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Antimicrobial Resistance and Infection... Mar 2022Pneumonia from SARS-CoV-2 is difficult to distinguish from other viral and bacterial etiologies. Broad-spectrum antimicrobials are frequently prescribed to patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pneumonia from SARS-CoV-2 is difficult to distinguish from other viral and bacterial etiologies. Broad-spectrum antimicrobials are frequently prescribed to patients hospitalized with COVID-19 which potentially acts as a catalyst for the development of antimicrobial resistance (AMR).
OBJECTIVES
We conducted a systematic review and meta-analysis during the first 18 months of the pandemic to quantify the prevalence and types of resistant co-infecting organisms in patients with COVID-19 and explore differences across hospital and geographic settings.
METHODS
We searched MEDLINE, Embase, Web of Science (BioSIS), and Scopus from November 1, 2019 to May 28, 2021 to identify relevant articles pertaining to resistant co-infections in patients with laboratory confirmed SARS-CoV-2. Patient- and study-level analyses were conducted. We calculated pooled prevalence estimates of co-infection with resistant bacterial or fungal organisms using random effects models. Stratified meta-analysis by hospital and geographic setting was also performed to elucidate any differences.
RESULTS
Of 1331 articles identified, 38 met inclusion criteria. A total of 1959 unique isolates were identified with 29% (569) resistant organisms identified. Co-infection with resistant bacterial or fungal organisms ranged from 0.2 to 100% among included studies. Pooled prevalence of co-infection with resistant bacterial and fungal organisms was 24% (95% CI 8-40%; n = 25 studies: I = 99%) and 0.3% (95% CI 0.1-0.6%; n = 8 studies: I = 78%), respectively. Among multi-drug resistant organisms, methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and multi-drug resistant Candida auris were most commonly reported. Stratified analyses found higher proportions of AMR outside of Europe and in ICU settings, though these results were not statistically significant. Patient-level analysis demonstrated > 50% (n = 58) mortality, whereby all but 6 patients were infected with a resistant organism.
CONCLUSIONS
During the first 18 months of the pandemic, AMR prevalence was high in COVID-19 patients and varied by hospital and geography although there was substantial heterogeneity. Given the variation in patient populations within these studies, clinical settings, practice patterns, and definitions of AMR, further research is warranted to quantify AMR in COVID-19 patients to improve surveillance programs, infection prevention and control practices and antimicrobial stewardship programs globally.
Topics: Anti-Bacterial Agents; Antifungal Agents; Bacteria; Bacterial Infections; COVID-19; Drug Resistance, Bacterial; Drug Resistance, Fungal; Fungi; Humans; Mycoses; SARS-CoV-2
PubMed: 35255988
DOI: 10.1186/s13756-022-01085-z -
The Journal of Infection Aug 2020In previous influenza pandemics, bacterial co-infections have been a major cause of mortality. We aimed to evaluate the burden of co-infections in patients with COVID-19. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
In previous influenza pandemics, bacterial co-infections have been a major cause of mortality. We aimed to evaluate the burden of co-infections in patients with COVID-19.
METHODS
We systematically searched Embase, Medline, Cochrane Library, LILACS and CINAHL for eligible studies published from 1 January 2020 to 17 April 2020. We included patients of all ages, in all settings. The main outcome was the proportion of patients with a bacterial, fungal or viral co-infection. .
RESULTS
Thirty studies including 3834 patients were included. Overall, 7% of hospitalised COVID-19 patients had a bacterial co-infection (95% CI 3-12%, n=2183, I=92·2%). A higher proportion of ICU patients had bacterial co-infections than patients in mixed ward/ICU settings (14%, 95% CI 5-26, I=74·7% versus 4%, 95% CI 1-9, I= 91·7%). The commonest bacteria were Mycoplasma pneumonia, Pseudomonas aeruginosa and Haemophilus influenzae. The pooled proportion with a viral co-infection was 3% (95% CI 1-6, n=1014, I=62·3%), with Respiratory Syncytial Virus and influenza A the commonest. Three studies reported fungal co-infections.
CONCLUSIONS
A low proportion of COVID-19 patients have a bacterial co-infection; less than in previous influenza pandemics. These findings do not support the routine use of antibiotics in the management of confirmed COVID-19 infection.
Topics: Bacterial Infections; Betacoronavirus; COVID-19; Coinfection; Coronavirus Infections; Humans; Mycoses; Pandemics; Pneumonia, Viral; SARS-CoV-2; Virus Diseases
PubMed: 32473235
DOI: 10.1016/j.jinf.2020.05.046 -
The Cochrane Database of Systematic... Jun 2023Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually... (Review)
Review
BACKGROUND
Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review.
OBJECTIVES
Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials.
DATA COLLECTION AND ANALYSIS
Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence). TNS plus azithromycin compared to TNS plus oral placebo Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence. Ciprofloxacin and colistin versus no treatment A single trial only reported one of our planned outcomes; there were no adverse effects in either group. AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence). Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin) IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost.
AUTHORS' CONCLUSIONS
We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.
Topics: Child; Child, Preschool; Humans; Infant; Anti-Bacterial Agents; Azithromycin; Ceftazidime; Ciprofloxacin; Colistin; Cystic Fibrosis; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin
PubMed: 37268599
DOI: 10.1002/14651858.CD004197.pub6 -
Clinical Microbiology and Infection :... Jul 2019The aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all...
SCOPE
The aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all settings.
METHODS
These evidence-based guidelines were produced after a systematic review of published studies on decolonization interventions targeting the following MDR-GNB: third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE), carbapenem-resistant Enterobacteriaceae (CRE), aminoglycoside-resistant Enterobacteriaceae (AGRE), fluoroquinolone-resistant Enterobacteriaceae (FQRE), extremely drug-resistant Pseudomonas aeruginosa (XDRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), cotrimoxazole-resistant Stenotrophomonas maltophilia (CRSM), colistin-resistant Gram-negative organisms (CoRGNB), and pan-drug-resistant Gram-negative organisms (PDRGNB). The recommendations are grouped by MDR-GNB species. Faecal microbiota transplantation has been discussed separately. Four types of outcomes were evaluated for each target MDR-GNB:(a) microbiological outcomes (carriage and eradication rates) at treatment end and at specific post-treatment time-points; (b) clinical outcomes (attributable and all-cause mortality and infection incidence) at the same time-points and length of hospital stay; (c) epidemiological outcomes (acquisition incidence, transmission and outbreaks); and (d) adverse events of decolonization (including resistance development). The level of evidence for and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached through a nominal-group technique for the final list of recommendations.
RECOMMENDATIONS
The panel does not recommend routine decolonization of 3GCephRE and CRE carriers. Evidence is currently insufficient to provide recommendations for or against any intervention in patients colonized with AGRE, CoRGNB, CRAB, CRSM, FQRE, PDRGNB and XDRPA. On the basis of the limited evidence of increased risk of CRE infections in immunocompromised carriers, the panel suggests designing high-quality prospective clinical studies to assess the risk of CRE infections in immunocompromised patients. These trials should include monitoring of development of resistance to decolonizing agents during treatment using stool cultures and antimicrobial susceptibility results according to the EUCAST clinical breakpoints.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Cross Infection; Drug Resistance, Multiple, Bacterial; Europe; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Pseudomonas aeruginosa; Stenotrophomonas maltophilia
PubMed: 30708122
DOI: 10.1016/j.cmi.2019.01.005 -
Journal of Infection and Public Health Mar 2023There is paucity of data describing the impact of COVID-19 pandemic on antimicrobial resistance. This review evaluated the changes in the rate of multidrug resistant... (Review)
Review
BACKGROUND
There is paucity of data describing the impact of COVID-19 pandemic on antimicrobial resistance. This review evaluated the changes in the rate of multidrug resistant gram negative and gram positive bacteria during the COVID-19 pandemic.
METHODS
A search was conducted in PubMed, Science Direct, and Google Scholar databases to identify eligible studies. Studies that reported the impact of COVID-19 pandemic on carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase inhibitor (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Pseudomonas aeruginosa (CPE) were selected. Studies published in English language from the start of COVID-19 pandemic to July 2022 were considered for inclusion.
RESULTS
Thirty eligible studies were selected and most of them were from Italy (n = 8), Turkey (n = 3) and Brazil (n = 3). The results indicated changes in the rate of multidrug resistant bacteria, and the changes varied between the studies. Most studies (54.5%) reported increase in MRSA infection/colonization during the pandemic, and the increase ranged from 4.6 to 170.6%. Five studies (55.6%) reported a 6.8-65.1% increase in VRE infection/colonization during the pandemic. A 2.4-58.2% decrease in ESBL E. coli and a 1.8-13.3% reduction in ESBL Klebsiella pneumoniae was observed during the pandemic. For CRAB, most studies (58.3%) reported 1.5-621.6% increase in infection/colonization during the pandemic. Overall, studies showed increase in the rate of CRE infection/colonization during the pandemic. There was a reduction in carbapenem-resistant E. coli during COVID-19 pandemic, and an increase in carbapenem-resistant K. pneumoniae. Most studies (55.6%) showed 10.4 - 40.9% reduction in the rate of CRPA infection during the pandemic.
CONCLUSION
There is an increase in the rate of multidrug resistant gram positive and gram negative bacteria during the COVID-19 pandemic. However, the rate of ESBL-producing Enterobacteriaceae and CRPA has decrease during the pandemic. Both infection prevention and control strategies and antimicrobial stewardship should be strengthen to address the increasing rate of multidrug resistant gram positive and gram negative bacteria.
Topics: Humans; Anti-Bacterial Agents; Pandemics; Gram-Negative Bacteria; Escherichia coli; Methicillin-Resistant Staphylococcus aureus; Gram-Positive Bacteria; COVID-19; Enterobacteriaceae; Klebsiella pneumoniae; Carbapenems; Microbial Sensitivity Tests
PubMed: 36657243
DOI: 10.1016/j.jiph.2022.12.022 -
European Respiratory Review : An... Jan 2024is the most commonly isolated pathogen in bronchiectasis and is associated with worse outcomes. Eradication treatment is recommended by guidelines, but the evidence... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
is the most commonly isolated pathogen in bronchiectasis and is associated with worse outcomes. Eradication treatment is recommended by guidelines, but the evidence base is limited. The expected success rate of eradication in clinical practice is not known.
METHODS
We conducted a systematic review and meta-analysis according to Meta-Analysis of Observational Studies in Epidemiology guidelines. PubMed, Embase, the Cochrane Database of Systematic Reviews and Clinicaltrials.gov were searched for studies investigating eradication treatment using antibiotics (systemic or inhaled) in patients with bronchiectasis. The primary outcome was the percentage of patients negative for at 12 months after eradication treatment. Cystic fibrosis was excluded.
RESULTS
Six observational studies including 289 patients were included in the meta-analysis. Our meta-analysis found a 12-month eradication rate of 40% (95% CI 34-45%; p<0.00001), with no significant heterogeneity (I=0%). Combined systemic and inhaled antibiotic treatment was associated with a higher eradication rate (48%, 95% CI 41-55%) than systemic antibiotics alone (27%, 13-45%).
CONCLUSION
Eradication treatment in bronchiectasis results in eradication of from sputum in ∼40% of cases at 12 months. Combined systemic and inhaled antibiotics achieve higher eradication rates than systemic antibiotics alone.
Topics: Adult; Humans; Pseudomonas Infections; Administration, Inhalation; Anti-Bacterial Agents; Bronchiectasis; Cystic Fibrosis; Pseudomonas aeruginosa
PubMed: 38296344
DOI: 10.1183/16000617.0178-2023 -
Emerging Microbes & Infections Dec 2022Antimicrobial resistance (AMR) and hospital-acquired infections (HAIs) are global health challenges. The burden of antibiotic resistance in HAIs is still unclear in low-... (Meta-Analysis)
Meta-Analysis
Antimicrobial resistance (AMR) and hospital-acquired infections (HAIs) are global health challenges. The burden of antibiotic resistance in HAIs is still unclear in low- and lower-middle-income countries (L-LMICs). This study summarizes recent data on antibiotic resistance in priority HAIs (ESKAPE-E) in L-LMICs and compares them with data from high-income countries (HICs). EMBASE, Web of Science, and Global Index Medicus were searched for studies on AMR patterns in HAIs published from 01/2010 to 10/2020. Random-effects meta-analyses were performed to obtain pooled estimates. In total, 163 eligible studies were included in the review and meta-analysis. The pooled methicillin resistance proportion in was 48.4% (95% confidence interval [95%CI] 41·7-55·2, n = 80). Pooled carbapenem resistance proportions were high in Gram-negative pathogens: : 16·6% (95%CI 10·7-23·4, n = 60); : 34·9% (95%CI 24·6-45·9, n = 50); : 37.1% (95%CI 24·6-45·9, n = 56); spp.: 51·2% (95%CI 27·5-74·7, n = 7); and 72·4% (95%CI 62·1-81·7%, n = 36). A higher resistance proportions were observed for third-generation cephalosporins: : 78·7% (95%CI 71·5-85·2, n = 46); 78·5% (95%CI 72·1-84·2%, n = 58); and spp.: 83·5% (95%CI 71·9-92·8, n = 8). We observed a high between-study heterogeneity (I > 80%), which could not be explained by our set of moderators. Pooled resistance proportions for Gram-negative pathogens were higher in L-LMICs than regional and national estimates from HICs. Patients in resource-constrained regions are particularly affected by AMR. To combat the high resistance to critical antibiotics in L-LMICs, and bridge disparities in health, it is crucial to strengthen local surveillance and the health systems in general.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Developing Countries; Drug Resistance, Bacterial; Hospitals; Humans; Klebsiella pneumoniae
PubMed: 35034585
DOI: 10.1080/22221751.2022.2030196 -
Germs Dec 2023is one of the most common causes of diabetic foot infection globally. This study aimed to determine the global distribution of isolated from diabetic foot ulcer... (Review)
Review
is one of the most common causes of diabetic foot infection globally. This study aimed to determine the global distribution of isolated from diabetic foot ulcer infection. PRISMA procedure was used to perform the current systematic review and meta-analysis. The Web of Science, MEDLINE/PubMed, Scopus, and other databases were searched for studies published in English from 2000 to 2022. Data was analyzed using the Comprehensive Meta-Analysis software (CMA). Keywords and MESH phrases included , diabetic foot ulcer, , and diabetic foot infection. As a result of this review, 16.6% of diabetic foot wound infections were caused by . About 37.9% of strains were multidrug resistant (MDR). infection rates in diabetic foot ulcers ranged from 0.5 to 100% globally. In total, the prevalence rates of in diabetic foot ulcer infection from Asia, Africa, and Western countries were reported at 18.5%, 16.3%, and 11.1%, respectively. Data have shown that the prevalence of , particularly MDR strains, isolated from diabetic foot ulcer infection was relatively high; inherent resistance to antibiotics is also high; the wound either does not heal or if it does, it will be delayed. Therefore, timely treatment is essential.
PubMed: 38361543
DOI: 10.18683/germs.2023.1406 -
Annals of Medicine and Surgery (2012) Jun 2023Ventilator-associated pneumonia (VAP) is the most common ICU acquired pneumonia among patients who are invasively intubated for mechanical ventilation. Patients with VAP...
Ventilator-associated pneumonia (VAP) is the most common ICU acquired pneumonia among patients who are invasively intubated for mechanical ventilation. Patients with VAP suffer an increased mortality risk, financial burden, and length of stay in the hospital. The authors aimed to review the literature to describe the incidence, mortality, and microbiological evidence of VAP. We selected 13 peer-reviewed articles published from 1 January 2010 to 15 September 2022 from electronic databases for studies among adult or pediatric patients diagnosed with VAP expressed per thousand days admitted in the ICU. The VAP rates ranged from 7 to 43 per thousand days, varying among different countries of the world. A significant rate of mortality was observed in 13 studies ranging from 6.3 to 66.9%. Gram-negative organisms like Acinetobacter spp., Pseudomonas aeruginosa Gram-positive organisms like Staphylococcus aureus were frequently found. Our findings suggest an alarming situation of VAP among patients admitted to the intensive care units with increasing incidence and mortality. The review also found that VAP is more common in males and that there is a significant variation in the incidence and mortality rates of VAP among different countries. The findings of this review can inform the development of infection control and prevention strategies to reduce the burden of VAP. Thus, there is a crucial need for control and preventive measures like interventional studies and educational programs on staff training, hand-hygiene, and the appropriate use of ventilator bundle approach to curb this preventable threat that is increasing at an alarming rate.
PubMed: 37363470
DOI: 10.1097/MS9.0000000000000836 -
Journal of Global Infectious Diseases 2018Multidrug-resistant (MDR ) is known as a serious threat to human health worldwide. Limited information is available concerning the prevalence of MDR in Iran. The aim...
BACKGROUND
Multidrug-resistant (MDR ) is known as a serious threat to human health worldwide. Limited information is available concerning the prevalence of MDR in Iran. The aim of the present study was to investigate the relative frequency of MDR in different parts of Iran.
MATERIALS AND METHODS
Using appropriate keywords and well-known English and Persian database, available data about MDR in Iran were retrieved. After applying predefined criteria, relevant studies were selected.
RESULTS
By using random-effect models, the pooled incidence of MDR was estimated 58% (95% confidence interval [CI]; 0.54-0.61). The highest and lowest prevalence of MDR were observed in Tehran (100%) (95% CI; 0.94-1.00) and Zahedan (16%) (95% CI; 0.10-0.24), respectively. The highest resistance rate was against ceftazidime (50%) (95% CI; 0.46-0.54) and amikacin (50%) (95% CI; 0.46-0.54).
CONCLUSION
Our findings are of concern since they demonstrate the high prevalence rate of MDR in the majority of Iranian hospitals.
PubMed: 30581263
DOI: 10.4103/jgid.jgid_113_17