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An antibiotic stewardship exercise in the ICU: building a treatment algorithm for the management of ventilator-associated pneumonia based on local epidemiology and the 2016 Infectious Diseases Society of America/American Thoracic Society guidelines

An antibiotic stewardship exercise in the ICU: building a treatment algorithm for the management... Journal name: Infection and Drug Resistance Article Designation: ORIGINAL RESEARCH Year: 2018 Volume: 11 Running head verso: Awad et al Infection and Drug Resistance Dovepress Running head recto: VAP treatment algorithm based on local data open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IDR.S145827 Open Access Full Text Article O RIG INAL RESEARCH An antibiotic stewardship exercise in the ICU: building a treatment algorithm for the management of ventilator-associated pneumonia based on local epidemiology and the 2016 Infectious Diseases Society of America/American Thoracic Society guidelines 1, Introduction: Management of ventilator-associated pneumonia (VAP), the most common infec- Lyn S Awad * 1, tion in patients on mechanical ventilation, should be tailored to local microbiological data. The Dania I Abdallah * 2,3 aim of this study was to determine susceptibility patterns of organisms causing VAP to develop Anas M Mugharbil 2,4 a treatment algorithm based on these findings and evidence from the literature. Tamima H Jisr Materials and methods: This is a retrospective analysis of the microbiological etiology of Nabila S Droubi VAP in the intensive care unit (ICU) of a Lebanese tertiary care hospital from July 2015 to Nabila A El-Rajab July 2016. We reviewed the latest clinical practice guidelines on VAP and tried to adapt these 2,6,7 Rima A Moghnieh recommendations to our setting. Pharmacy Department, Makassed Results: In all, 43 patients with 61 VAP episodes were identified, and 75 bacterial isolates General Hospital, Faculty of caused VAP. Extensively drug-resistant (XDR) Acinetobacter baumannii was the most common Medicine, Beirut Arab University, Department of Internal Medicine, organism (37%), and it had occurred endemically throughout the year. Pseudomonas aeruginosa Division of Hematology-Oncology, was the next most common organism (31%), and 13% were XDR. Enterobacteriaceae (15%) Department of Laboratory 5 and Stenotrophomonas maltophilia (12%) shared similar incidences. Our algorithm was based Medicine, Department of Internal Medicine, Department of Internal on guidelines, in addition to trials, systematic reviews, and meta-analyses that studied the Medicine, Division of Infectious effectiveness of available antibiotics in treating VAP. Diseases, Makassed General Hospital, Conclusion: Knowing that resistance can rapidly develop within a practice environment, more Department of Internal Medicine, Faculty of Medical Sciences, Lebanese research is needed to identify the best strategy for the management of VAP. University, Beirut, Lebanon Keywords: ventilator-associated pneumonia, Pseudomonas aeruginosa, Acinetobacter bauman- *These authors contributed equally to nii, local epidemiology, carbapenem-sparing strategy, guidelines this work Introduction Ventilator-associated pneumonia (VAP) is the most well-known nosocomial infection complicating the course of intubated patients and the leading cause of death in critical care settings worldwide, in addition to being the first cause of antibiotic prescription Correspondence: Rima A Moghnieh Department of Internal Medicine, in intensive care units (ICUs) despite the development of prevention bundles. Epi- Division of Infectious Diseases, Makassed sodes caused by multidrug-resistant (MDR), extensively drug-resistant (XDR), and General Hospital, Tarik Al-Jadida, PO Box 11-6301, Riad El-Solh, Beirut pandrug-resistant (PDR) organisms further aggravate the situation, thus imposing 1107 2210, Lebanon a considerable clinical and economic burden, along with the limited and exhausted Tel +961 3 82 9363 Email moghniehrima@gmail.com antibiotic armamentarium. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 17–28 Dovepress © 2018 Awad et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/IDR.S145827 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Awad et al Dovepress Infection control and antimicrobial stewardship programs procedures. Culture plates were incubated at 37°C for are mainstay strategies for curbing down resistance. Specifi- 24 hours. The Clinical and Laboratory Standards Institute cally, antibiotic treatment guidelines constitute a core element (CLSI) breakpoints for the available systemic antibiotics 3 6 of antimicrobial stewardship programs. Yet, clinical practice were used to determine susceptibility at our facility. No guidelines developed by international societies need to be interpretation data are available for tigecycline susceptibility tailored according to local epidemiology. Timely surveil- against Acinetobacter baumannii from CLSI or the Euro- lance for local microbiological data is extremely important pean Committee on Antimicrobial Susceptibility Testing in predicting the type of resistance that may be present in the (EUCAST) regardless of the testing method. Therefore, 3 8 etiologic agent causing a clinical infection. we applied clinical breakpoints suggested by Jones et al In July 2016, the Infectious Diseases Society of America (susceptible [S] ≥ 16 mm, intermediate [I] 13–15 mm, 6 7 (IDSA) and the American Thoracic Society (ATS) updated and resistant [R] ≤12 mm). Neither CLSI nor EUCAST their clinical practice guidelines for the management of guideline provides disk diffusion zone diameter breakpoints hospital-acquired pneumonia (HAP) and VAP. for colistin (CST) susceptibility against A. baumannii. In In this study, our aim was to determine susceptibility our center, CST susceptibility was determined using the patterns of the leading organisms causing VAP in the ICU of disk diffusion method with the following breakpoints: S ≥ our facility in order to develop a treatment algorithm based 11 mm and R ≤ 8 mm. on the 2016 IDSA/ATS guideline recommendations. We also Gram-negative organisms were labeled as MDR or XDR aimed to review available therapeutic options for the treat- as described by Magiorakos et al. XDR A. baumannii in ment of resistant organisms causing VAP, based on evidence our institution was carbapenem resistant and susceptible only from the literature. to polymyxins ± glycylcyclines. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were labeled XDR when resistant to all tested available antibiotics except for the Materials and methods polymyxins. Ceftolozane/tazobactam was not available for Setting and study design use in Lebanon at the time of the study. This is a retrospective analysis of the microbiological etiology In our study, a pathogen is considered endemic when of VAP in the ICU in a tertiary care hospital in Lebanon. Data challenges from admitting patients colonized or infected were retrieved from the medical microbiology laboratory with this organism are constantly present. Yet, an organ- logbooks and patients’ electronic medical records from July ism is considered as epidemic where there is an unexpected 2015 to July 2016. Data included bacterial species isolated increase in cases of infections due to this pathogen for a from endotracheal aspirate specimens along with their anti- short period of time. biotic susceptibility patterns. Duplicate isolates, colonizers, and organisms causing respiratory tract infections other than Development of our own VAP were omitted from the analysis. recommendations and VAP treatment The distribution of pathogens causing VAP was plotted against time. Endemic pathogens in the ICU were identified, algorithm as well as other organisms that caused occasional epidemics. The latest clinical practice guidelines endorsed by IDSA/ Antibiotic history within 90 days of the VAP episodes was ATS on the management of adults with HAP/VAP were also reviewed. As recommended by the World Health Orga- reviewed. We tried to adapt the stated recommendations to nization (WHO), antimicrobial consumption was reported our ICU epidemiology, when applicable. For certain resistant in defined daily dose (DDD) per 100 bed day (BD), a stan- organisms, no specific recommendations were made; hence, dardized figure that provides a degree of comparison among we conducted a profound literature search in order to base inpatients in different hospitals. our proposed choices on solid evidence. Our propositions were based on trials, case reports, systematic reviews, and Microbiological studies and breakpoints of resistance meta-analyses that studied the effectiveness of specific anti- Bacterial identification was performed according to standard biotic combinations in the treatment of VAP caused by MDR microbiologic procedures. Antibiotic susceptibility testing and XDR organisms. Finally, we proposed an algorithm for was performed using the Kirby–Bauer disk diffusion test empiric data and targeted antibiotic therapy for VAP as a on Mueller–Hinton agar (Oxoid Ltd.) according to standard basis for antibiotic stewardship in the ICU of our facility. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Dovepress VAP treatment algorithm based on local data According to the hospital infection control data, there Ethical approval was a constant challenge from admitting patients colo- The institutional review board committee of Makassed Gen- nized or infected with this organism to ICU. Subsequently, eral Hospital approved this study. A. baumanii was considered as an endemic organism. XDR P. aeruginosa was recovered sporadically from three cases Informed consent on three separate occasions during the year, and each was No informed consent was required due to the retrospective separated by a 2- to 4-month interval. It was considered as nature of this study. During the data collection phase, a spe- an organism causing separate ICU epidemics. However, cial form was used where patient initials and case numbers non-XDR P. aeruginosa is a common organism, isolated in were only included. At a later stage, a different number was a continuous manner throughout the year. It has been equally assigned to each of our cases to safeguard patient privacy. susceptible to LVX, CAZ, FEP, and TZP. Only one isolate All contributing authors performed data entry and analysis showed resistance to FEP plus LVX, and another was resistant as well as the drafting of the paper. to TZP plus LVX. With regard to Enterobacteriaceae, 3GC- sensitive isolates predominated over 3GC-resistant ones and Results were regularly isolated throughout the year. 3GC-resistant From July 2015 to July 2016, 776 patients were admitted to species were isolated sporadically in 2 months only and the ICU of our facility where total patient days were 4792 separated by a 6-month interval. The most active antibiotics and total ventilator days were 1533. During this period, 43 against the recovered Enterobacteriaceae were LVX and FEP. patients with 61 VAP episodes were identified, of which 47 None of the isolates were resistant to FEP plus LVX or TZP (77%) were monomicrobial episodes and 14 (23%) were plus LVX. Both XDR S. maltophilia and methicillin-resistant polymicrobial episodes. From all organisms isolated from S. aureus (MRSA) were isolated in 1 month only. endotracheal aspirate specimens (N=108 isolates), 75 iso- In our ICU, antimicrobial consumption measured using lates were implicated in causing VAP during this period: DDD/100 BD showed that carbapenems were the most com- 72 gram-negative isolates (96%) and three gram-positive monly used broad-spectrum antimicrobials (16.7 DDD/100 isolates (4%; Table 1). BD), followed by FQ (9.68 DDD/100 BD) and CST (5.74 Among the gram-negative isolates, A. baumannii pre- DDD/100 BD; Figure 1). dominated (37.33%), followed by P. aeruginosa (30.76%), Enterobacteriaceae (14.67%), and S. maltophilia (12%). Discussion Antibiotic susceptibility patterns are provided in Table 1. In this study, we described the microbiological etiology of Among A. baumannii (28 isolates), 92.86% were XDR, VAP in patients admitted to an ICU from July 2015 to July 3.57% were MDR, and 3.57% were PDR. With respect to 2016, and we proposed an antibiotic treatment pathway based P . aeruginosa (23 isolates) susceptibility to antibiotics, 56.5% on the most recent international guidelines. were susceptible to carbapenems, 69.6% to piperacillin/ tazobactam (TZP), 73.9% to ceftazidime (CAZ), and 78.3% Current local epidemiology of VAP to levofloxacin (LVX) and 13% were XDR. For Enterobac- The microbiological ecology and the frequency of specific teriaceae (11 isolates), 81.8% were susceptible to cefepime pathogens causing VAP vary by hospital, patient population, (FEP), 72.7% to third-generation cephalosporins (3GC) and exposure to antibiotics, and type of ICU patients, and they TZP, and 81.8% to fluoroquinolones (FQ). All isolates were change over time, emphasizing the need for timely local sur- fully susceptible to carbapenems. Among S. maltophilia (nine veillance data. According to the 2016 IDSA/ATS guidelines isolates), 55.6% were susceptible to CAZ, 77.8% to LVX, on VAP , each hospital should generate its own antibiograms and 88.9% to trimethoprim/sulfamethoxazole (TMP/SMX). to guide health care professionals in the optimal choice of One S. maltophilia isolate was resistant to CAZ, LVX, and antimicrobials to curb down resistance caused by the expo- TMP/SMX, yet found susceptible to CST and thus was con- sure to unnecessary antibiotics. sidered XDR. S. aureus was the only gram-positive species Studies from the Middle East involving the incidence, isolated for which one of the three isolates identified was microbiology, and antimicrobial susceptibility patterns of methicillin resistant. bacteria causing VAP are scarce. Only one study from Leba- The temporal distribution of ICU pathogens causing VAP non was published by Kanafani et al in 2003. It was a pro- is shown in Table 2. XDR A. baumannii was isolated from spective observational cohort study at a tertiary-care center ICU patients almost every month throughout the study period. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress Table 1 Distribution of bacteria causing VAP according to their antibiotic susceptibility patterns Organisms Number of isolates Percentage from Percentage from total (%) own species (%) (n=75 isolates) Gram-negative species 72 96 A. baumanii 28 37.33 MDR 1 3.57 1.33 XDR 26 92.86 34.67 PDR 1 3.57 1.33 P. aeruginosa 23 30.67 TZP S 16 69.57 21.33 TZP R 7 30.43 9.33 CAZ S 17 73.91 22.67 CAZ R 6 26.09 8 FEP S 16 69.57 21.33 FEP R 7 30.43 9.33 AMK S 15 65.22 20 AMK R 8 34.78 10.67 LVX S 18 78.26 24 LVX R 5 21.74 6.67 CAR S 13 56.52 17.33 CAR R 10 43.48 13.33 FEP and LVX R 4 17.39 5.33 TZP and LVX R 4 17.39 5.33 (FEP and LVX R) but CAR S 0 0 0 (TZP and LVX R) but CAR S 1 4.34 1.33 Non-XDR 20 86.96 26.67 XDR 3 13.04 4 Enterobacteriaceae 11 14.67 3GC S 8 72.73 10.67 3GC R 3 27.27 4 TZP S 8 72.73 10.67 TZP R 3 27.27 4 FEP S 9 81.82 12 FEP R 2 18.18 2.67 FQ S 9 81.82 12 FQ R 2 18.18 2.67 CAR S 11 100 14.67 CAR R 0 0 0 FEP and LVX R 1 9.09 1.33 TZP and LVX R 1 9.09 1.33 S. maltophilia 9 12 LVX S 7 77.78 9.33 LVX R 2 22.22 2.67 CAZ S 5 55.56 6.67 CAZ R 4 44.44 5.33 TMP/SMX S 8 88.89 10.67 TMP/SMX R 1 11.11 1.33 CST S NA NA NA XDR 1 11.11 1.33 B. cepacia 1 1.33 Gram-positive species 3 4 S. aureus 3 4 MET S 2 66.67 2.67 MET R 1 33.33 1.33 Notes: S. maltophilia is not tested routinely in the hospital for CST susceptibility, unless it is resistant to other alternatives (being an XDR). One isolate was XDR and was found susceptible to CST. Abbreviations: A. baumannii, Acinetobacter baumannii; AMK, amikacin; B. cepacia, Burkholderia cepacia; CAR, carbapenem; CAZ, ceftazidime; CST, colistin; FEP, cefepime; FQ, fluoroquinolones; LVX, levofloxacin; MDR, multi-drug resistant; MET, methicillin; NA, not available; P. aeruginosa , Pseudomonas aeruginosa; PDR, pandrug resistant; R, resistant; S, susceptible; S. aureus, Staphylococcus aureus; S. maltophilia, Stenotrophomonas maltophilia; TMP/SMX, trimethoprim/sulfamethoxazole; TZP, piperacillin/tazobactam; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant; 3GC, third-generation cephalosporins. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Dovepress VAP treatment algorithm based on local data submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Table 2 Temporal distribution of bacteria causing VAP (number of isolates) over 12-month period from July 2015 to July 2016 Organisms July August September October November December January February March April May June July 2015 2015 2015 2015 2015 2015 2016 2016 2016 2016 2016 2016 2016 A. baumannii 2 1 3 1 2 0 0 4 4 2 2 4 3 XDR 2 1 3 1 1 0 0 4 4 2 1 4 3 P. aeruginosa 1 1 1 1 3 0 0 6 2 0 2 3 3 TZP S 1 1 1 1 2 0 0 4 2 0 2 1 1 FEP S 1 1 1 1 2 0 0 4 1 0 2 2 2 CAZ S 1 1 1 1 2 0 0 3 1 0 2 2 2 LVX S 1 1 1 1 2 0 0 5 1 0 2 3 1 FEP or LVX S 1 1 1 1 1 0 0 5 1 0 2 3 2 TZP or LVX S 1 1 1 1 2 0 0 5 2 0 2 3 1 FEP and LVX R 0 0 0 0 0 0 0 0 1 0 0 0 0 TZP and LVX R 0 0 0 0 0 0 0 0 0 0 0 0 1 Non-XDR 1 1 1 1 2 0 0 5 2 0 2 3 2 XDR 0 0 0 0 1 0 0 1 0 0 0 0 1 Enterobacteriaceae 1 0 2 1 0 1 0 0 2 0 1 1 2 LVX S 0 0 1 1 0 1 0 0 2 0 1 1 2 TZP S 1 0 1 1 0 1 0 0 1 0 1 1 1 FEP S 1 0 0 1 0 1 0 0 2 0 1 1 2 3GC S 1 0 0 1 0 1 0 0 1 0 1 1 2 FEP or LVX S 1 0 1 1 0 1 0 0 2 0 1 1 2 TZP or LVX S 1 0 1 1 0 1 0 0 2 0 1 1 2 3GC R 0 0 2 0 0 0 0 0 1 0 0 0 0 FEP and LVX R 0 0 1 0 0 0 0 0 0 0 0 0 0 TZP and LVX R 0 0 1 0 0 0 0 0 0 0 0 0 0 S. maltophilia 0 0 0 0 0 0 1 3 1 0 0 0 4 LVX S 0 0 0 0 0 0 1 3 1 0 0 0 2 CAZ S 0 0 0 0 0 0 1 1 0 0 0 0 3 XDR 0 0 0 0 0 0 0 0 0 0 0 0 1 MRSA 0 0 0 0 0 0 0 1 0 0 0 0 0 Abbreviations: A. baumannii, Acinetobacter baumannii; CAZ, ceftazidime; FEP, cefepime, LVX, levofloxacin; MRSA, methicillin-resistant S. aureus; P. aeruginosa, Pseudomonas aeruginosa; R, resistant; S, susceptible; S. aureus, Staphylococcus aureus; S. maltophilia, Stenotrophomonas maltophilia; TZP, piperacillin/tazobactam; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant; 3GC: third-generation cephalosporins. Awad et al Dovepress CAR TZP FEP CAZ CRO AMG TGC CST GLY–LZDFQ Figure 1 Antibiotic consumption in the ICU of our facility during the study period (July 2015–July 2016) reported in DDD/100 BD. Note: x-axis, type of antimicrobial; y-axis, DDD/1000 bed days. Abbreviations: AMG, aminoglycosides; BD, bed day; CAR, carbapenems; CAZ, ceftazidime; CRO, ceftriaxone; CST, colistin; DDD, defined daily dose; FEP, cefepime; FQ, fluoroquinolones; GLY, glycopeptides (vancomycin and teicoplanin); ICU, intensive care unit; LZD, linezolid; TGC, tigecycline; TZP, piperacillin/tazobactam. involving all patients admitted to the ICU and respiratory care has been increasingly associated with nosocomial epidemics 14 15 unit from March to September 2001 who were on mechani- in the ICUs of our region and worldwide. Of particular cal ventilation for at least 48 hours. The most commonly concern is its environmental resilience, resulting in sustained isolated organisms were gram-negative bacilli, among which outbreaks and endemic situations, as well as its inherent and Acinetobacter and Pseudomonas species were predominant. acquired mechanisms of resistance to antibiotics, rendering With respect to the antibiotic susceptibility pattern, 50% of it the prototype of XDR bacteria. Non-XDR P. aeruginosa the gram-negative isolates were antibiotic resistant, yet 91% is another endemic pathogen in our facility, yet isolation of were still carbapenem susceptible at that time. Our study is XDR strains was sporadic. Acquisition of XDR P. aerugi- the second from the country involving VAP etiology in the nosa in the ICU, causing these epidemic bouts, depends on era of resistance and limited treatment options. variables including colonization pressure created by carriers In our facility, gram-negative bacteria predominated, and antibiotic-selective pressure. representing 96% of the total respiratory isolates. Compared to findings by Kanafani et al in 2003, A. baumannii and Antibiotic consumption in critical care P. aeruginosa are still the leading organisms; however, the Critical care units manage only a small proportion of hos- emergence of carbapenem-resistant strains in both species is pitalized patients but administer disproportionately large striking in our 2016 series. According to recently published quantities of broad-spectrum antimicrobials, which are antimicrobial resistance data from hospitals all across Leba- implicated in resistance. In Lebanon, a national surveil- non, A. baumannii and P. aeruginosa have emerged as fre- lance system for antimicrobial resistance and antimicrobial quent nosocomial pathogens, and carbapenem susceptibility consumption is not yet established. However, resistance has reached 18% and 73%, respectively, in this nationwide data and antibiotic prescription patterns are derived from 13,19 study. This rate of antimicrobial resistance constitutes a published multicenter studies. Our results showed that major threat in critical care units. carbapenems were the most widely prescribed during the study period (16.72 DDD/100 BD), followed by other broad- Temporal distribution of pathogens spectrum antibiotics, including third- and fourth-generation causing VAP cephalosporins (total of 9.83 DDD/100 BD) and FQ (9.68 With respect to the temporal distribution of pathogens causing DDD/100 BD; Figure 1). A recently published multicenter VAP throughout the study period (Table 2), XDR A. bauman- cross-sectional study assessed antibiotic consumption from nii has shown an endemic pattern in our ICU. Likewise, it pharmacy electronic records in 27 nonteaching Lebanese submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress 16.72 4.43 5.03 1.48 3.33 1.95 3.27 5.74 5.69 9.68 Dovepress VAP treatment algorithm based on local data hospitals during 2012. Antibiotic consumption was stratified gram-positive bacteria, S. aureus represented 4% of all according to the geographical location, occupancy rate, and isolated species, among which 67% were still methicillin number of beds, including the number of ICU beds. Results susceptible (Table 1). Thus, we chose not to include MRSA showed that the average carbapenem consumption in ICUs in the empiric therapy for VAP unless there is evidence with nine or more beds reached 6.16 DDD/100 BD, which of previous MRSA colonization or contact with another is much less in comparison with our results. This major dif- colonized/infected subject. Otherwise, the chosen empiric ference in carbapenem use may be attributed to the type of antimicrobial therapy should cover methicillin-susceptible facilities described. Ours is a tertiary-care teaching hospital, strains. Therefore, empiric therapy should be broadened to and the ones reported by Iskandar et al were primary- and include a beta-lactam/beta-lactamase inhibitor (TZP) plus an secondary-care nonteaching health care facilities. Moreover, antipseudomonal fluoroquinolone (LVX), plus an anti-gram- carbapenems are the drug of choice in cases of sepsis in negative antibiotic targeting XDR Acinetobacter strain. At a the hospital protocols due to the increasing prevalence of later stage, this regimen will be replaced by definitive therapy extended spectrum beta lactamase (ESBL)-producing organ- once deep tracheal aspirate culture results and corresponding isms in the community and hospital flora, according to recent antibiotic susceptibility patterns are available (Figure 2). 13,20 surveillance data. Yet, the extensive use of carbapenems Treatment options for specific organisms for the management of resistant organisms led to the selec- 14,21 tion of carbapenem-resistant species. Moreover, findings and streamlining antibiotic therapy in VAP from a recently published Lebanese study showed that recent in era of resistance antibiotic intake was an independent risk factor associated Once deep tracheal aspirate culture results are available, with the fecal carriage of ESBL-producing Enterobacteria- empiric therapy should be replaced by targeted therapy based ceae in long-term care facility residents. on susceptibility patterns and available therapeutic agents. Following are treatment options for each specific organism Strategy for choosing empiric therapy (Figure 2). for VAP The cumbersome task of choosing appropriate empiric XDR A. baumannii antibiotics for VAP remains. In addition, adequate timing of Almost all the A. baumannii isolates in our series were antibiotic administration, ideally within the first hour, is an resistant to carbapenems, yet were still susceptible to CST essential element in determining the outcome of critically and tigecycline. Susceptibility to sulbactam was not tested ill patients with infection. Combination antibiograms are since it is not available in the country. The 2016 IDSA/ATS important tools to optimize empiric therapy in the ICU guidelines on VAP expert panel recommended against the through identifying which antimicrobial combinations give use of tigecycline owing to its decreased therapeutic efficacy the highest likelihood of having at least one active agent in VAP and increased mortality rate in comparison to CST- 4,25 against all likely causative pathogens in a specific disease containing regimens. Thus, intravenous CST is the only state (VAP), thereby minimizing prolonged delays in insti- remaining therapeutic option for such cases. Yet, it is well 24 26 tuting appropriate antimicrobial therapy. Combination known for its nephrotoxic and neurotoxic profiles. The use antibiograms are advantageous to traditional ones because of adjunctive therapies with additive or synergistic effects they focus on the susceptibility of potential second agents for to CST was profoundly discussed in the 2016 IDSA/ATS combination (FQ) in the setting of resistance to the primary guidelines. The panel recommended the use of adjunctive agent (the beta-lactam). aerosolized CST, since it improved clinical outcomes without According to our results, empiric therapy targeting, first, increasing harms. Conversely, adjunctive rifampicin did not XDR A. baumannii is highly justified, especially because it improve outcomes and, therefore, was not recommended. has been an endemic pathogen in our facility, along with its Accordingly, we join the guidelines in adding intravenous highest incidence in VAP etiology (Tables 1 and 2). Second, plus inhaled CST to our selected empiric treatment regimen both P. aeruginosa and Enterobacteriaceae susceptible to for VAP. After definitive culture results are obtained indicat- FEP plus LVX or to TZP plus LVX represented ~95% and ing the isolation of XDR A. baumannii, intravenous plus ~99% of total isolates, respectively (Table 1). This would inhaled CST only will be used, and all other antibiotics will give us an at least 95% chance of using either combination be discontinued. If cultures are negative for A. baumannii, for targeting susceptible strains of both organisms. Regarding CST is discontinued. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress Empiric treatment for VAP: TZP+LVX+CST After DTA culture results are revealed, targeted therapy should be initiated according so susceptibility patterns XDR Acinetobacter Pseudomonas Stenotrophomonas Enterobacteriaceae baumannii aeruginosa maltophilia 1-TMP/SMX XDR Pseudomonas Clinically stable 2-CAZ Non-3GCR organism: aeruginosa: patient without a risk 3-LVX 3GCR organism: therapy based on IV + aerosolized CST IV + aerosolized CST Clinically unstable, of imminent death: –If an XDR strain is carbapenem susceptibility patterns septic patient at high monotherapy identified: IV+ and patient-specific risk of imminent according to aerosolized CST factors (preferably death: susceptibility patterns non-antispseudomonal Dual antipseudomonal (preferably CAZ or cephalosporin like therapy according to FEP) CRO) susceptibility patterns (preferably to include CAZ or FEP) Figure 2 Our proposed treatment algorithm for empiric and targeted treatment of VAP. Abbreviations: A. baumannii, Acinetobacter baumannii; CAZ, ceftazidime, CRO, ceftriaxone; CST, colistin; DTA, deep tracheal aspirate; FEP, cefepime; IV, intravenous; LVX, levofloxacin; P. aeruginosa, Pseudomonas aeruginosa; S. maltophilia, Stenotrophomonas maltophilia; TMP/SMX, trimethoprim/sulfamethoxazole; TZP, piperacillin/tazobactam; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant; 3GCR, third-generation cephalosporin resistant. stable patients who are not in septic shock and not at a high P. aeruginosa risk for death. Aminoglycoside monotherapy should not For the empiric treatment of suspected VAP due to be used due to poor lung tissue penetration, resulting in no P. aeruginosa, double coverage with two antipseudomonal detectable antipseudomonal activity within bronchial secre- antibiotics from different classes is warranted in patients tions despite therapeutic aminoglycoside serum in patients with risk factors for resistance. This applies in units where with Pseudomonas pulmonary infection. Moreover, there the rate of resistance to any of the antipseudomonal agents is is a lack of studies evaluating the effects of aminoglycoside greater than 10%. This 10% threshold for deciding whether monotherapy in VAP. In settings with a high prevalence to prescribe two antipseudomonal agents was chosen by the for XDR P. aeruginosa, routine antimicrobial susceptibil- expert panel of the IDSA/ATS guidelines with the aim of ity testing should include assessment of its sensitivity to optimizing empiric therapy. When applicable, individual polymyxins. Accordingly, for the empiric management of ICUs may choose to modify this threshold according to their P. aeruginosa in our facility, we propose to use FEP plus current local microbiologic data and patient-related risk LVX or TZP plus LVX for double coverage. With regard to factors. The choice of definitive therapy should be based direct therapy, CAZ or FEP monotherapy is preferred when on antibiotic susceptibility patterns. These guidelines state Pseudomonas isolates are susceptible to it. In our facility, that combination therapy using two antibiotics is indicated minimal inhibitory concentration (MIC) determination is in patients who remain in septic shock or who are at a high not routinely performed; thus, we propose using prolonged risk for death with a documented Pseudomonas infection. infusions of high-dose FEP. When Pseudomonas is proved The expert panel of the IDSA/ATS guidelines did not prefer to be XDR, only intravenous plus inhaled CST is to be used. a specific regimen against documented Pseudomonas infec- tion. However, imipenem may have outcomes inferior to other regimens based on a systematic review of randomized ESBL-producing Enterobacteriaceae trials by Zilberberg et al. However, no recommendation ICUs in the USA and Europe have witnessed an increase was made against using imipenem, since the results obtained in the incidence of ESBL-producing Enterobacteriaceae were derived from trials limited by risk of bias and impreci- infections. The optimum treatment for infections due to 4 33 sion. As for monotherapy, it is preferably used in clinically ESBL-producing pathogens has been a subject of debate. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Dovepress VAP treatment algorithm based on local data Carbapenems have been considered the agents of choice patient-specific characteristics, most notably severity of ill- 34 43 against these serious infections. However, the emerging ness, were more significant predictors of patient outcomes. and rapid spread of carbapenem resistance in different gram- In another multicenter retrospective study between 2002 and negatives, including Enterobacteriaceae, has led to initiating 2007, Lee et al showed that FEP is a potentially effective carbapenem-sparing strategies and alternative therapeutic option for treating bacteremia caused by ESBL-producing approaches for the treatment of ESBL infections. Empiri- Enterobacteriaceae, but only if the MIC of the infecting cal treatment covering ESBL-producing Enterobacteriaceae organism was sufficiently low (i.e., ≤ 1 μg/mL). A more recent should be based on the following criteria: geographical areas, study by Wang et al compared the empiric use of FEP to epidemiological settings, and individual risk factors. FEP carbapenems in propensity score-matched cohort patients and the β-lactam-β-lactamase inhibitors (BLBLIs) have been with ESBL-producing organisms. Similar to the findings the most widely studied carbapenem-sparing options based by Chopra et al, a nonsignificant trend toward increased on their favorable in vitro susceptibility profile to ESBL- mortality was observed in patients treated with FEP versus producing organisms. those treated with carbapenems. BLBLIs such as TZP have been recommended as an In our series, 3GC-resistant Enterobacteriaceae repre- alternative to carbapenems for ESBLs. In clinical practice, sented 4% of the total isolates causing VAP. In addition, BLBLIs are often perceived as inferior to carbapenems in Enterobacteriaceae isolates resistant to FEP plus LVX or to this setting, although there is no strong supporting evidence. TZP plus LVX represented 1.33% of the total isolates (Table The most relevant studies in this topic came to different con- 1). Accordingly, we elect to avoid carbapenem use in the clusions. In a single-center retrospective cohort study over empiric management of VAP despite the possibility of being 7 years involving 331 patients with bacteremia caused by caused by ESBL organisms and stick to the previously stated ESBL-producing Enterobacteriaceae, Tamma et al found that combination regimen (FEP plus LVX plus CST) awaiting the risk of mortality at day 14 in patients receiving TZP was culture results. The 2016 IDSA/ATS guidelines on VAP expert two times higher than in those who were empirically treated panel did not identify a preferable agent for the definitive with carbapenems. This finding was not confirmed by another treatment of VAP due to ESBL-producing Enterobacteriaceae, multinational prospective cohort study by Guttiérez-Guttiérez due to its low confidence in the available literature. If cultures et al who showed that BLBLIs, if active in vitro and used at show the presence of 3GC-resistant Enterobacteriaceae, all appropriate doses, appear to be as effective as carbapenems empiric antibiotics are discontinued and a carbapenem is for empiric and targeted ESBL-producing Enterobacteria- initiated. If a non-3GC-resistant organism is isolated, therapy ceae among relevant subgroups, including organism, source should be based on the results of antimicrobial susceptibility of infection, or severity of illness. Different factors may testing and patient-specific factors. The chosen antibiotic explain such divergent conclusions, including the geographic should be of the narrowest spectrum possible. variations in the distribution of ESBL phenotypes where the enzyme background plays a significant role and the likely S. maltophilia source of infection reflecting the inoculum effect. The results S. maltophilia is among the most commonly isolated organ- of a randomized controlled study (MERINO trial) comparing isms from patients hospitalized with pneumonia in the US and TZP to meropenem for the definitive treatment of bacteremia Europe. Risk factors for ICU-acquired S. maltophilia colo- caused by ceftriaxone non-susceptible Escherichia coli and nization and/or infection are prolonged use of broad-spectrum Klebsiella spp. are definitely awaited to resolve this important antibiotics, prolonged duration of mechanical ventilation, issue (MERINO, ClinicalTrials.gov: NCT02176122). severity of underlying disease, chronic lung disease, and FEP possesses an in vitro activity against ESBL- tracheostomy. This organism is well known for its intrinsic producing Enterobacteriaceae. Like TZP, the difference and acquired multidrug resistance to beta-lactam antibiotics, between in vitro activity and outcomes in infected patients aminoglycosides, macrolides, and tetracyclines. In the 2016 may be due to the presence of a significant inoculum effect IDSA/ATS guidelines on VAP, no specific recommendations for ESBL producers against FEP. One retrospective study were made for this organism, yet empiric therapy against showed a trend toward increased mortality in patients with gram-negative bacilli other than P. aeruginosa is warranted, ESBL-producing Enterobacteriaceae bacteremia treated according to local microbiological data. TMP/SMX is the empirically with FEP as compared to carbapenems, yet this recommended first-line treatment option, not to mention trend did not reach statistical significance. However, other that CST has also shown promising in vitro activity among submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress other suggested alternatives. In our series, S. maltophilia This is a retrospective study where all data were retrieved represented 12% of the total isolates, of which 56% were from electronic medical records and medical microbiology CAZ susceptible and 78% were LVX susceptible (Table 1). logbooks. Therefore, the inclusion of LVX in our selected empiric All authors have reviewed and agreed on this manuscript regimen would cover the susceptible strains and CST would and authorize its publication in case of acceptance. cover the rest, pending culture results. Definitive therapy is based on results of antibiotic susceptibility. TMP/SMX is the Disclosure preferred agent in cases of susceptible strains, followed by The authors report no conflicts of interest in this work. CAZ and LVX in cases of susceptibility, as well. Intravenous References and inhaled CST is the last resort treatment option if XDR 1. Kollef MH, Chastre J, Fagon JY, et al. 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An antibiotic stewardship exercise in the ICU: building a treatment algorithm for the management of ventilator-associated pneumonia based on local epidemiology and the 2016 Infectious Diseases Society of America/American Thoracic Society guidelines

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Journal name: Infection and Drug Resistance Article Designation: ORIGINAL RESEARCH Year: 2018 Volume: 11 Running head verso: Awad et al Infection and Drug Resistance Dovepress Running head recto: VAP treatment algorithm based on local data open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IDR.S145827 Open Access Full Text Article O RIG INAL RESEARCH An antibiotic stewardship exercise in the ICU: building a treatment algorithm for the management of ventilator-associated pneumonia based on local epidemiology and the 2016 Infectious Diseases Society of America/American Thoracic Society guidelines 1, Introduction: Management of ventilator-associated pneumonia (VAP), the most common infec- Lyn S Awad * 1, tion in patients on mechanical ventilation, should be tailored to local microbiological data. The Dania I Abdallah * 2,3 aim of this study was to determine susceptibility patterns of organisms causing VAP to develop Anas M Mugharbil 2,4 a treatment algorithm based on these findings and evidence from the literature. Tamima H Jisr Materials and methods: This is a retrospective analysis of the microbiological etiology of Nabila S Droubi VAP in the intensive care unit (ICU) of a Lebanese tertiary care hospital from July 2015 to Nabila A El-Rajab July 2016. We reviewed the latest clinical practice guidelines on VAP and tried to adapt these 2,6,7 Rima A Moghnieh recommendations to our setting. Pharmacy Department, Makassed Results: In all, 43 patients with 61 VAP episodes were identified, and 75 bacterial isolates General Hospital, Faculty of caused VAP. Extensively drug-resistant (XDR) Acinetobacter baumannii was the most common Medicine, Beirut Arab University, Department of Internal Medicine, organism (37%), and it had occurred endemically throughout the year. Pseudomonas aeruginosa Division of Hematology-Oncology, was the next most common organism (31%), and 13% were XDR. Enterobacteriaceae (15%) Department of Laboratory 5 and Stenotrophomonas maltophilia (12%) shared similar incidences. Our algorithm was based Medicine, Department of Internal Medicine, Department of Internal on guidelines, in addition to trials, systematic reviews, and meta-analyses that studied the Medicine, Division of Infectious effectiveness of available antibiotics in treating VAP. Diseases, Makassed General Hospital, Conclusion: Knowing that resistance can rapidly develop within a practice environment, more Department of Internal Medicine, Faculty of Medical Sciences, Lebanese research is needed to identify the best strategy for the management of VAP. University, Beirut, Lebanon Keywords: ventilator-associated pneumonia, Pseudomonas aeruginosa, Acinetobacter bauman- *These authors contributed equally to nii, local epidemiology, carbapenem-sparing strategy, guidelines this work Introduction Ventilator-associated pneumonia (VAP) is the most well-known nosocomial infection complicating the course of intubated patients and the leading cause of death in critical care settings worldwide, in addition to being the first cause of antibiotic prescription Correspondence: Rima A Moghnieh Department of Internal Medicine, in intensive care units (ICUs) despite the development of prevention bundles. Epi- Division of Infectious Diseases, Makassed sodes caused by multidrug-resistant (MDR), extensively drug-resistant (XDR), and General Hospital, Tarik Al-Jadida, PO Box 11-6301, Riad El-Solh, Beirut pandrug-resistant (PDR) organisms further aggravate the situation, thus imposing 1107 2210, Lebanon a considerable clinical and economic burden, along with the limited and exhausted Tel +961 3 82 9363 Email moghniehrima@gmail.com antibiotic armamentarium. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 17–28 Dovepress © 2018 Awad et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/IDR.S145827 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Awad et al Dovepress Infection control and antimicrobial stewardship programs procedures. Culture plates were incubated at 37°C for are mainstay strategies for curbing down resistance. Specifi- 24 hours. The Clinical and Laboratory Standards Institute cally, antibiotic treatment guidelines constitute a core element (CLSI) breakpoints for the available systemic antibiotics 3 6 of antimicrobial stewardship programs. Yet, clinical practice were used to determine susceptibility at our facility. No guidelines developed by international societies need to be interpretation data are available for tigecycline susceptibility tailored according to local epidemiology. Timely surveil- against Acinetobacter baumannii from CLSI or the Euro- lance for local microbiological data is extremely important pean Committee on Antimicrobial Susceptibility Testing in predicting the type of resistance that may be present in the (EUCAST) regardless of the testing method. Therefore, 3 8 etiologic agent causing a clinical infection. we applied clinical breakpoints suggested by Jones et al In July 2016, the Infectious Diseases Society of America (susceptible [S] ≥ 16 mm, intermediate [I] 13–15 mm, 6 7 (IDSA) and the American Thoracic Society (ATS) updated and resistant [R] ≤12 mm). Neither CLSI nor EUCAST their clinical practice guidelines for the management of guideline provides disk diffusion zone diameter breakpoints hospital-acquired pneumonia (HAP) and VAP. for colistin (CST) susceptibility against A. baumannii. In In this study, our aim was to determine susceptibility our center, CST susceptibility was determined using the patterns of the leading organisms causing VAP in the ICU of disk diffusion method with the following breakpoints: S ≥ our facility in order to develop a treatment algorithm based 11 mm and R ≤ 8 mm. on the 2016 IDSA/ATS guideline recommendations. We also Gram-negative organisms were labeled as MDR or XDR aimed to review available therapeutic options for the treat- as described by Magiorakos et al. XDR A. baumannii in ment of resistant organisms causing VAP, based on evidence our institution was carbapenem resistant and susceptible only from the literature. to polymyxins ± glycylcyclines. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were labeled XDR when resistant to all tested available antibiotics except for the Materials and methods polymyxins. Ceftolozane/tazobactam was not available for Setting and study design use in Lebanon at the time of the study. This is a retrospective analysis of the microbiological etiology In our study, a pathogen is considered endemic when of VAP in the ICU in a tertiary care hospital in Lebanon. Data challenges from admitting patients colonized or infected were retrieved from the medical microbiology laboratory with this organism are constantly present. Yet, an organ- logbooks and patients’ electronic medical records from July ism is considered as epidemic where there is an unexpected 2015 to July 2016. Data included bacterial species isolated increase in cases of infections due to this pathogen for a from endotracheal aspirate specimens along with their anti- short period of time. biotic susceptibility patterns. Duplicate isolates, colonizers, and organisms causing respiratory tract infections other than Development of our own VAP were omitted from the analysis. recommendations and VAP treatment The distribution of pathogens causing VAP was plotted against time. Endemic pathogens in the ICU were identified, algorithm as well as other organisms that caused occasional epidemics. The latest clinical practice guidelines endorsed by IDSA/ Antibiotic history within 90 days of the VAP episodes was ATS on the management of adults with HAP/VAP were also reviewed. As recommended by the World Health Orga- reviewed. We tried to adapt the stated recommendations to nization (WHO), antimicrobial consumption was reported our ICU epidemiology, when applicable. For certain resistant in defined daily dose (DDD) per 100 bed day (BD), a stan- organisms, no specific recommendations were made; hence, dardized figure that provides a degree of comparison among we conducted a profound literature search in order to base inpatients in different hospitals. our proposed choices on solid evidence. Our propositions were based on trials, case reports, systematic reviews, and Microbiological studies and breakpoints of resistance meta-analyses that studied the effectiveness of specific anti- Bacterial identification was performed according to standard biotic combinations in the treatment of VAP caused by MDR microbiologic procedures. Antibiotic susceptibility testing and XDR organisms. Finally, we proposed an algorithm for was performed using the Kirby–Bauer disk diffusion test empiric data and targeted antibiotic therapy for VAP as a on Mueller–Hinton agar (Oxoid Ltd.) according to standard basis for antibiotic stewardship in the ICU of our facility. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Dovepress VAP treatment algorithm based on local data According to the hospital infection control data, there Ethical approval was a constant challenge from admitting patients colo- The institutional review board committee of Makassed Gen- nized or infected with this organism to ICU. Subsequently, eral Hospital approved this study. A. baumanii was considered as an endemic organism. XDR P. aeruginosa was recovered sporadically from three cases Informed consent on three separate occasions during the year, and each was No informed consent was required due to the retrospective separated by a 2- to 4-month interval. It was considered as nature of this study. During the data collection phase, a spe- an organism causing separate ICU epidemics. However, cial form was used where patient initials and case numbers non-XDR P. aeruginosa is a common organism, isolated in were only included. At a later stage, a different number was a continuous manner throughout the year. It has been equally assigned to each of our cases to safeguard patient privacy. susceptible to LVX, CAZ, FEP, and TZP. Only one isolate All contributing authors performed data entry and analysis showed resistance to FEP plus LVX, and another was resistant as well as the drafting of the paper. to TZP plus LVX. With regard to Enterobacteriaceae, 3GC- sensitive isolates predominated over 3GC-resistant ones and Results were regularly isolated throughout the year. 3GC-resistant From July 2015 to July 2016, 776 patients were admitted to species were isolated sporadically in 2 months only and the ICU of our facility where total patient days were 4792 separated by a 6-month interval. The most active antibiotics and total ventilator days were 1533. During this period, 43 against the recovered Enterobacteriaceae were LVX and FEP. patients with 61 VAP episodes were identified, of which 47 None of the isolates were resistant to FEP plus LVX or TZP (77%) were monomicrobial episodes and 14 (23%) were plus LVX. Both XDR S. maltophilia and methicillin-resistant polymicrobial episodes. From all organisms isolated from S. aureus (MRSA) were isolated in 1 month only. endotracheal aspirate specimens (N=108 isolates), 75 iso- In our ICU, antimicrobial consumption measured using lates were implicated in causing VAP during this period: DDD/100 BD showed that carbapenems were the most com- 72 gram-negative isolates (96%) and three gram-positive monly used broad-spectrum antimicrobials (16.7 DDD/100 isolates (4%; Table 1). BD), followed by FQ (9.68 DDD/100 BD) and CST (5.74 Among the gram-negative isolates, A. baumannii pre- DDD/100 BD; Figure 1). dominated (37.33%), followed by P. aeruginosa (30.76%), Enterobacteriaceae (14.67%), and S. maltophilia (12%). Discussion Antibiotic susceptibility patterns are provided in Table 1. In this study, we described the microbiological etiology of Among A. baumannii (28 isolates), 92.86% were XDR, VAP in patients admitted to an ICU from July 2015 to July 3.57% were MDR, and 3.57% were PDR. With respect to 2016, and we proposed an antibiotic treatment pathway based P . aeruginosa (23 isolates) susceptibility to antibiotics, 56.5% on the most recent international guidelines. were susceptible to carbapenems, 69.6% to piperacillin/ tazobactam (TZP), 73.9% to ceftazidime (CAZ), and 78.3% Current local epidemiology of VAP to levofloxacin (LVX) and 13% were XDR. For Enterobac- The microbiological ecology and the frequency of specific teriaceae (11 isolates), 81.8% were susceptible to cefepime pathogens causing VAP vary by hospital, patient population, (FEP), 72.7% to third-generation cephalosporins (3GC) and exposure to antibiotics, and type of ICU patients, and they TZP, and 81.8% to fluoroquinolones (FQ). All isolates were change over time, emphasizing the need for timely local sur- fully susceptible to carbapenems. Among S. maltophilia (nine veillance data. According to the 2016 IDSA/ATS guidelines isolates), 55.6% were susceptible to CAZ, 77.8% to LVX, on VAP , each hospital should generate its own antibiograms and 88.9% to trimethoprim/sulfamethoxazole (TMP/SMX). to guide health care professionals in the optimal choice of One S. maltophilia isolate was resistant to CAZ, LVX, and antimicrobials to curb down resistance caused by the expo- TMP/SMX, yet found susceptible to CST and thus was con- sure to unnecessary antibiotics. sidered XDR. S. aureus was the only gram-positive species Studies from the Middle East involving the incidence, isolated for which one of the three isolates identified was microbiology, and antimicrobial susceptibility patterns of methicillin resistant. bacteria causing VAP are scarce. Only one study from Leba- The temporal distribution of ICU pathogens causing VAP non was published by Kanafani et al in 2003. It was a pro- is shown in Table 2. XDR A. baumannii was isolated from spective observational cohort study at a tertiary-care center ICU patients almost every month throughout the study period. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress Table 1 Distribution of bacteria causing VAP according to their antibiotic susceptibility patterns Organisms Number of isolates Percentage from Percentage from total (%) own species (%) (n=75 isolates) Gram-negative species 72 96 A. baumanii 28 37.33 MDR 1 3.57 1.33 XDR 26 92.86 34.67 PDR 1 3.57 1.33 P. aeruginosa 23 30.67 TZP S 16 69.57 21.33 TZP R 7 30.43 9.33 CAZ S 17 73.91 22.67 CAZ R 6 26.09 8 FEP S 16 69.57 21.33 FEP R 7 30.43 9.33 AMK S 15 65.22 20 AMK R 8 34.78 10.67 LVX S 18 78.26 24 LVX R 5 21.74 6.67 CAR S 13 56.52 17.33 CAR R 10 43.48 13.33 FEP and LVX R 4 17.39 5.33 TZP and LVX R 4 17.39 5.33 (FEP and LVX R) but CAR S 0 0 0 (TZP and LVX R) but CAR S 1 4.34 1.33 Non-XDR 20 86.96 26.67 XDR 3 13.04 4 Enterobacteriaceae 11 14.67 3GC S 8 72.73 10.67 3GC R 3 27.27 4 TZP S 8 72.73 10.67 TZP R 3 27.27 4 FEP S 9 81.82 12 FEP R 2 18.18 2.67 FQ S 9 81.82 12 FQ R 2 18.18 2.67 CAR S 11 100 14.67 CAR R 0 0 0 FEP and LVX R 1 9.09 1.33 TZP and LVX R 1 9.09 1.33 S. maltophilia 9 12 LVX S 7 77.78 9.33 LVX R 2 22.22 2.67 CAZ S 5 55.56 6.67 CAZ R 4 44.44 5.33 TMP/SMX S 8 88.89 10.67 TMP/SMX R 1 11.11 1.33 CST S NA NA NA XDR 1 11.11 1.33 B. cepacia 1 1.33 Gram-positive species 3 4 S. aureus 3 4 MET S 2 66.67 2.67 MET R 1 33.33 1.33 Notes: S. maltophilia is not tested routinely in the hospital for CST susceptibility, unless it is resistant to other alternatives (being an XDR). One isolate was XDR and was found susceptible to CST. Abbreviations: A. baumannii, Acinetobacter baumannii; AMK, amikacin; B. cepacia, Burkholderia cepacia; CAR, carbapenem; CAZ, ceftazidime; CST, colistin; FEP, cefepime; FQ, fluoroquinolones; LVX, levofloxacin; MDR, multi-drug resistant; MET, methicillin; NA, not available; P. aeruginosa , Pseudomonas aeruginosa; PDR, pandrug resistant; R, resistant; S, susceptible; S. aureus, Staphylococcus aureus; S. maltophilia, Stenotrophomonas maltophilia; TMP/SMX, trimethoprim/sulfamethoxazole; TZP, piperacillin/tazobactam; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant; 3GC, third-generation cephalosporins. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Dovepress VAP treatment algorithm based on local data submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Table 2 Temporal distribution of bacteria causing VAP (number of isolates) over 12-month period from July 2015 to July 2016 Organisms July August September October November December January February March April May June July 2015 2015 2015 2015 2015 2015 2016 2016 2016 2016 2016 2016 2016 A. baumannii 2 1 3 1 2 0 0 4 4 2 2 4 3 XDR 2 1 3 1 1 0 0 4 4 2 1 4 3 P. aeruginosa 1 1 1 1 3 0 0 6 2 0 2 3 3 TZP S 1 1 1 1 2 0 0 4 2 0 2 1 1 FEP S 1 1 1 1 2 0 0 4 1 0 2 2 2 CAZ S 1 1 1 1 2 0 0 3 1 0 2 2 2 LVX S 1 1 1 1 2 0 0 5 1 0 2 3 1 FEP or LVX S 1 1 1 1 1 0 0 5 1 0 2 3 2 TZP or LVX S 1 1 1 1 2 0 0 5 2 0 2 3 1 FEP and LVX R 0 0 0 0 0 0 0 0 1 0 0 0 0 TZP and LVX R 0 0 0 0 0 0 0 0 0 0 0 0 1 Non-XDR 1 1 1 1 2 0 0 5 2 0 2 3 2 XDR 0 0 0 0 1 0 0 1 0 0 0 0 1 Enterobacteriaceae 1 0 2 1 0 1 0 0 2 0 1 1 2 LVX S 0 0 1 1 0 1 0 0 2 0 1 1 2 TZP S 1 0 1 1 0 1 0 0 1 0 1 1 1 FEP S 1 0 0 1 0 1 0 0 2 0 1 1 2 3GC S 1 0 0 1 0 1 0 0 1 0 1 1 2 FEP or LVX S 1 0 1 1 0 1 0 0 2 0 1 1 2 TZP or LVX S 1 0 1 1 0 1 0 0 2 0 1 1 2 3GC R 0 0 2 0 0 0 0 0 1 0 0 0 0 FEP and LVX R 0 0 1 0 0 0 0 0 0 0 0 0 0 TZP and LVX R 0 0 1 0 0 0 0 0 0 0 0 0 0 S. maltophilia 0 0 0 0 0 0 1 3 1 0 0 0 4 LVX S 0 0 0 0 0 0 1 3 1 0 0 0 2 CAZ S 0 0 0 0 0 0 1 1 0 0 0 0 3 XDR 0 0 0 0 0 0 0 0 0 0 0 0 1 MRSA 0 0 0 0 0 0 0 1 0 0 0 0 0 Abbreviations: A. baumannii, Acinetobacter baumannii; CAZ, ceftazidime; FEP, cefepime, LVX, levofloxacin; MRSA, methicillin-resistant S. aureus; P. aeruginosa, Pseudomonas aeruginosa; R, resistant; S, susceptible; S. aureus, Staphylococcus aureus; S. maltophilia, Stenotrophomonas maltophilia; TZP, piperacillin/tazobactam; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant; 3GC: third-generation cephalosporins. Awad et al Dovepress CAR TZP FEP CAZ CRO AMG TGC CST GLY–LZDFQ Figure 1 Antibiotic consumption in the ICU of our facility during the study period (July 2015–July 2016) reported in DDD/100 BD. Note: x-axis, type of antimicrobial; y-axis, DDD/1000 bed days. Abbreviations: AMG, aminoglycosides; BD, bed day; CAR, carbapenems; CAZ, ceftazidime; CRO, ceftriaxone; CST, colistin; DDD, defined daily dose; FEP, cefepime; FQ, fluoroquinolones; GLY, glycopeptides (vancomycin and teicoplanin); ICU, intensive care unit; LZD, linezolid; TGC, tigecycline; TZP, piperacillin/tazobactam. involving all patients admitted to the ICU and respiratory care has been increasingly associated with nosocomial epidemics 14 15 unit from March to September 2001 who were on mechani- in the ICUs of our region and worldwide. Of particular cal ventilation for at least 48 hours. The most commonly concern is its environmental resilience, resulting in sustained isolated organisms were gram-negative bacilli, among which outbreaks and endemic situations, as well as its inherent and Acinetobacter and Pseudomonas species were predominant. acquired mechanisms of resistance to antibiotics, rendering With respect to the antibiotic susceptibility pattern, 50% of it the prototype of XDR bacteria. Non-XDR P. aeruginosa the gram-negative isolates were antibiotic resistant, yet 91% is another endemic pathogen in our facility, yet isolation of were still carbapenem susceptible at that time. Our study is XDR strains was sporadic. Acquisition of XDR P. aerugi- the second from the country involving VAP etiology in the nosa in the ICU, causing these epidemic bouts, depends on era of resistance and limited treatment options. variables including colonization pressure created by carriers In our facility, gram-negative bacteria predominated, and antibiotic-selective pressure. representing 96% of the total respiratory isolates. Compared to findings by Kanafani et al in 2003, A. baumannii and Antibiotic consumption in critical care P. aeruginosa are still the leading organisms; however, the Critical care units manage only a small proportion of hos- emergence of carbapenem-resistant strains in both species is pitalized patients but administer disproportionately large striking in our 2016 series. According to recently published quantities of broad-spectrum antimicrobials, which are antimicrobial resistance data from hospitals all across Leba- implicated in resistance. In Lebanon, a national surveil- non, A. baumannii and P. aeruginosa have emerged as fre- lance system for antimicrobial resistance and antimicrobial quent nosocomial pathogens, and carbapenem susceptibility consumption is not yet established. However, resistance has reached 18% and 73%, respectively, in this nationwide data and antibiotic prescription patterns are derived from 13,19 study. This rate of antimicrobial resistance constitutes a published multicenter studies. Our results showed that major threat in critical care units. carbapenems were the most widely prescribed during the study period (16.72 DDD/100 BD), followed by other broad- Temporal distribution of pathogens spectrum antibiotics, including third- and fourth-generation causing VAP cephalosporins (total of 9.83 DDD/100 BD) and FQ (9.68 With respect to the temporal distribution of pathogens causing DDD/100 BD; Figure 1). A recently published multicenter VAP throughout the study period (Table 2), XDR A. bauman- cross-sectional study assessed antibiotic consumption from nii has shown an endemic pattern in our ICU. Likewise, it pharmacy electronic records in 27 nonteaching Lebanese submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress 16.72 4.43 5.03 1.48 3.33 1.95 3.27 5.74 5.69 9.68 Dovepress VAP treatment algorithm based on local data hospitals during 2012. Antibiotic consumption was stratified gram-positive bacteria, S. aureus represented 4% of all according to the geographical location, occupancy rate, and isolated species, among which 67% were still methicillin number of beds, including the number of ICU beds. Results susceptible (Table 1). Thus, we chose not to include MRSA showed that the average carbapenem consumption in ICUs in the empiric therapy for VAP unless there is evidence with nine or more beds reached 6.16 DDD/100 BD, which of previous MRSA colonization or contact with another is much less in comparison with our results. This major dif- colonized/infected subject. Otherwise, the chosen empiric ference in carbapenem use may be attributed to the type of antimicrobial therapy should cover methicillin-susceptible facilities described. Ours is a tertiary-care teaching hospital, strains. Therefore, empiric therapy should be broadened to and the ones reported by Iskandar et al were primary- and include a beta-lactam/beta-lactamase inhibitor (TZP) plus an secondary-care nonteaching health care facilities. Moreover, antipseudomonal fluoroquinolone (LVX), plus an anti-gram- carbapenems are the drug of choice in cases of sepsis in negative antibiotic targeting XDR Acinetobacter strain. At a the hospital protocols due to the increasing prevalence of later stage, this regimen will be replaced by definitive therapy extended spectrum beta lactamase (ESBL)-producing organ- once deep tracheal aspirate culture results and corresponding isms in the community and hospital flora, according to recent antibiotic susceptibility patterns are available (Figure 2). 13,20 surveillance data. Yet, the extensive use of carbapenems Treatment options for specific organisms for the management of resistant organisms led to the selec- 14,21 tion of carbapenem-resistant species. Moreover, findings and streamlining antibiotic therapy in VAP from a recently published Lebanese study showed that recent in era of resistance antibiotic intake was an independent risk factor associated Once deep tracheal aspirate culture results are available, with the fecal carriage of ESBL-producing Enterobacteria- empiric therapy should be replaced by targeted therapy based ceae in long-term care facility residents. on susceptibility patterns and available therapeutic agents. Following are treatment options for each specific organism Strategy for choosing empiric therapy (Figure 2). for VAP The cumbersome task of choosing appropriate empiric XDR A. baumannii antibiotics for VAP remains. In addition, adequate timing of Almost all the A. baumannii isolates in our series were antibiotic administration, ideally within the first hour, is an resistant to carbapenems, yet were still susceptible to CST essential element in determining the outcome of critically and tigecycline. Susceptibility to sulbactam was not tested ill patients with infection. Combination antibiograms are since it is not available in the country. The 2016 IDSA/ATS important tools to optimize empiric therapy in the ICU guidelines on VAP expert panel recommended against the through identifying which antimicrobial combinations give use of tigecycline owing to its decreased therapeutic efficacy the highest likelihood of having at least one active agent in VAP and increased mortality rate in comparison to CST- 4,25 against all likely causative pathogens in a specific disease containing regimens. Thus, intravenous CST is the only state (VAP), thereby minimizing prolonged delays in insti- remaining therapeutic option for such cases. Yet, it is well 24 26 tuting appropriate antimicrobial therapy. Combination known for its nephrotoxic and neurotoxic profiles. The use antibiograms are advantageous to traditional ones because of adjunctive therapies with additive or synergistic effects they focus on the susceptibility of potential second agents for to CST was profoundly discussed in the 2016 IDSA/ATS combination (FQ) in the setting of resistance to the primary guidelines. The panel recommended the use of adjunctive agent (the beta-lactam). aerosolized CST, since it improved clinical outcomes without According to our results, empiric therapy targeting, first, increasing harms. Conversely, adjunctive rifampicin did not XDR A. baumannii is highly justified, especially because it improve outcomes and, therefore, was not recommended. has been an endemic pathogen in our facility, along with its Accordingly, we join the guidelines in adding intravenous highest incidence in VAP etiology (Tables 1 and 2). Second, plus inhaled CST to our selected empiric treatment regimen both P. aeruginosa and Enterobacteriaceae susceptible to for VAP. After definitive culture results are obtained indicat- FEP plus LVX or to TZP plus LVX represented ~95% and ing the isolation of XDR A. baumannii, intravenous plus ~99% of total isolates, respectively (Table 1). This would inhaled CST only will be used, and all other antibiotics will give us an at least 95% chance of using either combination be discontinued. If cultures are negative for A. baumannii, for targeting susceptible strains of both organisms. Regarding CST is discontinued. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress Empiric treatment for VAP: TZP+LVX+CST After DTA culture results are revealed, targeted therapy should be initiated according so susceptibility patterns XDR Acinetobacter Pseudomonas Stenotrophomonas Enterobacteriaceae baumannii aeruginosa maltophilia 1-TMP/SMX XDR Pseudomonas Clinically stable 2-CAZ Non-3GCR organism: aeruginosa: patient without a risk 3-LVX 3GCR organism: therapy based on IV + aerosolized CST IV + aerosolized CST Clinically unstable, of imminent death: –If an XDR strain is carbapenem susceptibility patterns septic patient at high monotherapy identified: IV+ and patient-specific risk of imminent according to aerosolized CST factors (preferably death: susceptibility patterns non-antispseudomonal Dual antipseudomonal (preferably CAZ or cephalosporin like therapy according to FEP) CRO) susceptibility patterns (preferably to include CAZ or FEP) Figure 2 Our proposed treatment algorithm for empiric and targeted treatment of VAP. Abbreviations: A. baumannii, Acinetobacter baumannii; CAZ, ceftazidime, CRO, ceftriaxone; CST, colistin; DTA, deep tracheal aspirate; FEP, cefepime; IV, intravenous; LVX, levofloxacin; P. aeruginosa, Pseudomonas aeruginosa; S. maltophilia, Stenotrophomonas maltophilia; TMP/SMX, trimethoprim/sulfamethoxazole; TZP, piperacillin/tazobactam; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant; 3GCR, third-generation cephalosporin resistant. stable patients who are not in septic shock and not at a high P. aeruginosa risk for death. Aminoglycoside monotherapy should not For the empiric treatment of suspected VAP due to be used due to poor lung tissue penetration, resulting in no P. aeruginosa, double coverage with two antipseudomonal detectable antipseudomonal activity within bronchial secre- antibiotics from different classes is warranted in patients tions despite therapeutic aminoglycoside serum in patients with risk factors for resistance. This applies in units where with Pseudomonas pulmonary infection. Moreover, there the rate of resistance to any of the antipseudomonal agents is is a lack of studies evaluating the effects of aminoglycoside greater than 10%. This 10% threshold for deciding whether monotherapy in VAP. In settings with a high prevalence to prescribe two antipseudomonal agents was chosen by the for XDR P. aeruginosa, routine antimicrobial susceptibil- expert panel of the IDSA/ATS guidelines with the aim of ity testing should include assessment of its sensitivity to optimizing empiric therapy. When applicable, individual polymyxins. Accordingly, for the empiric management of ICUs may choose to modify this threshold according to their P. aeruginosa in our facility, we propose to use FEP plus current local microbiologic data and patient-related risk LVX or TZP plus LVX for double coverage. With regard to factors. The choice of definitive therapy should be based direct therapy, CAZ or FEP monotherapy is preferred when on antibiotic susceptibility patterns. These guidelines state Pseudomonas isolates are susceptible to it. In our facility, that combination therapy using two antibiotics is indicated minimal inhibitory concentration (MIC) determination is in patients who remain in septic shock or who are at a high not routinely performed; thus, we propose using prolonged risk for death with a documented Pseudomonas infection. infusions of high-dose FEP. When Pseudomonas is proved The expert panel of the IDSA/ATS guidelines did not prefer to be XDR, only intravenous plus inhaled CST is to be used. a specific regimen against documented Pseudomonas infec- tion. However, imipenem may have outcomes inferior to other regimens based on a systematic review of randomized ESBL-producing Enterobacteriaceae trials by Zilberberg et al. However, no recommendation ICUs in the USA and Europe have witnessed an increase was made against using imipenem, since the results obtained in the incidence of ESBL-producing Enterobacteriaceae were derived from trials limited by risk of bias and impreci- infections. The optimum treatment for infections due to 4 33 sion. As for monotherapy, it is preferably used in clinically ESBL-producing pathogens has been a subject of debate. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Dovepress VAP treatment algorithm based on local data Carbapenems have been considered the agents of choice patient-specific characteristics, most notably severity of ill- 34 43 against these serious infections. However, the emerging ness, were more significant predictors of patient outcomes. and rapid spread of carbapenem resistance in different gram- In another multicenter retrospective study between 2002 and negatives, including Enterobacteriaceae, has led to initiating 2007, Lee et al showed that FEP is a potentially effective carbapenem-sparing strategies and alternative therapeutic option for treating bacteremia caused by ESBL-producing approaches for the treatment of ESBL infections. Empiri- Enterobacteriaceae, but only if the MIC of the infecting cal treatment covering ESBL-producing Enterobacteriaceae organism was sufficiently low (i.e., ≤ 1 μg/mL). A more recent should be based on the following criteria: geographical areas, study by Wang et al compared the empiric use of FEP to epidemiological settings, and individual risk factors. FEP carbapenems in propensity score-matched cohort patients and the β-lactam-β-lactamase inhibitors (BLBLIs) have been with ESBL-producing organisms. Similar to the findings the most widely studied carbapenem-sparing options based by Chopra et al, a nonsignificant trend toward increased on their favorable in vitro susceptibility profile to ESBL- mortality was observed in patients treated with FEP versus producing organisms. those treated with carbapenems. BLBLIs such as TZP have been recommended as an In our series, 3GC-resistant Enterobacteriaceae repre- alternative to carbapenems for ESBLs. In clinical practice, sented 4% of the total isolates causing VAP. In addition, BLBLIs are often perceived as inferior to carbapenems in Enterobacteriaceae isolates resistant to FEP plus LVX or to this setting, although there is no strong supporting evidence. TZP plus LVX represented 1.33% of the total isolates (Table The most relevant studies in this topic came to different con- 1). Accordingly, we elect to avoid carbapenem use in the clusions. In a single-center retrospective cohort study over empiric management of VAP despite the possibility of being 7 years involving 331 patients with bacteremia caused by caused by ESBL organisms and stick to the previously stated ESBL-producing Enterobacteriaceae, Tamma et al found that combination regimen (FEP plus LVX plus CST) awaiting the risk of mortality at day 14 in patients receiving TZP was culture results. The 2016 IDSA/ATS guidelines on VAP expert two times higher than in those who were empirically treated panel did not identify a preferable agent for the definitive with carbapenems. This finding was not confirmed by another treatment of VAP due to ESBL-producing Enterobacteriaceae, multinational prospective cohort study by Guttiérez-Guttiérez due to its low confidence in the available literature. If cultures et al who showed that BLBLIs, if active in vitro and used at show the presence of 3GC-resistant Enterobacteriaceae, all appropriate doses, appear to be as effective as carbapenems empiric antibiotics are discontinued and a carbapenem is for empiric and targeted ESBL-producing Enterobacteria- initiated. If a non-3GC-resistant organism is isolated, therapy ceae among relevant subgroups, including organism, source should be based on the results of antimicrobial susceptibility of infection, or severity of illness. Different factors may testing and patient-specific factors. The chosen antibiotic explain such divergent conclusions, including the geographic should be of the narrowest spectrum possible. variations in the distribution of ESBL phenotypes where the enzyme background plays a significant role and the likely S. maltophilia source of infection reflecting the inoculum effect. The results S. maltophilia is among the most commonly isolated organ- of a randomized controlled study (MERINO trial) comparing isms from patients hospitalized with pneumonia in the US and TZP to meropenem for the definitive treatment of bacteremia Europe. Risk factors for ICU-acquired S. maltophilia colo- caused by ceftriaxone non-susceptible Escherichia coli and nization and/or infection are prolonged use of broad-spectrum Klebsiella spp. are definitely awaited to resolve this important antibiotics, prolonged duration of mechanical ventilation, issue (MERINO, ClinicalTrials.gov: NCT02176122). severity of underlying disease, chronic lung disease, and FEP possesses an in vitro activity against ESBL- tracheostomy. This organism is well known for its intrinsic producing Enterobacteriaceae. Like TZP, the difference and acquired multidrug resistance to beta-lactam antibiotics, between in vitro activity and outcomes in infected patients aminoglycosides, macrolides, and tetracyclines. In the 2016 may be due to the presence of a significant inoculum effect IDSA/ATS guidelines on VAP, no specific recommendations for ESBL producers against FEP. One retrospective study were made for this organism, yet empiric therapy against showed a trend toward increased mortality in patients with gram-negative bacilli other than P. aeruginosa is warranted, ESBL-producing Enterobacteriaceae bacteremia treated according to local microbiological data. TMP/SMX is the empirically with FEP as compared to carbapenems, yet this recommended first-line treatment option, not to mention trend did not reach statistical significance. However, other that CST has also shown promising in vitro activity among submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress other suggested alternatives. In our series, S. maltophilia This is a retrospective study where all data were retrieved represented 12% of the total isolates, of which 56% were from electronic medical records and medical microbiology CAZ susceptible and 78% were LVX susceptible (Table 1). logbooks. Therefore, the inclusion of LVX in our selected empiric All authors have reviewed and agreed on this manuscript regimen would cover the susceptible strains and CST would and authorize its publication in case of acceptance. cover the rest, pending culture results. Definitive therapy is based on results of antibiotic susceptibility. TMP/SMX is the Disclosure preferred agent in cases of susceptible strains, followed by The authors report no conflicts of interest in this work. CAZ and LVX in cases of susceptibility, as well. Intravenous References and inhaled CST is the last resort treatment option if XDR 1. Kollef MH, Chastre J, Fagon JY, et al. 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Agents. 2014;43(4):328–334. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 Dovepress Awad et al Dovepress Infection and Drug Resistance Dovepress Publish your work in this journal Infection and Drug Resistance is an international, peer-reviewed open- resistance and the mechanisms of resistance development and diffusion access journal that focuses on the optimal treatment of infection (bacte- in both hospitals and the community. The manuscript management rial, fungal and viral) and the development and institution of preventive system is completely online and includes a very quick and fair peer- strategies to minimize the development and spread of resistance. The review system, which is all easy to use. Visit http://www.dovepress.com/ journal is specifically concerned with the epidemiology of antibiotic testimonials.php to read real quotes from published authors. 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