Empirical antibiotic treatment of HAP with MDRO.
Chapter 1: "Permanent Maxillary and Mandibular Incisors"\n
Chapter 2: "The Permanent Maxillary and Mandibular Premolar Teeth"\n
Chapter 3: "Dental Anatomical Features and Caries: A Relationship to be Investigated"\n
Chapter 4: "Anatomy Applied to Block Anaesthesia"\n
Chapter 5: "Treatment Considerations for Missing Teeth"\n
Chapter 6: "Anatomical and Functional Restoration of the Compromised Occlusion: From Theory to Materials"\n
Chapter 7: "Evaluation of the Anatomy of the Lower First Premolar"\n
Chapter 8: "A Comparative Study of the Validity and Reproducibility of Mesiodistal Tooth Size and Dental Arch with the iTero Intraoral Scanner and the Traditional Method"\n
Chapter 9: "Identification of Lower Central Incisors"\n
The book is aimed toward dentists and can also be well used in education and research.',isbn:"978-1-78923-511-1",printIsbn:"978-1-78923-510-4",pdfIsbn:"978-1-83881-247-8",doi:"10.5772/65542",price:119,priceEur:129,priceUsd:155,slug:"dental-anatomy",numberOfPages:204,isOpenForSubmission:!1,isInWos:null,hash:"445cd419d97f339f2b6514c742e6b050",bookSignature:"Bağdagül Helvacioğlu Kivanç",publishedDate:"August 1st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/5814.jpg",numberOfDownloads:7224,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:3,hasAltmetrics:0,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2016",dateEndSecondStepPublish:"October 25th 2016",dateEndThirdStepPublish:"July 16th 2017",dateEndFourthStepPublish:"August 16th 2017",dateEndFifthStepPublish:"October 16th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"178570",title:"Dr.",name:"Bağdagül",middleName:null,surname:"Helvacıoğlu Kıvanç",slug:"bagdagul-helvacioglu-kivanc",fullName:"Bağdagül Helvacıoğlu Kıvanç",profilePictureURL:"https://mts.intechopen.com/storage/users/178570/images/7646_n.jpg",biography:"Bağdagül Helvacıoğlu Kıvanç is a dentist, a teacher, a researcher and a scientist in the field of Endodontics. She was born in Zonguldak, Turkey, on February 14, 1974; she is married and has two children. She graduated in 1997 from the Ankara University, Faculty of Dentistry, Ankara, Turkey. She aquired her PhD in 2004 from the Gazi University, Faculty of Dentistry, Department of Endodontics, Ankara, Turkey, and she is still an associate professor at the same department. She has published numerous articles and a book chapter in the areas of Operative Dentistry, Esthetic Dentistry and Endodontics. She is a member of Turkish Endodontic Society and European Endodontic Society.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"174",title:"Dentistry",slug:"dentistry"}],chapters:[{id:"56461",title:"Permanent Maxillary and Mandibular Incisors",doi:"10.5772/intechopen.69542",slug:"permanent-maxillary-and-mandibular-incisors",totalDownloads:1475,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Mohammed E. Grawish, Lamyaa M. Grawish and Hala M. 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\r\n\tNeuroblastoma is a complex genetic pediatric malignancy arising from the peripheral nervous system and affects infants and young children with a low survival rate. The source of neuroblastoma is from neural crest cells and the tumor has heterogeneous biological, morphological, genetic, and clinical presentations. There is a significant increase in our understanding of the genetic determinants and molecular events that predispose to the formation of neuroblastoma. Understanding of genetic basis of neuroblastoma has helped us to understand the molecular events which drive tumorigenesis, develop novel therapeutic strategies, and also to precisely stratifying the risk and to interpret the prognosis. This information facilitates identifying the high-risk patients who may get benefitted from combination chemotherapy before surgery or many adjuvant management options (autologous stem cell transplantation, local radiation, or immunotherapy).
\r\n\r\n\tThe present book shall try to bring the researchers together to describe various characteristics of neuroblastomas including biological characteristics, various molecular markers, clinal behavior, imaging characteristics, management strategies including the role of modern immunotherapy, outcomes in these patients, and future scope of the research.
",isbn:"978-1-83969-051-8",printIsbn:"978-1-83969-050-1",pdfIsbn:"978-1-83969-052-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"1508e958926b0a4ce958fda35fba8cbc",bookSignature:"Prof. Amit Agrawal",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10340.jpg",keywords:"Genetic Susceptibility, Spontaneous Regression, Neuroblastoma, Metastasis Neuroblastoma, Neuroblastoma Origin, Neuroblastoma Imaging, Neuroblastoma Immunotherapy, Neuroblastoma Pathogenesis, Tumour Microenvironment Neuroblastoma, Neuroblastoma Immuno-Oncology, Radiotherapy, Adjuvant Therapy",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 7th 2020",dateEndSecondStepPublish:"November 16th 2020",dateEndThirdStepPublish:"January 15th 2021",dateEndFourthStepPublish:"April 5th 2021",dateEndFifthStepPublish:"June 4th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Agrawal is a self-motivated, enthusiastic, and results-oriented professional with more than 16 years of rich experience in research and development, as well as teaching and mentoring in the field of neurosurgery. He has published more than 750 articles in the medical field covering various topics in several national and international journals.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"100142",title:"Prof.",name:"Amit",middleName:null,surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal",profilePictureURL:"https://mts.intechopen.com/storage/users/100142/images/system/100142.jfif",biography:"Dr. Amit Agrawal completed his neurosurgery training from the National Institute of Mental Health and Neurosciences, Bangalore, India, in 2003. Dr. Agrawal is a self-motivated, enthusiastic, and results-oriented professional with more than 16 years of rich experience in research and development, as well as teaching and mentoring in the field of neurosurgery. He is proficient in managing and leading teams for running successful process operations and has experience in developing procedures and service standards of excellence. He has attended and participated in many international- and national-level symposiums and conferences, and delivered lectures on vivid topics. He has published more than 750 articles in the medical field covering various topics in several national and international journals. His expertise is in identifying training needs, designing training modules, and executing the same while working with limited resources. He has excellent communication, presentation, and interpersonal skills with proven abilities in teaching and training for various academic and professional courses. Presently, he is working at the All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India.",institutionString:"All India Institute of Medical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"5",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"184402",firstName:"Romina",lastName:"Rovan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/184402/images/4747_n.jpg",email:"romina.r@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"563",title:"Brain Injury",subtitle:"Pathogenesis, Monitoring, Recovery and Management",isOpenForSubmission:!1,hash:"6e40d2cf6eebee2041b76a70987f4258",slug:"brain-injury-pathogenesis-monitoring-recovery-and-management",bookSignature:"Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/563.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2034",title:"Brain Injury",subtitle:"Functional Aspects, Rehabilitation and Prevention",isOpenForSubmission:!1,hash:"97fb870ccfe237f3270c3ae1b7a7dacd",slug:"brain-injury-functional-aspects-rehabilitation-and-prevention",bookSignature:"Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/2034.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5261",title:"Neurooncology",subtitle:"Newer Developments",isOpenForSubmission:!1,hash:"ae1dcb26219bb62290c5a171c87d6936",slug:"neurooncology-newer-developments",bookSignature:"Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/5261.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6503",title:"Brain Tumors",subtitle:"An Update",isOpenForSubmission:!1,hash:"055b45888e92391890d4992da9e8a4c3",slug:"brain-tumors-an-update",bookSignature:"Amit Agrawal, Luis Rafael Moscote-Salazar",coverURL:"https://cdn.intechopen.com/books/images_new/6503.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5517",title:"Hemorrhagic Stroke",subtitle:"An Update",isOpenForSubmission:!1,hash:"33690ae286c58afffac09491a13b3a29",slug:"hemorrhagic-stroke-an-update",bookSignature:"Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/5517.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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In particular, intensive care units (ICUs) are confronted with increasing number of patients with marked co-morbidities, severe acute pathology or immune suppression, and intrinsic infectious risk factors. Additionally, given the pathogenicity changes of potentially hospital-acquired pathogens, most healthcare-associated infections (HCAIs) are caused by multidrug-resistant organisms (MDRO).
Pneumonia is one of the infections frequently requiring hospital admission and urgent antimicrobial treatment due to the risk of rapid evolution to respiratory and multiple organ failure, especially in immunocompromised patients, or when caused by MDRO. The diagnosis of severe pneumonia requires ICU admission given the need for assisted ventilation or oxygen therapy, in the presence of radiological changes, confirming the rapid progression, as well as the evolution towards sepsis [1, 2].
Community-acquired pneumonia (CAP) is caused by bacteria in 85% of cases, the most frequently involved pathogens being Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Severe CAP cases may also be produced by other pathogens (influenza viruses, coronaviruses, Hanta virus, Legionella).
Pneumonia may trigger acute myocardial infarction in patients with heart diseases, while in splenectomised patients or with spleen dysfunction, S. pneumoniae may cause severe sepsis with lethal outcome within 12–24 h from onset, even under antibiotic therapy.
The treatment of CAP must cover both typical and atypical pathogens. Clinical studies have shown that monotherapy with respiratory fluoroquinolones or tigecycline is almost as effective as therapy with antibiotic associations (ceftriaxone plus doxycycline, azithromycin, or respiratory quinolones) [3].
On the other hand, presently ICUs are especially confronted with respiratory infections acquired during hospitalisation. According to 2012/506/EU European Parliament Decision, hospital-acquired pneumonia (HAP) occurs 48 h or more after admission and was not incubating at the time of admission, while ventilated-associated pneumonia (VAP) arises in 48 h after endotracheal intubation [4]. The microorganisms involved in the aetiology of these pneumonia cases originate in the oropharyngeal or upper airways colonisation flora or by direct inoculation of contaminated solutions, via an endotracheal catheter, or exogenous contamination of respiratory equipment caused by health care staff.
The hospital-acquired risk factors associated with this type of infection are:
long time sedation,
general anaesthesia with endotracheal intubation,
other invasive procedures: bronchoscopy, nasogastric catheterisation,
prolonged use of assisted ventilation,
reintubation, change of ventilation circuits at intervals under 48 h,
post-trauma intubation,
tracheostomy,
corticotherapy or other immunosuppressive treatments,
antibiotic therapy, administration of antacids or H2 blockers, barbituric therapy after cranial traumas,
thoracic or upper abdominal surgery,
emergency surgery,
administration of over 4 units of blood before the surgical intervention [5, 6].
These factors disturb respiratory functions leading to obstructions, decreased pulmonary volume, decreased filtration of inhaled air, and decreased secretion clearance. The insertion of an endotracheal tube allows the direct access of pathogens into the lower airways or may cause lesions of the epithelial mucosa, which represent breaches. Additionally, inadequate hand hygiene of medical personnel, lack of adherence to universal precautions, errors in decontamination of equipment or in the practice of endotracheal aspiration may favour not only cross-contamination but also the direct access of a massive bacterial inoculum.
This pneumonia is caused by a wide range of pathogens, and it may be plurietiological and is only rarely caused by viruses or fungi. The aetiological agents frequently involved in such infections are not only Gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella spp., Escherichia coli) but also Gram-positive cocci such as Staphylococcus aureus. The frequency of MDRO is increasing and influences the treatment, as in the case of methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Pseudomonas, fluoroquinolones, antipseudomonal penicillins and cephalosporins, extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL), Acinetobacter baumannii, etc. The risk factors for MDRO infections are the use of antibiotics during the previous 90 days, the onset of pneumonia after 4 days of hospitalisation, circulation of such pathogens in the health care unit in question, as well as the presence of comorbidities (immune suppression or immunosuppressive treatments).
The diagnosis of HAP should be rapidly reached, and the antibiotic treatment has to be promptly introduced, and any delay potentially aggravates the evolution and prognosis. The first antibiotic of choice depends on infection severity, patient’s risk factors, and the number of hospitalisation days accumulated until the onset of pneumonia.
The empirical treatment of HAP or VAP occurring during the first five hospitalisation days in patients without risk factors for MDRO must include antibiotics active against not only aerobic Gram-negative bacilli (Enterobacter spp., E. coli, Klebsiella spp., Proteus spp., Serratia spp.), pathogens with respiratory tropism (Haemophilus influenzae and Streptococcus pneumoniae), but also methicillin-sensitive S. aureus (MSSA). Recommendations include therapeutic schemes based on ceftriaxone or a fluoroquinolone (ciprofloxacin or levofloxacin) or ampicillin-sulbactam or ertapenem (Figure 1).
Antibiotic therapy in HAP.
In the case of patients with HAP or VAP who are at risk for MDRO infection, regardless of the infection’s severity, the antibiotic treatment must be directed against P. aeruginosa, K. pneumoniae (ESBL-producing strains), Acinetobacter spp. and MRSA. Antibiotic associations including antipseudomonal cephalosporins (ceftazidime), an antipseudomonal carbapenem (imipenem) or beta-lactam/beta-lactamase inhibitors (piperacillin-tazobactam), will be administered, in association with antipseudomonal fluoroquinolones (ciprofloxacin) or an aminoglycoside (tobramycin) and vancomycin or linezolid, to cover MRSA. If a Legionella infection is suspected, a macrolide (azithromycin) must also be associated [7] (Table 1).
Empirical antibiotic treatment of HAP with MDRO.
The duration of the antibiotic treatment in HAP must be adjusted to the severity of the disease, the time required to obtain clinical improvement and the aetiological agent, but it has to exceed with at least 3 days the time to clinical improvement. The clinical response occurs after at least 48–72 h, a period during which the recommendation is to maintain the therapeutic scheme. If, after this interval of empirical treatment, the clinical status of the patient did not improve, the therapeutic scheme must be broadened, potential complications (pleurisy, pulmonary abscess) and/or non-infectious causes must be sought.
The generalised septicaemic infection is an infection with an unpredictable outcome, high severity and increased mortality in the absence of adequate treatment. The correct choice of empirical antibiotic treatment depends on the intelligent use of clinical knowledge and epidemiological and microbiological data regarding the pathology in the area where the patient comes from. The lack of knowledge on the local resistance prevalence is a predictive factor for an incorrect treatment. The basic principle, which guides the treatment of the critical patient, is to rapidly initiate antibiotic treatment at correct doses, concordant with the pharmacokinetic and pharmacodynamic characters of the chosen drug and to adapt the treatment to the changes occurring in the clinical evolution and to the results of the antimicrobial sensitivity tests as soon as these become available.
Immediately after a patient with suspected sepsis is admitted, an attentive anamnesis and a thorough clinical examination are conducted in order to establish the entry and the location of the primary and secondary septic sites. The first emergency microbiological investigations are conducted (repeated blood cultures, cultures from secretions, lesions, urine, sputum, exudates, pleural fluid, etc.) together with evaluations of the renal, hepatic functions and state of consciousness, thus determining the severity of the case [8, 9].
The practical approach includes the emergency admission of the patient into the ICU where prevention or correction of hypovolemia, functional and metabolic dysfunctions are attempted, concomitantly with the prompt initiation of antibiotic treatment according to the maximal probability criterion.
The correct antibiotic treatment targets the resident microbial flora in the organ presumed to be the source of the infectious process.
The empirical treatment of sepsis consists of the association of bactericidal antibiotics with synergistic actions or monotherapy with an ultra-broad-spectrum antibiotic; antibiotics are administered intravenously in order to rapidly achieve an effective concentration in the infection site.
Empirical antibiotic therapy proved to be equally effective in beta-lactam-aminoglycoside associations, monotherapy with carbapenems, broad-spectrum penicillins/beta-lactamase inhibitors (ticarcillin/clavulanic acid, piperacillin/tazobactam) or third- and fourth-generation cephalosporins [10].
The aetiology of sepsis varies with the age of the patient, and the empirical treatment must be adapted to the most probable aetiology, but correlated with age, weight and associated pathology.
Adults with severe sepsis of unknown source must be treated with antibiotics effective against Gram-negative bacilli, Staphylococcus aureus, streptococci, respectively carbapenems (meropenem or imipenem) plus vancomycin. Septic shock requires the urgent refilling of the vascular system by infusions with saline solutions until the central venous pressure is re-established (over 80 mm at 6 h from hospital admission); at the same time, the primary source of infection is investigated, blood culture is collected and the first dose of antibiotic is administered, knowing that the time from admission to the initiation of antibiotic therapy is the strongest prognostic factor.
Patients admitted in a state of septic or toxic-septic shock will not be treated with beta-lactam (The bacterial load is very high, the pathogens are in a stationary phase with low protein synthesis, hence with a low synthesis of penicillin-binding proteins, so antibiotics lack their target.)
Colistin has a rapid antibacterial effect completed by a significant post-antibiotic effect against P. aeruginosa, A. baumannii and K. pneumoniae. The most effective administration regimen is at 8 h. Colistin proved an important alternative in the treatment of MDR Gram-negative bacilli. Resistance to colistin is caused by sub-optimal doses. Colistin dosage must be optimised, as this antibiotic is the last option in the treatment of MDRO [11, 12, 13].
When a biliary infection is suspected to be at the origin of bacteraemia, the most frequently encountered bacteria are enterococci and aerobic Gram-negative bacilli, which respond well to piperacillin/tazobactam or ticarcillin/clavulanate; alternatively, ceftriaxone, ciprofloxacin or levofloxacin associated to metronidazole may be administered.
A great part (around 25%) of sepsis cases occur as a result of community or hospital-acquired urinary tract infections (UTI), evolving with a renal or complication of prostatic parenchyma. In such cases, the time from hospital admission to the initiation of antibiotic treatment is also decisive for the evolution. After collection of samples for blood and urine cultures, the first dose of broad-spectrum antibiotic active against E.coli, Proteus spp., Enterobacter spp., Klebsiella spp., P. aeruginosa is administered; more rare cases of sepsis of urinary origin may be caused by Gram-positive bacteria (15%) or by Pseudomonas spp., especially in patients with immune deficits. For an effective treatment of community-acquired urosepsis, depending on the type of local susceptibility, a third-generation cephalosporin or a fluoroquinolone may be indicated; in urosepsis following urologic surgery in patients with long-term urinary catheters, the association of a third-generation cephalosporin active against Pseudomonas or piperacillin/tazobactam with an aminoglycoside or a carbapenem is useful, this association being required to cover MDRO [14].
It should be noted that treatment in sepsis is complex, antibiotic therapy being accompanied with measures to eradicate the entry site and septic metastases, to correct tissue hypoxia and to maintain hydro-electrolyte and acid-base balance.
Invasive devices (endotracheal, intra-vascular catheters) increase the risk of HCAI especially with MDRO, by colonisation and biofilm formation on the internal surface of these devices. All types of intra-vascular devices may become complicated with blood infections, but arterial catheters used for the haemodynamic monitoring and peripheral catheters show lower infection risks than central venous caterers (Table 2).
Distribution of the infection risk in the intra-vascular catheterisation.
The removal of intra-vascular, gastric or bladder catheters, neurosurgical shunts, etc. as soon as they are no longer needed, represents an infection prevention measure. Both their insertion and removal is done by specialised staff, trained to work under sterile conditions, avoiding the risk of contamination. Knowing that invasive devices, catheters included, are the most frequent cause of HCAIs, their insertion must be conducted under aseptic conditions, choosing the most suitable site (for instance, sub-clavian rather than femoral), after ensuring the asepsis of the cutaneous area, preferably with chlorhexidine, and not with alcohol or iodine solutions. In severely immunocompromised patients, the recommendation is to use antibiotic-impregnated catheters. Clinical studies confirm the significant reduction in catheter-associated infections when these are removed as soon as their role is no longer essential [15, 16, 17].
An increasing number of patients require central venous catheters for long periods of time (for haemodialysis, total parenteral nutrition, chemotherapy), which favours complications such as thrombosis or infection. Central venous catheter-associated bacteraemia imposes the removal of the catheter and systemic administration of antibiotics. The clinical decision to remove a catheter suspected of infection relies on the presence of local infection signs. The decision to maintain the device is made in the absence of severity signs in patients with technical difficulties of catheter reinsertion in a new site.
There are situations when catheters may not be removed or replaced (lack of venous approach, counter indication of a new intervention, etc.). In such cases, attempts are made to save the venous line by eliminating the intra-luminal colonisation before the onset of bacteraemia or, once bacteraemia is present, the general administration of antibiotic is associated with exposing the inner surface of the catheter, after its closure, at a very high concentration of the adequate antibiotic meant to eradicate the colonisation. This technique proved effective in the case of Gram-negative bacilli and coagulase-negative staphylococci, but it is not recommended in colonisations with S. aureus [18].
UTIs are the most frequent HCAIs. In most hospitals, catheter-related bacteriuria represents 40% of all HCAI within 1 year. The decision to treat is made after discriminating between the presence of bacteria (colonisation) and symptomatic infectious processes. The signs of catheter-associated UTIs are fever, lateral lumbar pain, sensitivity in the costovertebral angle, haematuria and delirium with recent onset. After catheter removal, pollakiuria or dysuria may be present.
The Infectious Disease Society of America defines asymptomatic bacteriuria as the absence of symptoms with the presence of over 105 colony forming units/ml of one or more bacterial species in a catheterised patient. In most cases of asymptomatic bacteriuria, the treatment led to the temporary sterilisation of urine and not to the eradication of pathogens [19]. Additionally, in 33–50% of patients, after catheter removal, the bacteriuria spontaneously resolved. This is why treating an asymptomatic bacteriuria increases the risk of antimicrobial resistance or of adverse reactions associated with useless antibiotic treatment.
Some pathogenic bacteria produce biofilms, which consist of an adherent layer of microorganisms and their extracellular products. The biofilm protects the pathogens against the host’s defence mechanisms and against antibiotic therapy. Migration to the urinary bladder occurs in 1–3 days. The duration of catheterization is an important risk factor, with almost all patients who are catheterised for more than 30 days developing bacteriuria. These patients are at risk of upper urinary tract inflammation, which increases the risk of bacteraemia. Infections linked to long-term catheterisation are often polymicrobial, which involves a broad-spectrum treatment.
The selection of antibiotics used for the treatment of catheter-associated UTIs depends on the result of the microscopical examination, as well as on the colonial characters. In 60–80% of cases, the causative agent is a Gram-negative bacillus (E.coli, Klebsiella spp., Pseudomonas spp., Proteus spp., Enterobacter spp.). The remaining 20–40% is caused by Gram-positive bacteria, most often species of staphylococci or enterococci. The empirical treatment has to take the following factors, which increase the risk of antibiotic resistance: the duration of hospitalisation, previous administration of antibiotics, and local resistance patterns.
Urinary fluoroquinolones (ciprofloxacin and levofloxacin) are administered to patients with mild and moderate infections, who are considered haemodynamically stable and do not present an altered mental status. Moxifloxacin is not recommended, as it does not reach effective urine concentrations. Broad-spectrum cephalosporins, ceftriaxone or cefepime, may also be used. In patients with urosepsis or in those haemodynamically unstable (hypothermia, tachycardia over 90/minute, tachypnoea over 20 respirations/minute or Pco2 under 33 mmHg, leukocytosis over 12,000/mm3 or leukopenia under 4000/mm3) piperacillin-tazobactam is administered.
In medium clinical forms, ciprofloxacin, 400 mg iv, for every 12 h or levofloxacin 500 mg iv /24 h or ceftriaxone for 1 g iv/day are administered.
The recommended treatments in severe forms include: cefepime 2 g iv/12 h, ceftazidime 2 g iv/8 h, imipenem 500 mg iv/6 h, doripenem 500 mg iv/8 h, meropenem 1 g/8 h and piperacillin/tazobactam 3.375 g iv/6 h.
The treatment of UTIs associated with bladder catheterisation is done with antibiotics for 3 days in women aged over 65 years, from whom the catheter has been removed; otherwise, the treatment is given for 7 days. The duration of levofloxacin treatment is 5 days.
Most hospital-acquired UTIS are expensive and may be prevented. The implementation of protocols based on present guidelines will reduce the inadequate use, as well as the antimicrobial resistance. When catheterisation is necessary, its duration should be limited. In case infections occur, the empirical treatment should be conducted according to the suspected pathogens and on the hospital’s antibiogram. When the results of cultures become available, antibiotics narrow their spectrum. The treatment should be limited to 7–14 days, depending on the response to treatment. Catheter removal is a key factor because catheterisation increases the risk for hospital-acquired UTI and other complications, resulting in prolonged hospitalisation and increased costs [20, 21].
Intra-abdominal infections include a series of diseases with variable severity, from uncomplicated appendicitis to faecal peritonitis. Uncomplicated infections involve a single organ and may not reach the peritoneum, and they may be solved either by surgical resection or by administration of antibiotics. Complicated intra-abdominal infections are those which extend to the peritoneum causing localised or generalised peritonitis; in order to solve these, the infection source must be solved by both surgery and antibiotic therapy.
The antimicrobial therapy of intra-abdominal infections, which are to be solved percutaneously or by surgery, has the following goals: to accelerate the elimination of the infecting microorganisms, to decrease the recurrence risk of the intra-abdominal infection, to shorten the clinical evolution, to limit the expansion of the infection to the abdominal wall and to decrease the risk of generalisation of the infectious process.
The antibiotic therapy is initiated after hydroelectrolyte rebalance, the restored volemia determining the restoration of the visceral perfusion and a better distribution of the medication. Moreover, this diminishes the side effects of antibiotics, which have been exacerbated by the deficitary perfusion of internal organs.
The empirical antibiotic treatment is initiated in concordance with the most probable microbiological spectrum, the type and density of germs being dependant on the level where the perforation of the digestive tract has occurred. By gastric, duodenal and proximal jejunal perforations, a low number of aerobic Gram-positive and anaerobic Gram-negative bacteria, generally sensitive to cephalosporins, are released into the peritoneum. Candida albicans has also been isolated, but antifungal treatment is only required in the case of patients under immunosuppressive treatment or in patients with recurrent intra-abdominal infections. The perforations of the distal small intestine often evolve as localised abscesses and peritonitis only takes place when these are ruptured. The intra-abdominal infections propagated from the colon into the peritoneum are caused by anaerobic or facultative anaerobic Gram-negative bacteria; Bacteroides fragilis is sometimes present.
The selection of the antibiotic should then be guided by the results of the cultures from the biological specimens obtained by percutaneous drainage or during the surgical intervention, but until these become available, it is necessary and useful to perform the microscopical examination directly on a Gram-stained smear. If high numbers of Gram-positive cocci are present, these are very likely to be enterococci or other faecal streptococci, which imposes the association of vancomycin.
Aerobic and anaerobic Gram-negative cocci may be covered by administration of cefoxitin, ampicillin/sulbactam, piperacillin/tazobactam, imipenem, meropenem, moxifloxacin, while aerobic Gram-negative bacilli may be destroyed with aminoglycosides, second-, third- and fourth-generation cephalosporins, aztreonam, antipseudomonal penicillins or fluoroquinolones (ciprofloxacin, levofloxacin). It must be mentioned that ertapenem is not active on Pseudomonas aeruginosa and Acinetobacter spp., and in the case of critical patients infected with P. aeruginosa, the dose of meropenem must be increased to 1 g administered for every 6 h. Vancomycin-resistant enterococci produce extremely difficult to treat infections, the only useful antibiotic being daptomycin. Tigecycline has been approved for the treatment of complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, E. coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible), MSSA, MRSA and some anaerobic bacteria [22].
The antibiotic, which is active only against Gram-negative bacilli and anaerobic bacteria, is metronidazole, for which no resistance has been reported.
The patients at high risk of unfavourable evolution and reserved prognosis have a high APACHE II score, poor nutritional status, significant cardiovascular diseases, immune suppression induced by medicines or by co-morbidities, while the infection source cannot be controlled. The predictive factors of therapeutic failure include the duration of the evolution prior to hospital admission, more than 2 days of presurgical treatment, as well as the presence of the MDRO. These patients should be treated similarly to those with hospital-acquired infections with carbapenems and vancomycin, but also considering the local antibiotic resistance.
The antibiotic treatment must be administered until the resolution of the clinical signs of infection (normalisation of the thermal curve, restoration of the intestinal transit) and normalisation of the biological inflammatory syndrome.
In cases with recurrent intra-abdominal infections, the diagnosis must be reassessed after 5–7 days of treatment and the investigations should be broadened (echography, CT). Often, the antibiotic therapy must be adjusted or a new surgical intervention is required in order to eliminate the site of infection.
The antibiotic treatment must be urgently initiated, immediately after blood collection for blood culture and after performing the lumbar puncture. Delayed administration of the first dose of antibiotic is associated with an aggravated prognosis, and it is a strong independent factor of increased mortality, exceeding the importance of disease severity upon hospital admission and of the isolation of a penicillin-resistant strain.
The most frequent cause of delayed antibiotic therapy is the missed diagnosis due to an atypical form of meningitis (absence of fever, headache or neck stiffness). Another possible cause of temporization is represented by scheduling the imagistic investigation immediately after admitting the patient in whom the spinal tap is not safe: risk of a cerebral hernia after cerebrospinal fluid (CSF) collection, in cases of expansive intra-cranial processes accompanied by papilledema or focal signs. In this latter situation, computerised tomography (CT) or nuclear magnetic resonance (NMR) examinations should be conducted after blood collection for blood culture and after the first dose of antibiotic, despite the risk of excessive treatment.
The antibiotic administration route in meningitis is intravenous, which is capable to ensure the CSF bactericidal concentrations; the exception is for rifampicin, which may be administered orally and is useful in the treatment of meningitis caused by beta-lactam-resistant pneumococcus and coagulase-negative staphylococci.
Antibiotic selection: in the treatment of bacterial meningitis, bactericidal antibiotics able to cross the blood-brain barrier are administered, so that optimal CSF concentrations are ensured regardless of the meningeal inflammation degree (meningeal inflammation favours the penetration of the antibiotic in the sub-arachnoid space at the onset of the disease, but as the inflammation regresses under treatment, the concentration tends to decrease, so that higher doses are required as compared to other diseases) [23].
Patients with suspected bacterial meningitis will be initially treated with a broad-spectrum antibiotic concordant to the most probable aetiology, the selection being made depending on the age and comorbidities. After establishing the aetiology and antibiotic susceptibility of the isolated pathogen, the antibiotic therapy will be focused, maintaining the high doses and intravenous administration.
The lumbar puncture should be repeated after the first 24–36 h from the initiation of the treatment in order to assess CSF cytological, biochemical and bacteriological changes.
The immune competent adult with bacterial meningitis requires an initial antibiotic treatment aiming at meningococcus and pneumococcus, consisting in the association of ceftriaxone (2 g/12 h) or cefotaxime (2 g/6 h) with vancomycin (30–60 mg/kg/day for every 8 or 12 h); third-generation cephalosporins must be administered even if the antibiogram shows that the respective strain presents intermediate sensitivity or resistance, because vancomycin acts synergically and increases the efficiency of the therapy [24].
Patients with bacterial meningitis and compromised cell immunity due to pre-existing conditions or immunosuppressive treatment, but with conserved renal function, should be treated with vancomycin (60 mg/kg/day divided into two or three doses) plus cefepime (6 g/day divided into three doses) or meropenem (6 g/day divided into three doses).
If a Listeria infection is suspected, the empirical treatment may consist in the association between vancomycin and moxifloxacin (400 mg in a single daily dose) plus trimethoprim-sulfamethoxazole (10–20 mg/kg/day divided at 6 or 12 h).
The duration of the antibiotic treatment in meningitis is not standardised, but it should be individualised based upon the clinical response of each patient, but usually 7 days of treatment is sufficient for meningococcal and H. influenzae meningitis, 10–14 days for pneumococcal meningitis, 14–21 days for meningitis with S. agalactiae and 21 days or more for meningitis with L. monocytogenes; meningitis with aerobic Gram-negative bacilli requires antibiotic administration for 21 or 14 days after the last CSF sterile culture.
Hospital-acquired bacterial meningitis (HABM) may be the result of an invasive procedure (craniotomy, insertion of internal or external ventricular catheter, lumbar puncture, intrathecal medication, spinal anaesthesia), of a complicated cranial trauma or, in more rare cases, of an infectious metastasis in patients with hospital-acquired bacteraemia. Such meningitis is caused by microorganisms with different spectra from community-acquired cases, and the disease is the result of particular pathogenetic mechanisms.
Bacterial meningitis is a redoubtable complication of craniotomy, occurring in 0.8–1.5% of the patients who undergo this procedure. One-third of the post-craniotomy meningitis cases develop during the first week after the surgical intervention, another third during the second week and one-third after the second week from the intervention, sometimes even years after the surgical procedure. The risk of post-surgical meningitis may be minimised by the attentive use of surgical techniques, especially those which decrease the possibility of liquid fistulae. Other factors associated with meningitis after craniotomy include concomitant infection at the incision site and duration of procedure exceeding 4 h.
The incidence of meningitis associated with internal ventricular catheters (cerebrospinal shunt) used in the treatment of hydrocephaly varies between 4 and 17%. The most important causative factor is the colonisation of the catheter at the time of insertion so that most infections become manifest in less than 1 month from the procedure.
External ventricular catheters are used to monitor intra-cranial pressure or to temporarily deviate the CSF if there is an obstruction in the system or as a treatment component in cases of infection of the internal catheter. The rate of external catheter-associated infection is around 8%.
The incidence of meningitis after moderate or severe cranial trauma is 1.4%. The open cranial trauma is encountered in 5% of cranial trauma and is complicated by meningitis in 2–11% of cases. Most patients in whom meningitis occurs as a complication of closed cranial trauma present a skull base fracture, which creates a communication between the sub-arachnoid space and the sinus cavities, posing an infection risk of up to 25%. The average time interval between the trauma and the onset of meningitis is 11 days. The CSF leak is the major risk factor, even though most post-traumatic leaks are not diagnosed. Most fistulae resolve spontaneously within 7 days, a surgical intervention is recommended if the breach persists. The cranial trauma is the most frequent cause of recurrent meningitis.
The diagnostic procedure relies on neuroimagistic investigations, CSF analysis (cell count, biochemical tests for glucose, proteins, Gram staining, cultures) and blood cultures. Neuroimagistics is indicated in most patients as it allows the ventricular size evaluation and brings information on a possible poor functioning of the shunt or the presence of residual catheters after previous surgical interventions.
The most frequently encountered bacteria in these cases are Gram-negative bacilli (Klebsiella pneumoniae, Pseudomonas aeruginosa), S. aureus and coagulase-negative staphylococci.
The empirical antibiotic therapy in HABM depends on the pathogenesis of the infectious process. In patients with meningitis occurring after neurosurgical interventions, or in patients with long-term hospitalisation after open cranial trauma or skull base fractures, vancomycin is associated with cefepime, ceftazidime or meropenem; the second antibiotic is selected depending on the local chemotherapeutics susceptibility profiles of Gram-negative bacilli. The empirical treatment in skull base fracture or early after ENT surgery includes vancomycin plus a third-generation cephalosporin (cefotaxime, ceftriaxone). After isolating the involved pathogen, antimicrobial therapy is changed for an optimal management. Linezolid and daptomycin are effective in staphylococcal meningitis; linezolid has good pharmacokinetic properties—CSF penetration is around 80%.
The initiation of empirical treatment is recommended in all patients with post-surgical signs of meningitis; this is withdrawn after 72 h in case the results of CSF cultures are negative. The treatment must be individualised, especially in patients previously treated with antibiotics, in whom the treatment is continued despite the negative results of cultures.
Given the emergence of MDR Gram-negative bacilli, the antimicrobial therapy of HABM caused by these pathogens becomes problematic. This is especially true in cases of HABM caused by Acinetobacter baumannii species, bacteria with acquired resistance to third- and fourth-generation cephalosporins and even to carbapenems. The treatment of Acinetobacter meningitis includes meropenem associated with an aminoglycoside administered intra-ventricularly or intrathecally. If the identified isolate is resistant to carbapenems, intra-ventricular or intrathecal administration of colistin or polymyxin B will be given instead of meropenem.
Treatment protocols recommended depending on the pathogenesis of the infectious process:
Infection after neurosurgical procedure—Gram-negative bacilli (including P. aeruginosa), Staphylococcus aureus and coagulase-negative staphylococci (S. epidermidis) may be involved. Vancomycin plus cefepime or meropenem are recommended.
Ventricular or lumbar catheter—coagulase-negative staphylococci, S. aureus, Gram-negative bacilli (P. aeruginosa) and Propionibacterium acnes may be present. Vancomycin plus cefepime or meropenem are recommended.
Penetrating trauma: S. aureus, coagulase-negative staphylococci, Gram-negative bacilli. Vancomycin plus cefepime or meropenem is administered.
Skull base fracture: Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes. Vancomycin plus a third-generation cephalosporin (ceftriaxone or cefotaxime) is recommended.
With the increasing incidence of MRSA, skin and soft tissue infections require more frequent admission of patients presenting tissue necrosis, fever, hypotension, intense pain, altered consciousness, respiratory, hepatic or renal failure, to the ICU. When choosing the therapeutic scheme, the possibility of a polymicrobial infection must be considered, with consecutive need to cover not only MRSA but also Gram-negative and anaerobic bacteria. An inadequate initial empirical treatment is associated with prolonged evolution and hospital stay [25].
Perianal infections and abscesses, infected decubitus ulcers, and moderate and severe infections of the diabetic foot frequently involve multiple aetiologies and require coverage for streptococci, MRSA, aerobic and anaerobic Gram-negative bacilli until the results of microbiological investigations become available.
In the case of patients with non-suppurative cellulitis, a beta-lactam antibiotic, such as cefazolin, may be initially prescribed, which is to be replaced in case of unsatisfactory clinical evolution. The replacement will be made according to the result of the antimicrobial susceptibility test or with an antibiotic active on MRSA, if the pathogen has not been isolated in the culture. The empirical treatment of MRSA infections may include vancomycin, linezolid, daptomycin, tigecycline and telavancin. Linezolid, daptomycin, vancomycin and telavancin additionally also cover streptococcal infections and not only MRSA.
In case of a documented or suspected staphylococcal infection, the recommendation is to immediately initiate the antibiotic treatment according to maximal probability criteria and according to local data on the sensitivity of strains circulating in the respective area. The doses of antibiotic must be adequate, because sub-inhibitory concentrations favour the release of staphylococcal toxins and virulence factors (PVL—Panton-Valentine leukocidin), which trigger the onset of skin, lung or bone necrotic lesions. Catheters and intra-vascular devices must be removed. In cases with detected abscesses, these should be drained; the localised infection of a prosthetic joint requires the removal of the prosthesis, but if the infection is located on a valvular prosthesis, its removal is not always required.
The treatment of MRSA infections frequently includes the administration of vancomycin. The increased vancomycin consumption has posed an increasing selection pressure of staphylococcal strains resistant to this antibiotic. The concentration of vancomycin required to inhibit most S. aureus strains is 0.5–2 mg/l. The strains with a minimum inhibitory concentration (MIC) of vancomycin between 8 and 16 mg/l are classified as intermediate sensitive or VISA (vancomycin-intermediate S. aureus), while strains with MIC ≥32 mg/l are considered resistant or vancomycin-resistant S. aureus (VRSA). The resistance mechanisms are different in the two types of strains: in VISA strains, the bacterial cell wall is thickened by the altered biosynthesis process and the glycopeptides targets are hidden in its thickness and in the case of VRSA strains, the target of glycopeptides is itself modified.
Surgical wound infections are another category of infections frequently confronting ICUs. In their most frequently polymicrobial aetiology, Gram-positive cocci (especially MRSA), Enterobacteriaceae and non-fermentative Gram-negative bacilli (P. aeruginosa) are among the most frequently isolated pathogens. The empirical treatment of these infections consists of associating cefepime or meropenem with an aminoglycoside or a fluoroquinolone.
Many extrinsic risk factors are inter-connected with intrinsic factors or are found in association, for which reason, the Study on the Efficacy of Nosocomial Infections Control (SENIC), a risk index, has been proposed for surgical wound infections. When compared to the traditional Altemeier system, this index predicts the risk of post-surgical infection two times better and the inclusion of other items does not seem to improve its predictive capacity [26]. The National Surveillance System of Nosocomial Infections in the USA proposed the NNIS risk index, further completed with the item on the use of laparoscopic techniques (Tables 3 and 4).
Risk indexes for post-surgical wound infections.
Risk of post-surgical wound infection depending on the Altemeier classification.
The choice of antibiotics is conditioned by:
the characteristics of the isolated or suspected aetiological agent,
patient characteristics, which may influence the efficiency and toxicity of the treatment (age, physiological status, comorbidities, infection site),
pharmacodynamic and pharmacokinetic characteristics of the antibiotic (adsorption, tissue distribution, concentration in the infectious focus, metabolisation and elimination of the antibiotic).
In the case of the critical patients, the early administration of an effective antibiotic treatment is essential and determining, the time until the initiation of therapy being a strong predictor of mortality. A retrospective cohort study showed that the delay of effective treatment after the onset of recurrent or persistent hypotension was associated with an increased death risk; the survival rate in patients with treatment administered during the first hour was of 79.9%, with each hour of delay in antibiotic therapy leading to a 7.6% decrease in this rate [27].
Optimization of doses. The antibiotic requirement is calculated depending on the characteristics of the patient (age, weight, renal function), on the pathogenic microorganism, infection site (endocarditis, pneumonia, meningitis, osteomyelitis) and the pharmacokinetic and pharmacodynamic characteristics of the drug [28].
The loading dose is probably the most important and depends on the distribution volume of the drug and on the intended plasmatic concentration, regardless of the renal function. Antibiotics are classified according to multiple criteria, one being the criterion, which influences the dosage: the doses of hydrophilic antibiotics (beta-lactam) must be increased during the first stages of sepsis, together with the increase in the extravascular space. The doses of lipophilic antibiotics are influenced by other factors, such as obesity [7, 28].
Before establishing the rational antibiotics administration regimen, the antimicrobial activity in time must be understood, i.e., the pharmacodynamics of the drug in question (the relationship between its serum concentration and its therapeutic effect). From a pharmacodynamic perspective, antimicrobial agents may be divided into:
The bactericidal effect of beta-lactam antibiotics is independent of their concentration, as long as this exceeds the MIC and they do not possess a significant post-antibiotic effect (PAE) (The inhibition of bacterial growth continued for a variable period after the concentration of antibiotic at the infection site has dropped under the MIC.) The strategy to obtain optimal results is to increase the exposure time of microbes to plasmatic concentrations of antibiotic exceeding the MIC, which is accomplished by frequent doses, by the administration at short time intervals or by continuous infusion.
The bactericidal effect of vancomycin, carbapenems, macrolides, clindamycin, azoles, linezolid is independent of their concentration, if this is higher than the MIC, but it is time dependent. The PAE is intermediate (The serum antibiotic levels may drop under the MIC for a short while.) The antibiotics in this group produce optimal results when administered in lower but with more frequent doses.
The bactericidal effect of aminoglycosides, fluoroquinolones and metronidazole is dose dependent and has a significant post-antibiotic effect (Bacterial growth is prevented even if tissue levels decrease under the MIC for longer periods of time.) This is why higher doses, but at larger intervals, may be administered, with 2–4 h between the doses after being admitted, during which time the plasmatic concentration of these antibiotics may be undetectable, which reduces their nephrotoxicity.
The time-dependent bactericidal effect is achieved by optimising the duration of bacterial exposure to antibiotics, while the dose-dependent bactericidal effect is maximal when the antibiotic concentration is maximal [7].
Polymyxins are concentration-dependent antibiotics; they are active on carbapenemase-producing bacteria, and they are increasingly kept as last therapeutic option in infections with resistant pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. We must underline the fact that if sub-optimal doses of colistin are administered, the pathogen gains resistance.
First-line antibiotic treatment in severe acute infections.
Severe acute infections are classified as community-acquired, healthcare-associated and hospital-acquired infections. For the practical assessment of a case, Yehuda Carmeli proposed a score, which allows the stratification of risk factors for the infections with resistant or MDRO, depending on the previous contact of the patient with the health care sector, on the existence in his/her medical history of antibiotic treatments, as well as on associated factors (immune suppression, co-morbidities):
Risk assessment for infections with resistant or MDR pathogens:
Contact with the health care sector:
No contact—1
Contact without invasive procedures—2
Repeated contacts with invasive procedures—3
Previous antibiotic treatment:
No antibiotics—1
With antibiotics—2
Characteristics of the patient:
Young, without co-morbidities—1
Elderly, with co-morbidities—2
Immunocompromised patient (AIDS, neoplastic diseases)—3
According to this score, the value 1 corresponds to community-acquired infections, the value 2 corresponds to HCAI and the value 3 to hospital-acquired infections. The Carmeli score may only be 1, 2 or 3, and it is given by the highest value obtained from the answers to the three categories of questions [29]. This classification allows a correlation between the type of infection, the most probable aetiology and the estimation of the antibiotic susceptibility of the microorganism in question.
The empirical or first-line treatment is especially important for the evolution of the infection; the delayed initiation of an effective antimicrobial treatment leads to increased morbidity and mortality, aggravated and generalised infections, as well as increased health care costs. If the initial treatment has not been effective, adding a new antibiotic or replacing the initial one with a broader spectrum antibiotic (escalation) will not increase the chance of favourable evolution. The adjustment of antibiotic treatment after the microbiological results become available might be tardy and ineffective, if the initial treatment has been inadequate, especially in the case of hospital-acquired infections (multivariate analysis have demonstrated that inadequate empirical treatment increased the risk of mortality). The association of antibiotics of different classes is useful in the initial treatment of infections with MDRO.
In patients with severe infections, the recommendation is to administer the antibiotic treatment during the first hour after the diagnosis, but not before collection of blood and other biological samples required for the identification of the aetiological agent and testing for its sensitivity to chemotherapeutics. Patients with meningitis will receive antibiotic treatment during the first 30 min after hospital admission, immediately after collection of blood and CSF [1, 10].
The empirical or first-line antibiotic treatment is initiated according to the most probable microbiological spectrum and consists of the administration of a broad-spectrum antibiotic (covering Gram-positive cocci, including MRSA and enterococci, as well as Gram-negative bacilli, including Acinetobacter spp., Pseudomonas aeruginosa and Enterobacter spp.) for a short period of time, i.e., for 2–3 days. Depending on the clinical evolution of the patient and on the results of microbiological tests, the initial treatment scheme may be modified by decreasing the number of antibiotics or reducing the spectrum (de-escalation). Narrowing the therapeutic regimen does not only refer to the shift from a broad-spectrum to a narrow-spectrum antibiotic, but also to adjusting (reducing) the doses and treatment duration [30].
The Principles of de-escalation are as follows:
administration of an ultra-broad-spectrum antibiotic for a short period of time,
identification of the aetiology within this covered period,
replacement of the initial antibiotic with a narrow-spectrum antibiotic.
If, after 48–72 h of treatment with a broad-spectrum antibiotic, the status of the patient does not improve, the available microbiological data are attentively reanalysed and the possibility of MDRO infection, a non-bacterial or even a non-infectious aetiology, are considered. The evaluation must also include the possibility of a complication, such as the formation of an abscess, empyema, etc. [31].
Decreasing the risk of adverse reactions, the decreased selection pressure of resistant strains, as well as the reduction of costs represent the benefits of de-escalation and treatment cessation after a shorter time. Examples of benefits in the administration of antibiotics in short cures and/or reduction of the antibiotics spectrum include the decrease in the incidence of cases of diarrhoea with Clostridium difficile and of infections with resistant bacteria and Candida spp. (Figure 2).
Algorithm for initiation of antibiotic therapy.
We live in the “Plastic Age”. From its creation in the early 1870, plastic material has largely contributed to the society development making everyday life easier. Plastic material offer good advantages as it can be customized with specific shapes and chemical and physical properties i.e., elasticity, hardness, lightness, transparency and durability. Due to this, the production has dramatically boosted annual plastic production from 0.5 million tons in the 40s to 550 million tons in 2018 [1]. However, plastics sturdiness presents some negative implications as the increasing rate of plastic consumption worldwide its release in the environment associated with a low degradation rate is resulting in its accumulation in coastal and marine sediments, pelagic and benthic biota from coastal to open ocean areas at each latitude from the poles to the equator. Depending on sources and formation mechanisms plastic fragments are split into “primary” and “secondary”. Primary plastics are resulting from the direct input of freshly manmade emissions, adding new micronized size by-design plastic material to the environment. According to this definition, major sources primary plastics are: (A) polymers intentionally produced and used as such. In this group belong i.e., personal care consumer products, industrial or commercial products and other specialty chemicals with plastic microbeads; (B) inherent collateral products of other industrial activities or (C) plastic sourced as accidental or deliberate spillage i.e., pellets loss from plastic factories and transport. In contrast, secondary plastics are associated as secondary pollution sources where larger plastic items undergo degradation and subsequent fragmentation leads to the formation of smaller plastic pieces as they start to break down by photo-oxidative degradation followed by thermal and/or chemical degradation [2].
\nWhile addressing the comprehension of plastics degradation mechanisms in marine aquatic environments it is useful to divide them into plastics with a carbon-carbon backbone and plastics with heteroatoms in the main chain. Some of the most environmentally recurrent polymers like polyethylene, polypropylene, polystyrene and polyvinylchloride have a pure carbon-based backbone. On the contrary, polyethylene terephthalate and polyurethane plastics have heteroatoms in the main chain. Most packaging materials are made of plastics with a carbon-carbon backbone structure. As they are very often discarded after a short period of time, there is a high potential to observe significant loading in the environment. All these polymers are susceptible to photo-initiated oxidative degradation, which is believed to be their most important abiotic degradation pathway in aerobic outdoor environments. This degradation pathway consists of a complex sequential multi-step process where initially chemical bonds in the main polymer chain are broken down by light, by heat or by a combination of both to produce a free radical formation [3, 4]. Polymer radicals react with oxygen and form a peroxy-radical species. As a side effect, the co-occurring formation of hydroperoxides promotes a further complex pathway of radical reactions leading to significant autoxidation of the target polymer. These processes ultimately lead to chain scission, branching and creation of oxygen-containing functional groups. As the molecular weight of the polymers is reduced, the material becomes fragile and is more vulnerable to fragmentation, which makes a higher surface area reactive to further degradation. Nevertheless, anti-oxidants and stabilizers used as additives inhibit the degradation of the polymer. Thus, degradation rates depend strongly on used additives and plasticizers [4]. In most cases these are well-known toxic chemicals not covalently bonded to the polymer and therefore capable of leaching out from the plastic during the degradation process, and easily enters into the aquatic environment representing a further point of concern for eco-toxicologists. On the other hand, different degradation mechanisms cause degradation of plastics with heteroatoms in the main chain. They show an increased thermal stability compared to polymers with a simple carbon backbone. Under marine environmental conditions the degradation processes of plastics like polyethylene terephthalate (PET) or polyurethane (PU) are normally controlled by hydrolytic cleavage. Similar to carbon-carbon backbone plastic polymers, PET can undergo photo-induced autoxidation via radical reactions leading to the ultimate formation of a carboxylic acid end groups, which show a promoting effect on thermo- as well as photo-oxidative degradation. Weathering of PET in the marine environment occurs mainly by photo-induced oxidation and secondly by hydrolytic degradation processes which cause the yellowing of the polymer. For thermo-oxidative degradation the consequences are an in the content of the some end groups i.e., carboxylic acid as well as a general decrease in molecular weight of the main polymer [4]. Hydrolysis also leads to a reduction in molecular weight and an increase in carboxylic acid end groups. PET is highly resistant to environmental biodegradation because of its compact structure [4]. On the other hand, polyurethane-like compounds show carbon, oxygen and nitrogen in the main chain demonstrating enhanced susceptibility to degradation via photo-oxidation, hydrolysis and biodegradation. Plastic floating on the ocean surface is exposed to moderate temperatures, solar radiation at wavelengths of 300 nm and longer, as well as oxidizing conditions. Since temperatures are moderate, the most important factors initiating abiotic degradation are oxygen and sunlight. According to recent studies, fragmentation patterns first occur at the plastic surface, which is exposed and available for chemical or photo-chemical attack. The process is more efficient with smaller plastic fragments as they show a higher surface to volume ratio [5]. Changes in color and crazing of the surface are the initial visual effects of polymer degradation. Surface cracking makes the inside of the plastic material available for further degradation, which eventually leads to embrittlement and disintegration. Furthermore, almost all commercial plastics include additives. These co-production chemicals embedded in the polymers can also leach into the aquatic environment, which is an additional point of concern. As these substances enhance plastics’ resistance to degradation, it becomes difficult to quantitatively estimate the fragmentation patterns since different plastic products can vary in their composition. On the other hand, additional factors can significantly influence degradation rates as floating plastic may develop biofilms that shield it from UV radiation. The formation of biofilm in plastic microliter collected from the marine aquatic environment has been previously documented worldwide [6, 7, 8]. Such phenomena could lead to a reduction in photo-initiated degradation. So far, there have been very few studies of degradation mechanisms for plastic polymers in the marine environment although some promising early findings have been reported by ongoing joint research initiatives (e.g., JPI-Weather Mic and JPI-PlasTox). The biofilm formation can also affect the vertical distribution of plastic fragments largely affecting their distribution in the water column or in the sedimentary environment. Most synthetic polymers are buoyant in water and substantial quantities of plastic debris that are buoyant enough to float in seawater are transported and potentially washed ashore. The polymers that are denser than seawater tend to settle near the point where they entered the environment; however, they can still be transported by underlying currents. Table 1 resumes the theoretical densities of the most recurring polymers found in the environment. Microbial films rapidly develop on submerged plastics and change their physicochemical properties such as surface hydrophobicity and buoyancy [9, 10]. All in all, plastic debris is a mixture of molecules and chemicals, its size ranging from some meters to a few micrometers and probably nanometers. It is derived from a broad variety of origins, such as fishing gear, nets, bottles, bags, food packaging, taps, straws, cigarette butts and cosmetic microbeads and the associated fragmentation of all of these. Plastic debris has become ubiquitous in all environmental compartments of the marine ecosystem form sediments to sea surface. Thus, the observed loadings floating in the ocean represents only a limited portion of the total input. It has been previously reported that most plastic litter ends up on the seabed with a remaining fraction distributed on beaches or floating on the seawater surface leading one to consider that merely quantifying floating plastic debris may lead to a significant underestimation of the actual amount of plastics in aquatic environments [11].
\nPolymer | \nAbbreviation | \nDensity (g/cm3) | \nApplications | \n
---|---|---|---|
Expanded polystyrene | \nEPS | \n0.01–0.04 | \nBait boxes, floats, cups | \n
Low density polyethylene | \nLDPE | \n0.89–0.93 | \nPlastic bags, bottles, gear, cages | \n
High density polyethylene | \nHDPE | \n0.94–0.98 | \nPlastic bags, bottles, gear, cages | \n
Polypropylene | \nPP | \n0.83–0.02 | \nRope, bottle caps, | \n
Polypropylene terephthalate | \nPET | \n0.96–1.45 | \nBottles, gear | \n
Styrene butadiene rubber | \nSBR | \n0.94 | \nCar tyre | \n
Polyamide | \nPA | \n1.02–1.16 | \nGera, fish farm nets, rope | \n
Polystyrene | \nPS | \n1.04–1.10 | \nContainers, packaging | \n
Polymethyl methacrylate | \nPMMA | \n1.09–1.20 | \nInsulation, packaging | \n
Polyvinylchloride | \nPVC | \n1.16–1.58 | \nFilm, pipe, containers | \n
Polycarbonate | \nPC | \n1.20–1.22 | \nTextiles, leisure boats | \n
Polyurethane | \nPU | \n1.20 | \nInsulation, floats | \n
Alkyd | \nALK | \n1.24–2.10 | \nPaints, packaging | \n
Polyester | \nPES | \n1.24–2.3 | \nTextiles, | \n
Polytetrafluoroethylene | \nPTFE | \n2.1–2.3 | \nPersonal care products | \n
Theoretical densities of the most recurring polymers found in the environment.
Overall ecosystem health can be significantly affected by the accumulation of trash and plastics in our seas. Ingestion of and entanglement in marine debris directly impacts marine life. Laboratory studies provide a strong proof of evidence for the effects of microplastic ingestion observed in organisms collected from the natural environment. Indeed, in laboratories, under natural like conditions, microplastics have been shown to be ingested by amphipods, barnacles, lugworms and bivalves [12, 13, 14]. In the same organisms, the uptake of microplastics caused notable ultrastructural changes in the investigated tissues including histological changes as well as cell functioning impairments [15]. In field observations, the occurrence of MPs in the gastrointestinal tract and gills of pelagic and demersal fish and marine mammals has been documented [16, 17]. Past reports have shown that many marine organisms wrongly identify plastic debris for food. Ingestion of marine debris induce different deleterious effects such as pathological alteration, starvation and mechanical blockages of digestive processes. Furthermore, the interaction of plastic fragments, especially those at micrometric and nanometric scales, with organic pollutants are of importance in relation to environmental contamination and biological effects on organisms in the water column as well as in the sedimentary environment [18, 19]. Hydrophobic pollutants co-occurring in the aquatic environment may in fact adsorb onto MP debris. According to the different sizes, plastic fragments have the potential to transport contaminants more effectively through biological membranes and ultimately inside cells of aquatic organisms. The presence of organic pollutants on marine plastics has been illustrated for a wide range of chemicals in natural aquatic conditions [20, 21]. The exposure routes of organic pollutant-enriched MPs are varied, while the toxicity is largely inversely correlated to the size of the particles, as the smaller the particle the further into the organism it can penetrate releasing toxic chemicals under acidic gut conditions [22]. According to the properties of the adsorbed chemicals, several toxicity mechanisms are represented by increased oxidative stress, genotoxicity, depletion of immune competence, impairment of key cell functioning, loss in reproductive performance, disorders in energy metabolism, and changes in liver physiology [23, 24, 25].
\nDifferent methods have been developed for identifying plastics, including meso, micro and nanoplastics in water, sediments and biota as well as to a lesser extent in soil. The percentage of organic matter (OM) in general as well as some recurring specific macromolecules, such as fats and proteins may hamper the analysis, thus hiding plastic fragments in visual analyses and distort signals in Fourier transformed infrared (FT-IR) and Raman spectroscopy, two of the most frequently used methods for plastic identification [26, 27]. Hence, identifying and quantifying plastic materials in organic matter enriched samples may be a challenge. In sediments, several available protocols recommend a preliminary sorting of plastic size grounding and sieving. After sieving, the mineral phase of soils might be removed easily using density fractionation methods. Different density solutions have been used including NaCl, ZnCl2, NaI and more recently 3Na2WO4 9WO3 H2O to obtain dense floating solutions [28, 29]. However, it has been shown that simple density fractionations will not succeed in separating organic matter from plastic materials in sediments because most of the OM show densities between 1.0 and 1.4 g/cm3, similar to that of several environmentally recurring plastic types like PET, PP, PE and Nylon. Sufficient removal of OM without destroying small plastic polymers is challenging because large parts of OM are refractory. At the same time, polymers show strong sensitivity to acidic or strong oxidizing treatment conditions, which induce permanent modifications (e.g. yellowing), thus hampering their classification by microscope-oriented techniques. To efficiently remove OM, multistep extraction, purification processes based on alkaline treatments possibly combined with multi-enzymatic digestion steps have been suggested for the analyses of biota water or sediments. Enzymatic digestion has been promising for the removal of organic as well as other interferents, such as chitin, agar and lipid enriched samples [27]. Strong alkali digestions have been pointed out as being effective for sediments as well as biological samples, without altering the plastic itself [30]. While on the contrary and as previously mentioned, strong acidic conditions induce partial dissolution of polycarbonate as well as partial digestion of polyethylene and polypropylene [13]. Another largely exploited strategy to remove organic matter relies on the application of concentrated hydrogen peroxide [26]. However, its use must be critically evaluated in terms of digestion conditions as treatments with incubation exceeding 48 h with temperatures exceeding 50C, which may degrade plastic polymers like polyethylene and polypropylene [31]. In this context, some authors have recently suggested an effective combined multistep method based on a sequence of enzymatic digestions followed by a short hydrogen peroxide treatment for the removal of organic matter from complex environmental matrices (e.g., wastewater samples). In summary, several promising methods have been tested for extracting, purifying and pre-concentrating plastic materials from sediments and marine biota, all of them having potential limitations. More research is needed to develop a standard protocol for isolating plastics from a range of different environmental matrices, ideally at low cost and without altering plastic properties.
\nOnce isolated, plastic fragments can be tracked and characterized by different analytical techniques. Some are defined as “surface oriented” methods like Raman spectroscopy, Fourier Transformed Infra-Red (FTIR), Scanning Electron Microscopy/Energy Dispersive X-Ray Spectroscopy (SEM-EDS) and environmental scanning electron microscope (ESEM) with an attached X-ray energy dispersive system (ESEM-EDS). Plastic fragments are visually sorted and analyzed coupled with microscopy. However, as discussed above, the use of strong oxidant/acidic agents applied during the extraction from sometimes complex environmental matrices (e.g., organic matter enriched marine sediments, or fat rich marine biota) may induce alteration in the plastic surface like partial dissolution, yellowing and polymer structure disruption leading to erroneous characterization of microparticles. Furthermore, some compounds of natural origin occurring in marine samples (e.g., chitin) have shown spectroscopic properties similar to those of the most recurrent plastic polymers leading to inaccurate polymer characterizations and overall abundance estimation. In addition, these microscopy-based techniques are time consuming and unable to process large numbers of samples. However, significant advances in the automatic and semi-automatic FTIR spectra recognition have been recently presented as promising time saving solutions (Jes recent paper). Alternatively, promising solutions include the Pyrolysis-gas chromatography in combination with mass spectrometry (Pyr-GC-MS) as well as the Thermogravimetric analysis coupled with mass spectrometry (TGA-MS). Pyr-GC-MS in particular can be used to assess the chemical composition of potential microplastic particles by analyzing their thermal degradation products. The polymer origin of particles is identified by comparing their characteristic combustion products with reference pyrograms of known virgin-polymer samples. Py-GC/MS had the advantage of being able to analyze the polymer type and OPA content in one run without using any solvents and with few background contaminations. Additionally, the Pyr-GC/MS method has an appropriate degree of sensitivity for analyzing plasticizers in microplastic particles with limited sample masses. However, although the pyrolysis-GC/MS approach allows for a good assignment of potential microplastics to polymer type it has the disadvantage of being a “destructive” technique as the sample is burned to obtain the pyrolytic products. Furthermore, due to limitations in the quantity of sample loaded in the pyrolysis cup only particles of a certain minimum size can be processed resulting in a lower size limitation of particles that can be analyzed. Each of these methods have their own limitations and advantages, therefore, their combined use, especially for the analysis of complex environmental samples, is a recommended strategy to reduce the effect of interferents in the analysis and obtain reliable results.
\nWith some of the most significant amounts of solid waste generated annually per person (208–760 kg/year), the Mediterranean Sea is one of the world’s areas most affected by litter [32]. The estimated amount is 62 million of macrolitter items floating on the surface of the whole basin [33]. Litter enters the seas from land-based sources, ships and other infrastructure at sea and can travel long distances before being deposited on the seabed or along the coasts. Mean densities of floating microplastics in the Mediterranean Sea of more than 100,000 items/km2 [34] indicate the importance of this threat for the basin. In this context, the Adriatic Sea represents a hot spot for plastic litter both because of peculiarities in its oceanographic conditions as well as the high degree of anthropogenic pressure related to tourism, artisanal and industrial activities coexisting in a narrow area. The Adriatic Sea is an elongated basin, located in the central Mediterranean, between the Italian peninsula and the Balkans, with its major axis in the NW-SE direction. The northern area is very shallow, gently sloping, with an average depth of about 35 m, while the central part is on average 140 m deep, with the two Pomo depressions reaching 260 m. The northern and central parts of the basin are affected by a great number of rivers along the Italian coast, of which the Po river is the most relevant. River discharge and wind stress are the main drivers of the water circulation. West Adriatic Current (WAC), flowing SE along the western coast, and East Adriatic Current (EAC), flowing NE along the eastern coast are the main currents affecting the Adriatic circulation. There are two main cyclonic gyres, one in the northern part and the other in the south. The Bora wind (from NE) causes free sea surface to rise close to the coast enhancing the WAC and the Sirocco wind (from SE), which is the major wind affecting the Adriatic Sea, leads flood events in the shallow lagoons along the basin coast [35]. A vertical thermohaline front parallel to the coast and extending throughout the water mass, divides the coastal waters from the open sea. This retains the materials flowing from rivers and other water sources within the coastal area. A stratification characterizes the water column separating the warmer surface waters with lower salinity from deeper, colder and more saline ones during summer [35].
\nAcross the Mediterranean, but in the Adriatic Sea in particular, there is a continued demand to increase aquaculture production to fulfill the increasing market demand. Mussels, clams, sea bass and seabream production has become a significant source of regional income. Aquaculture was developed to support consumers’ demand for seafood and the methods of production have continued to expand with the growing consumer market. As the need for fish and mussel aquaculture has increased, the development and expansion of aquaculture facilities in coastal and open water locations has increased accordingly. The expansion of the industry and the diversity of materials used to build and maintain aquaculture systems have paralleled the development of synthetic polymers over recent decades. Synthetic fibers offer greater strength and durability than natural fiber ropes; they are cheap, durable and easier to handle compared to their natural counterparts. Most modern aquaculture activities use plastic-based lines, cages, or nets suspended from buoyant or submergible structures (in part made of plastic) and have nanotech plastic-based biofouling and paint applied. Today, tanks, pens, nets, floats, pontoons as well as the pipes of the fish feed supplying systems are made of plastic materials. All plastic material within an aquaculture site is maintained and controlled for chemical degradation, biofouling and corrosion, and is regularly inspected to ensure strength and stability. In the context of global plastic pollution to the oceans, aquaculture may be a contributor to this. However, the estimation of their contribution remains a knowledge gap and lost or derelict gear as well as other possible plastics emissions from aquaculture can be a locally important contributor especially in coastal areas with intensive activity. New reports also point out a potential micro and nanoplastic contamination in wild and cultured seafood products even if the extent of such phenomena is still unknown. There is also concern regarding fisheries as a source of microplastics to the marine environment because both sectors use plastics that may degrade/fragment into microplastics. The coastal areas of Emilia Romagna and the Croatian coast represent sites of intense mussel and fish aquaculture production with hundreds of tons produced yearly. On the other hand, intense fishing activities coexist with a variety of fishing gear and methods being used in industrial and small-scale fisheries. Fishing gear for capture fisheries includes trawl nets, dredges, surrounding nets, lift nets, seine nets, traps, hook and lines. Nets and floats are made from a range of plastics including PP, PET, NyL, PVC, polyamide (PA) and PS.
\nIn oil and gas exploration, drilling fluids based on plastic microbeads were introduced a decade ago. Teflon strengthened particles have been largely applied for drilling purposes internationally. Despite the use of Teflon and other polymers with specific features being used extensively in production, waste treatment processes are not designed for, and give no mention of how to handle plastic particles, so this has clearly not been addressed as an issue in the past. Therefore, there is a substantial lack of information on potential loadings of microplastics used in this sector. To date, few fragmentary studies have addressed this topic. CEFAS’s report entitled, “The discharge of plastic materials during offshore oil and gas operations” suggests that 532 tons of plastics and 7475 tons of “possible plastics” have been released from the UK offshore oil sector. Although knowledge about microplastic from oil and gas extraction activities is limited, it is very likely they represent a potential contributor in the emissions of plastics in aquatic environments, including microplastic and fibers, emphasizing that it should certainly be considered in future source assessments. The mapping of the distribution of rigs and platforms in the Adriatic Sea where tens of oil fields with hundreds of medium sized oil rigs occur, may provide estimations about the geographic distribution of the potential input related to these industrial activities.
\nShips and maritime installations contain many plastic items, like insulation, coating, electrical wiring, furniture and textiles. Ideally, installations should be stripped of all potentially hazardous materials before dismantling. However, plastics items are not identified in the list of harmful materials. Therefore, polymer-based coatings and several kinds of insulation and wiring are rarely stripped.
\nThe distribution of products can contribute to the release of plastics in the environment. Most transferring of stock will occur alongside the transport infrastructure network. However, even if recognized as an important source of pollution, the contribution from releases during transportation, and as is the case for shipping, a map of the main transportation network including roads and harbors is still lacking. Systematic mapping in the Adriatic context has been suggested to improve the understanding of the areas where potential inputs can occur, providing a proxy for the potential intensity for release. The Adriatic Ship Traffic Database also contains information on ports in the Adriatic Sea that could be used to gauge the intensity of port activity to identify which of the port areas could potentially be receiving the largest inputs. Furthermore, the cruise ship industry is pointed out as a significant contributor to the problem of plastic pollution in the Adriatic sea. However, very limited data are available and no specific regulations in place for their plastic waste management and/or assessment of their environmental impact [36].
\nAt a global level, the major challenge to tackle the input of plastic debris from land into the ocean is the lack of adequate waste management in coastal regions with a high and growing population density. Due to a generally high population density in coastal areas of the Adriatic, the pressure resulting from land-based inputs should be relatively high overall. Given such levels of anthropogenic pressure, the lack of, or deficient local waste management systems may lead to locally high inputs linked to industrial or domestic waste management.
\nThere are no studies looking specifically at the leakage and marine input of plastic debris linked to these waste management systems, but ongoing work to quantify and characterize beach litter here points toward potential input from inadequate waste management on the eastern shores of Croatia where the islands of the Quarnero natural park present high loadings of plastic fragments. The composition of the waste accumulated resembles the composition of surveys carried out in the mid-Adriatic region where influence from higher population densities along the coastline is being registered. In addition, a study looking into microplastics near Venice has detected exceptionally high concentrations of small plastic fragments and microplastics in a nearby sandy beach [52]. Though not specified in this report, this exceptionally high concentration of microplastics, including large amounts of plastic fibers and film, could be linked to this location being close to the harbor as well as the lack of waste management facilities. To gain further insight into the potential release of plastics associated with waste management, it would be useful to map the distribution of population density as well as the location of urban agglomerations and settlements as this information will provide an indication of potential localized points of release of plastic waste into the environment. This kind of information is readily available at a sufficient resolution to allow identification of the areas within the Adriatic Sea that need more attention to this potential source of plastic pollution.
\nA rough estimation predicts that 70–80% of marine litter, composed primarily of plastics, originate from inland sources, ending in rivers and oceans. However, inland deposition of MP has not been investigated thoroughly. Potential sources include sewage treatment plants (STPs) and runoff from urban, agricultural, tourist, and industrial areas. As the retention capacity of conventional wastewater treatment processes to MPs appears to be variable in both magnitude and specificity, a characterization of MP emission by STPs and other sources is needed to map major sources of freshwater and terrestrial MPs. A relevant input to the terrestrial ecosystem is by fertilizers obtained by processing sewage sludge, as it typically contains more MPs than liquid effluents. Such fertilizers are frequently used in agriculture, implying a potential accumulation of plastic particles in the soil with continued use, and a systematic examination and quantification has been addressed by several research groups around the world. However, due to runoff, deposited plastic items are most likely transported to rivers and other waterways and ultimately discharged into estuarine and marine environments.
\nThe north of Italy and Croatia represent areas of intense horticultural activities where the agricultural practice of plastic mulching is prevalent. Plastic sheets are used to cover soil in order to preserve moisture, improve fertility and reduce weed infestation. Very often, fragments of plastic films are left behind after use and may accumulate in the soil, further fragmenting to produce nanometric particles. It has been estimated that 125–850 tons of microplastic per million inhabitants are added each year to agricultural soils in Europe, with an annual total of 63,000–430,000 tons of microplastic added to European farmlands. The northern part of Italy and Croatia is an area of significant agricultural and horticultural activities, therefore representing a potential hot spot for the release of plastic fragments in the terrestrial ecosystem. However, due to runoff phenomena these plastic items are most likely transported to rivers and other waterways and ultimately discharged into the estuarine and marine environments.
\nThe first pilot studies of microplastic abundance in confined areas of heavily populated areas like the Oslo fjord noted that a large fraction of particles may be related to city dust (e.g. asphalt and car tires). City dust in urban runoff is known as a significant source of pollution to waterways. Plastics, such as styrene-butadiene, styrene-ethylene-butylene-styrene copolymer, are also used in road materials to make the asphalt more elastic [37]. Another potential contributor to the emissions of plastic fragments is road marking paint as these paints have a variable fraction (1–10%) of thermoplastic component (e.g. styrene-isoprene-styrene, ethylene-vinyl acetate, polyamide and acryl-monomer). On the other hand, the tread of car tires is largely based on styrene-butadiene rubber, a synthetic polymer formulation. Therefore, road dust entering the sea through air or storm water carries a significant fraction of microplastic from road materials, marking paint and car tires.
\nThe description and understanding of the pathways of the entry of marine plastic pollution into the Adriatic Sea is a central element in tracing the pollution back to its sources and developing effective plastic pollution preventing policies. A complete understanding of the input of plastic pollution into the aquatic environment needs to consider the source sectors and the mechanisms of transportation, distribution and partition through different environmental matrices. If the release occurs in the terrestrial environment, rivers and wind or atmospheric circulation constitute the logic pathways. When considering the presence of plastic debris and microplastics in a part of the global Mediterranean Sea there is a need to consider the transfer of marine plastic pollution into the relevant part of the large water bodies through the regional circulation pathway like the Adriatic Sea. The understanding of the input through these pathways is crucial in gauging the relative importance of local sea-based or coastal sources versus remote sources within the Arctic watershed or from other parts of the ocean.
\nThe Adriatic Sea has a limited watershed. The largest rivers in the area are mostly located in the northern sector and include the Po, Adige, Tagliamento, and Arsa rivers. In terms of discharge, the Po River has the largest discharge with 1540 m3/s followed closely by the Adige River with 235 m3/s. The Po Basin is home to some 14 million people and extends over 24% of Italy’s territory. The Po catchment is densely populated and subjected to high anthropogenic pressure heavily anthropized. Indeed, it represents the largest cultivated area in Italy and accounts for one third of national’s agricultural production. The area account also for one of the highest concentrations of economic activities. Such massive river discharges make terrestrial influences particularly strong in the Adriatic Sea. However, to date there is no monitoring of the flux of plastics from rivers into the Adriatic Sea and though it has been identified as a possible pathway, the contribution of riverine discharge to plastic input is expected to be high because these rivers flow through densely populated and anthropized watersheds.
\nIt has been speculated that at the global level much less plastic debris is transported by wind than by rivers [38, 39]. However, wind transport of plastic debris may be significant, particularly in coastal areas dominated by strong periodic winds. Wind may be a significant contributor in lightweight debris distribution. During intense storms wind can mobilize debris that would not normally be available for transport and carry it directly into rivers and the sea. Wind-blown litter is likely to be considerable as the Adriatic Sea is characterized by periodically windy shorelines. Atmospheric circulation has been proven to provide an efficient pathway for the transportation of floating microfibers and small plastic particles in the Mediterranean Sea as well as in other areas [33, 40]. Furthermore, some preliminary transport models tailored to the Adriatic oceanographic conditions, considering the contribution of waves and wind in the surface plastic distribution, define the Adriatic Sea as a highly “dissipative” system with respect to floating plastics with a calculated half-life of floating condition of 43.1 days [41, 42]. The authors conclude by pointing out that by construction the Adriatic coastline may be responsible for the main sink of floating plastic debris.
\nThe contribution of inputs through the movement of marine water masses by currents also needs to be considered in the global distribution model. The Adriatic region is poorly connected to the Mediterranean through the southern edges of the Otranto strait and the Ionian Sea exchanging with the Mediterranean Sea. The exchange of water, and possibly any moving plastic pollution, from and to the Mediterranean Sea has recently been addressed by the modeling work of Liubartseva et al. [40] and partially by the results of Pasquini et al., [40] which pointed out the formation of an accumulation zone corresponding to the three well known gyres located northside, central and in the southern sector of the Adriatic Sea.
\nSome key research projects have recently addressed the need of defining the baseline levels of litter (macro-, meso- and microplastics) in the intertidal areas of beaches within the Adriatic Sea. Blašković et al. [41] investigated the occurrence of plastic debris in several sites of the Natural Park of Telaščica (Croatia). In all analyzed sites, fibers were the most recurring shape (90%) within the identified plastic debris while films where the second most common plastic fragment observed (7%) followed by pellet, foams, granules and unrecognized plastic pieces. Most of the plastic debris belonged to the size fraction from 1 mm and 64 μm (88%) followed by the fraction between 1 and 2 mm (11%). These results confirm previous characterization efforts of Laglbauer et al. [43] in six Slovenian beaches located in the gulf of Trieste (North-East Adriatic Sea). Within this assessment the authors sorted out a total of 5870 macro-debris units, yielding a median density of 1.25 items/m2. The detailed analyses of the processed samples revealed a dominant secondary microplastics source being fibers the 85% of the total observed plastics and a number of 155 particles m2 in the infralittoral zone, and 133 particles m2 on the shoreline. On the Adriatic beaches surveyed, plastic dominated in terms of abundance, followed by paper and other groups. The average density was 0.2 litter items m2, but at one beach it raised to 0.57 items m2. Among plastic, cigarette butts were the most frequently found type of litter, and other plastic items with the highest occurrence were: small fragments, bottles and bottle caps, cutlery, and mesh bags. Their presence is a good indicator of pollution from beach users [44]. Most of the beached marine litter are from land-based sources, but with different sources and contributors. The main source of litter was primarily touristic activities, accounting for 37.9% of found litter which is lower than r the Mediterranean average (52%; [45, 46]). Filter cigarette were the second litter origin, but with a value (25.5%) lower than indicated for the Mediterranean (40%) [44]. The high percentages of in situ deposited litter found in the investigated sites are caused by the high number of visitors, more than 700,000 annually mainly during the touristic season (see i.e.,
Few studies have addressed the occurrence of floating plastic debris in the surface water of the Adriatic Sea. Suaria et al. [33] reported by a larger study addressing the Mediterranean Sea and partially the Adriatic sector a clear prevalence of smaller particles. Quantitative estimations collected by a 400 μm net mesh pointed out values ranging from 0.4 ± 0.7 to 1.0 ± 1.8 items/m3. The overall result the study pointed out that, within a total no. of 14,106 scored particles, 26% of all counted particles were smaller than 300 μm while 51% were smaller than 500 μm being the mean abundance of these meso-particles of 0.016 ± 0.028 particles/m2. PE was the predominant form with an overall frequency of 52%, followed by PP (16%) and synthetic paints (7.7%). Polyamides (PA) accounted for 4.7% of all categorized particles which accounted alone for 2%), while PVC, PS and PVA represented equally contributed with 3% of the total. Other less frequent polymers (<1%) included: PET, polyisoprene, poly(vinyl stearate) (PVS), ethylene-vinyl acetate (EVA) and cellulose acetate. Noteworthy the authors concluded that the composition of western Mediterranean samples was dominated by low-density polymers such as polyethylene and polypropylene while the processed Adriatic samples instead were more heterogeneous and rather characterized by a higher presence of paint chips, PS, PVC, PVA and PAs. Within the “Derelict Fishing Gear Management System project – “DeFishGear” project co-funded by IPA-Adriatic Cross-border Cooperation Programme and the European Union, 120 visuals transect surveys were conducted during three cruises, covering a total length of 922.2 km [47]. A total of 1364 macro marine debris objects were observed floating on the Adriatic. The densities of the recorded floating debris were 5.66 items/km2. The authors estimated that the observed floating marine debris was mostly originated from coastal segments close the high-density population cities and major rivers and transported by cyclonic surface circulation until either stranding. They calculated an average time from source to the sighting point of 22.8 days. These outcomes support Carlson and co-workers [48] previous assessment where an average residence time of 22.9 days but with also an average transit times of 20–60 days from a coastal region in the northwest Adriatic to a coastal region in the southwest [47]. The transport pathways, residence times, and probable sources and sinks identified further support with previous studies of the Adriatic Sea surface circulation and marine debris published by Liubartseva et al., [40].
\nData regarding macro- and mesolitter on the sea-floor in the Adriatic Sea are also available from the “SoleMon” Project (Solea Monitoring—Rapido trawl survey in the Northern Adriatic Sea), carried out since 2005 in the Northern and Central Adriatic Sea [49]. Plastic litter was divided by the authors in three sub-categories based on its source: fishing nets, mussel culture debris and other plastic e.g., bottles, plastic glasses, bags. Lost fishing nets and mussel culture debris accounted for 50% of the overall plastic litter collected over the investigated period. The remaining plastic comprised a wide range of objects such as garbage bags, shopping bags, cups, bottles, food packaging, dishes, other kitchen stuffs and industrial packaging [40, 48]. Results of this study indicated that the largest amount of mussel culture debris was found close to the coast and its distribution was constant over the years. These nets might have been accidentally lost/abandoned at sea during the collection and preparation of the product [50]. In the meantime, the fishing nets were found mainly close to the coast within 3 nm. This distribution was explained as fishing nets were mainly set-nets used by small scale fisheries that usually fish not further than 3 nm where there is not trawl fishing that can destroy these nets. A significant contribution of plastic litter found close to the coast was represented by food packaging, plastic bags, bottles and dishes or kitchen tools. The land origin is due to the municipal solid waste [48]. The authors concluded considering that the distribution varied among the years, but the occurrence was mostly related to both the close position of the sampling site to large cities along the coast, where the population density increases during the touristic season as well as the contribution of river [40, 50, 51]. As regards the microliter in the sedimentary environment, a preliminary assessment of microplastics in marine sediments along a coast- off-shore transect in the Central Adriatic was performed by Munari et al. [44]. Plastic fragments recollected from 64 samples were scored, weighted and identified by FTIR. Microplastics ranging 1–30 mm were found in all analyzed samples. The most recurring shapes were filaments-like (69.3%), followed by fragments-like (16.4%), and film-like (14.3%). In term of size distribution, plastic fragments in a range from 1 to 5 mm accounted for 65.1% of debris, while larger fragments (5–20 mm) contributed with the 30.3% of total amount, while larger fragments >20 mm represented the 4.6% of total. Six were the most recurring polymer types: nylon, polyethylene and ethylene vinyl alcohol copolymer. Furthermore, sediments from several sampling sites located in Italy, Slovenia, Croatia, and Greece were also analyzed for plastic debris content by the “DeFishGear” project. Plastic fragments in beach sediments were ranked into large sized particles (1–5 mm) and small microplastic particles (<1 mm). In general, microplastic from 1 to 5 mm ranged from 11 to 710 items/m2. On the other hand, the fraction of smaller size scored from 70 to 6724 items/kg of dry sediments. The mean concentration for all Adriatic region was calculated as 113 ± 101 items/kg for the larger sized fragments and 1133 ± 1271 items/kg of dry sediments for the smaller ones. In detail, the selected Croatian beaches showed considerably greater presence of smaller microplastic per kg of sediment with value of approx. 227 items/kg of sediment while the larger sized fragments sored values approx. Ten times lower (17–28 items/kg of dry sediments). The composition of sorted fragments <1 mm showed the prevalence of plastic fragments as fragments represented approx. 70% of the total while filaments represented the left 29% of the total while a limited amount (1.8 and 0.9%) were film and foams. The chemical characterization of microplastic of the larger particles was performed on foams, pellets, fragments and filaments, while filaments and films were analyzed among the smaller sized particles. Beside the PE and PP in a few percent also PA, PET, PES, PS, PO, nylon and acrylic fibers were present among larger particles, while among the smaller viscose was detected. In the Greek sector data were obtained from three sites: the Halikounas, Issos and Acharavi beaches. The mean concentration of 1–5 mm sized debris varied from 68 items/m2 (Halikounas) to 58 items/m2 (Acharavi) while the small sized fraction of Ø > 1 mm showed values from 19 to 7 items/m2 respectively for Halikounas and Acharavi. The most abundant categories on Halikounas beach were fragments and foam, while on the contrary pellets were the most abundant in Issos and Acharavi beaches. Chemical characterization of fragments, for Halikounas beach were done being both PE and PP the most recurring polymers in the larger particles while PP was the most occurring polymer in the smaller size fraction. The same project also addressed the occurrence in the Italian sector. High amount of small microplastic particles (<1 mm), up to 2526 items/kg of sediment, was found in the Cesenatico area. In the meantime, a limited amount corresponding to 0.56–1.02 items/kg of large particles (1–5 mm) were reported. Overall, 73% of the small microplastic particles were characterized by fragments while the remaining 26% as filaments. On the other hand, the large microplastic particles had different amount of all categories; however, fragments resulted the most abundant category (44%). The chemical identification showed PE as the most abundant material, followed by PP, PO, PES, PS and PAN. In the Slovenian coastline the selected sampling site showed a higher abundance of small microplastic particles (615 items/kg) respect of large microplastic particles (516 items/kg). In detail, the analysis of the small size fraction reported filaments being the predominant type of the microplastic composition, with representation of approx., 76% of the total. The second most common type of microplastic category were fragments and the third were films, with occurrence high as 9.5%. The chemical identification pointed out PE as the most recurring polymer type in the analyzed sediment samples, followed by PP, PET and PVC. Finally, Vianello and co-workers investigated the Venice Lagoon, a fragile estuarine ecosystem dominated by diversified anthropogenic activities, suspected to be a hot spot of plastic debris contamination [53]. Plastic debris of ≤1 mm or less was investigated in sediments collected from 10 sites chosen in shallow areas. Total abundances of plastic fragments varied from 2175 to 672 items/kg with higher concentrations generally found in the inner parts of the Lagoon. PE, PP, ethylene propylene (PEP), polyester (PEst), polyacrylonitrile (PAN), PS, alkyd resin (Alkyd), PVC, polyvinyl alcohol (PVOH) and NyL were identified. PE and PP were the most recurring polymer in the investigated samples which accounted for more than 82% of the total detected plastic debris in the whole sampling area. Among all classified shapes, irregular fragments accounted of the 87% of the total while films (2%) and pellets/granules (1%) were only occasionally recognized [54].
\nThe first report on the harmful effects of plastic debris ingestion on marine species in the Adriatic Sea was published in 1999 [55]. A dead dolphin S. coeruleoalba with the stomach occluded by different kinds of plastic materials was found near the island Krk, in the North Adriatic Sea. A following study on the logger head sea turtles, C. caretta, revealed a percentage of 35.2% of turtles sampled in the eastern Adriatic Sea were affected by plastic debris [55]. Occurrence of MPs in the gastrointestinal tract and gills of pelagic and demersal fish and marine mammals have been reported [56]. Few plastic debris accumulation studies have been performed in the Adriatic Sea. Pellini et al. [57] aimed at characterizing the occurrence, amount, typology of microplastic litter in the gastrointestinal tract of a benthic fish, S. solea, in the northern and central Adriatic Sea. The digestive tract contents of over 500 individuals were collected from 60 sampling sites and examined for microplastics. These were recorded in 95% of sampled fish, with more than one microplastic item found in around 80% of the examined specimens. The most commonly found polymers were PVC, PP, PE, polyester (PES) and PA. In details, 72% of the total classified plastic debris were fragments and 28% were identified as fibers. The mean number of ingested microplastics was 1.6–1.7 items/fish. PVC and PA showed the highest densities in the northern Adriatic Sea, both inshore and off-shore while PE, PP and PET were more concentrated in coastal areas with the highest values offshore from the port of Rimini. These results confirm previous observations of Avio and co-workers [13] in various fish species collected along the Adriatic Sea. FTIR analyses indicated PE as the predominant polymer (65%) in the stomach of fish. More than 100 fish representatives of five commercial species like S. pilchardus, S. acanthias, M. merlucius, M. barbatus C. lucernus were collected from the Central and North Adriatic Sea. The mean number of ingested microplastics was 1.0–1.7 items/fish. In details, the shape of the plastic debris observed in the stomachs of the investigated samples was mostly fragments and line followed by film and pellet. The 18% of extracted microplastics exhibited the larger size class (from 5 to 1 mm), 43% was between 1 and 0.5 mm, 23% between 0.5 and 0.1 mm, and the 16% lower than 0.1 mm. The chemical characterization pointed out that approximately 65% of analyzed plastic fragments were PE, followed by PET, PS, PVC, Nylon and PP. These early findings suggest the possible accumulation of plastic debris through the food web. Despite of some recent findings point out that at the bottom of the food pyramid, filter feeders, such as mussels can ingest and incorporate MPs in their tissues [58], more research is needed to unveil the abundance, distribution and polymeric composition of plastic debris in marine organisms at different levels ecological web in areas like the Adriatic Sea were multiple anthropogenic activities coexist.
\nThe few available studies in the area prove the ubiquity of plastic pollution in the Adriatic Sea. The peculiar oceanographic conditions as well as the high levels of plastic debris recorded in all investigated matrices tend to classify such enclosed area as a hot spot of plastic contamination. Despite the distribution and circulation models appear to accurately estimate fluxes and final fate of marine plastic debris, sinks, sources, fate and residence times of different polymers at sea are the knowledge gaps that need to be addressed in the future to provide concrete info to support concrete actions toward plastic contamination reduction and remediation solutions.
\nThe authors wish to thank The International Research Institute of Stavanger and the National Research Council of Italy- Institute of Marine Science for technical assistance and financial support to publish this work.
\nThe authors declare no conflict of interest.
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