome in MDR GNB infections [75, 76] and is recommended. The PK parameters for minocycline were achieved better for CRAB pneumonia with higher doses of 200 mg twice daily [77].

3.4 Monotherapy vs. combination therapy

The rationale for combination therapy is built on the concept of various in vitro synergism, pharmacotherapeutic advantage of overcoming the poor pharmacodynamics of individual agents, unfavorable clinical outcomes of invasive CRAB infections, and the higher possibility in prevention of emerging resistance [78, 79].

Several studies demonstrate better clinical cure with combination therapies, most often containing colistin and others have shown higher microbiological cure rates. A Bayesian analysis that included 23 studies compared colistin monotherapy with combination regimens, which depicted sulbactam to have the highest survival benefit among critically ill [71].

3.4.1 Colistin with meropenem

This was an advocated as a common modality earlier based on in vitro experiments indicating synergy and reduced bacterial growth with the combination [80]. But disproved clinically, by two randomized control trials in ICU patients that showed no difference between the clinical cure rate or 28–day mortality rates between colistin monotherapy and colistin with meropenem combination [81, 82]. The in vitro benefits could not be translated clinically with these studies as colistin levels in ELF are lower, especially in the critically ill, and the isolates in these studies had a high level of carbapenem resistance [79].

3.4.2 Three-drug combination

With the addition of ampicillin sulbactam to the above combination, the results show significant improvement in terms of 30-day mortality also, with one of the recent study reporting on a likely suppression of resistance emergence among COVID-19 patients with CRAB infections [83, 84]. Another triple therapy consisting of colistin, tigecycline, and sulbactam showed the highest clinical cure rate among various treatment options for MDR and extremely drug-resistant (XDR) A. baumannii infections [64]. Thus, triple therapy is a suggested approach for extremely resistant CRAB than other dual combinations [78, 79].

3.4.3 Polymyxin-based combination therapy

The main researched combinations included colistin combinations with either sulbactam, tigecycline, fosfomycin, or rifampicin, which have mixed evidence in terms of clinical cure and microbiological cure. A meta-analysis on 29 studies consisting of over 2000 patients revealed a higher microbiological cure for the sulbactam—colistin combination when compared to colistin with tigecycline or colistin alone [64]. In vitro synergy testing by checkerboard method and time-kill analysis indicates the highest synergy between minocycline and colistin [85, 86]. Whereas, colistin with tigecycline showed an antagonism, but such inhibition is absent in clinical trials, where it has shown better microbiological cure rates but not improved mortality benefits [72, 87, 88].

Combinations with rifampicin and fosfomycin have a good microbiological response even within 72 hours of therapy, but there is no evidence of significant difference in mortality from monotherapy [89, 90]. The combination of rifampicin and tigecycline with colistin, respectively, has a good anti-biofilm action that can be used effectively for antibiotic lock therapy [91, 92]. Notably, most studies on polymyxin combinations included colistin and nephrotoxicity was an associated adverse drug event (ADE), and this ADE could have been easily avoided with the use of polymyxin B, an active form of colistin, which not only has a lower risk of nephrotoxicity but also has better steady-state concentrations in plasma. Only few studies based on polymyxin B have been conducted and a combination with this agent is preferred with reduced mortality among critically ill [59, 60, 93, 94].

3.4.4 Sulbactam combination therapies

Sulbactam combinations are the mainstay for moderate to severe invasive CRAB infections, as stated by the latest IDSA AMR guidance document and endorsed by the ESCMID 2022 guidelines. Combination of high-dose sulbactam with tigecycline and quinolone has shown the best clinical outcome, but the numbers are less compared to colistin-based regimens [95, 96]. There is a need for focus on research of such combination therapy for the better understanding of dosing and efficacy in critically ill.

3.4.5 Other combinations

Strong synergy exists between cefiderocol and meropenem as shown by an in vitro study but has not been clinically evaluated [97]. Combination of colistin with glycopeptides has been studied, but combination with vancomycin has shown high nephrotoxicity [98, 99]. Such combinations do not have enough supporting data and is to be avoided.

However, failure with combination therapy has been shown in patients with sepsis. A metanalysis on drug-resistant A. baumannii showed only three studies to depict a superiority of combination vs. monotherapy from a total of 12 studies. The concern with combination therapy arises with the associated increased cost and toxicity from multiple antimicrobial agents used. The risk of C. difficile can also increase when inciting antibiotics are given for treatment [78]. Thus, de-escalation to susceptible agents based on culture reports when available is advised in mild cases of invasive CRAB infections [5, 59].

3.5 Role of inhaled antimicrobials

Aminoglycosides and colistin are often nebulized for patients with MDR gram-negative bacterial (GNB) VAP or tracheobronchitis. The role of nebulized antibiotics is controversial, with IDSA against its administration with or without IV antimicrobials. Studies using high dose (5 million units twice daily) colistin with vibrating nebulizer along with intravenous (IV) antimicrobial agent have shown benefits [100]. For tracheobronchitis and when susceptible in non-resolving cases of CRAB pneumonia, nebulization can be attempted as an adjunctive therapy (Figure 1).

Figure 1.

Algorithm for treatment of invasive CRAB infections based on IDSA/ESCMID guidelines. ^*Ampicillin sulbactam is the current fixed drug combination that is available widely.

3.6 Duration of therapy

There is a lack of consensus for specific duration for MDR infections and in particular CRAB. Studies on patients with MDR infections with VAP and BSI have used a range of 7–22 days of therapy [101, 102, 103]. RCT and prospective studies on VAP have shown no difference in mortality with shorter courses of 3–8 days [104, 105, 106]. But few studies show an occurrence of relapses in few patients following short courses for gram-negative pathogens are of concern according to some [106, 107].

Duration of empiric therapy for CRAB, where cultures are negative or limited resources for diagnostics, should be based on site and severity of infection and discontinued if an alternative diagnosis is confirmed. For carbapenem-sensitive AB infection therapy, duration is based on site and severity of infection and longer duration of therapy required for meningitis and joint infections. Whereas, a longer duration is suggested for severe CRAB infections with a minimum of 14 days of therapy and even longer, up to 4 to 8 weeks in the presence of complicated infections, such as post-neurosurgical meningitis/ventriculitis or joint infections. In meningitis or ventriculitis, the duration of intraventricular antimicrobial will depend on three negative CSF samples according to the IDSA recommendations [108].

4. Novel treatment strategies

4.1 Newer antimicrobial agents

Antimicrobial options are limited for treatment of CRAB, with resistance developing rapidly in the organism. Newer options are sought to overcome the glitches in the treatment options that are available currently such as toxicity, pharmacokinetic issues, emergence of resistance, and availability.

4.1.1 Cefiderocol

A siderophore cephalosporin with a wide range of beta-lactamase resistance, and hence suggested for CRE, CRPA, and CRAB. The FDA approved its use in complicated UTI, including pyelonephritis and hospital-acquired pneumonia. In spite of the promising in vitro actions of the drug, two large studies found no significant difference in mortality compared to colistin-based therapies for CRAB [109, 110, 111] and higher mortality rates with monotherapy [112]. Also, the Italian study discovered four out of eight isolates from microbiologically failed cases to be cefiderocol resistant [109]. This led the IDSA to suggest cefiderocol as a last resort and only to be given as combination therapy for CRAB infections [59].

4.1.2 Durlobactam: Sulbactam

This is the most recently FDA-approved agent for treatment of CRAB pneumonia [113]. Durlobactam is a next generation diazabicyclooctanone (DBO) beta-lactamase inhibitor that is resistant to lyses by Class A, C, and D oxacillinases. Combined with sulbactam, it potentiates the action of sulbactam against CRAB up to 32-fold of MIC [55]. A phase three trials on CRAB pneumonia patients on either sulbactam durlobactam or colistin with a combination agent showed non-inferiority in terms of 28-day mortality and lower adverse events [114].

4.1.3 Eravacycline

A novel synthetic fluorocycline, such as tigecycline, displays good in vitro action against MDR pathogens, including GNB and GPC microorganisms. It has a lower MIC in CRAB than tigecycline or minocycline with reliable in vitro activity against oxacillinases and colistin-resistant isolates [115]. Nevertheless, the clinical trials on UTI and IAI show non-inferiority of the drug when compared to inactive agents, such as carbapenems and quinolones [116, 117, 118]. The proportion of CRAB infections in these studies is very low, and thus, we will need more research on its in vivo action on CRAB.

Omadacycline and plazomicin are some other new agents that are active on CRAB isolates. A newer tetracycline, Omadacycline, has a spectrum of activity similar to minocycline and has action against CRAB isolates [119, 120]. Whereas, plazomicin is a next generation aminoglycoside with extended spectrum, including CRAB. This drug is approved by FDA for the treatment of carbapenem-resistant Enterobacterales but has shown promising activity against CRAB, including in combination with other drugs [121, 122].

4.2 Other therapeutic options

Bacteriophage, antimicrobial peptides (AMP), immunotherapy, monoclonal antibodies, and endolysin are some of the potential non-antimicrobial agents that are being extensively researched [123]. Phage-related therapy is unique in the sense that it is highly specific to the targeted pathogens and have lesser toxicity. But the clinical efficacy associated with such therapies are yet to be demonstrated. Phage SH-Ab15519 and Acinetobacter phage Βϕ-R2096 are novel Acinetobacter phages, which are considered safe based on genomic studies [124, 125]. Phage-antibiotic combinations based on a phenomenon termed phage-antibiotic synergy has been exhibited in A. baumannii on colistin MIC [126] and also depicted in human trial [127]. AMP formed from other living organisms as part of their innate immune mechanisms can be used against infections as an adjunctive therapy. This has an advantage of lower chances of resistance development [128].

5. Conclusion

Acinetobacter baumannii remains a “high priority” pathogen and of great clinical significance, especially in the critically ill ICU patient. With a significant proportion of the isolates demonstrating resistance to traditional “drugs of choice,” such as carbapenems, we have moved on to repurposed older drugs—polymyxins and high-dose Sulbactam—as primary drugs for treating serious infections. Tetracyclines—old tigecycline, minocycline at “double dose” and new (Eravacycline and Omadacycline) have been the next plausible treatment options. We also fall back upon combination therapy with older drugs/with or without the newer options for pan-drug-resistant isolates. Drugs, such as cefiderocol and sulbactam-durlobactam, hold promise for the future. However, the identification or differentiation of a patient colonized with Acinetobacter baumannii versus true invasive infection/disease constitutes the most important treatment decision.

Conflict of interest

The authors declare no conflict of interest.

Appendices and nomenclature

ADC	Acinetobacter-derived cephalosporinases
ADE	adverse drug event
ANC	absolute neutrophil count
AMR	antimicrobial resistance
BSI	infection
CAESAR	Central Asian and European surveillance of antimicrobial resistance
CPIS	clinical-pulmonary infection score
CRAB	carbapenem-resistant Acinetobacter baumannii
CRE	carbapenem-resistant enterobacterales
CRP	C-reactive protein
CRPA	carbapenem-resistant pseudomonas aeruginosa
CSF	cerebrospinal fluid
CLSI	The clinical and laboratory standards institute
ECDC	European centre for disease prevention and control
ELF	endothelial lung fluid
ESBL	extended spectrum Beta-lactamase
ESCMID	European society of clinical microbiology and infectious diseases
ET	endotracheal secretions
EUCAST	European society of clinical microbiology and infectious diseases
FDA	food and drug administration
FiO2	fraction of inspired oxygen
HAP	hospital-acquired pneumonia
ICU	intensive care unit
IDSA	infectious diseases society of America
IV	intravenous
LFT	liver function test
LPS	lipopolysaccharide
MDR	multidrug resistant
MDRO	multidrug-resistant organism
MIC	minimum inhibitory concentration
PaO2	partial pressure of oxygen in arterial blood
PBP	penicillin-binding protein
PK	pharmacokinetic
RCT	randomized controlled trial
TEM	Class A beta-lactamase first isolated from a patient called Temoneira
UTI	urinary tract infection
VAP	ventilator-associated pneumonia
XDR	extremely drug resistant