Colistin utilization at a tertiary hospital in South Africa: an opportunity for antimicrobial stewardship practices.

Introduction. Colistin (polymyxin E) has emerged as a last-resort treatment option for multidrug-resistant infections.Hypothesis/Gap Statement. Studies on the use, safety and efficacy of colistin in South Africa are limited.Aim. This study aims to describe the use of colistin and its clinical outcomes at a tertiary public hospital in South Africa.Methodology. We conducted a retrospective review of adult and paediatric patients who received parenteral colistin between 2015 and 2019.Results. A total of 69 patients (26 adults, 13 children and 30 neonates) were reviewed. Acinetobacter baumannii was the most common causative pathogen isolated (70.1 %). Colistin was predominately used to treat septicaemia (75.4 %). It was primarily administered as definitive therapy (71.0 %) and as monotherapy (56.5 %). It was used in 11.5 % of adults with infections susceptible to other antibiotics. Loading doses of intravenous colistin were administered in only 15 (57.7 %) adult patients. Neurotoxicity and nephrotoxicity occurred in 5.8 % and 43.5 % of patients, respectively. Clinical cure was achieved in 37 (53.6 %) patients. On multivariate logistic regression analysis, adults [adjusted odds ratio (aOR), 25.54; 95 % CI, 2.73-238.65; P < 0.01] and children (aOR, 8.56; 95 % CI, 1.06-69.10; P < 0.05) had higher odds of death than neonates.Conclusion. The study identified significant stewardship opportunities to improve colistin prescription and administration. Achieving optimal patient outcomes necessitates a multidisciplinary approach and vigilant monitoring of colistin use.

The impact of colistin-based regimens on mortality compared to other antimicrobials in patients with carbapenem-resistant Enterobacterales bacteremia in South African hospitals: a cross-sectional study.

BACKGROUND: Treatment of carbapenem-resistant Enterobacterales (CRE) infections in low-resource settings is challenging particularly due to limited treatment options. Colistin is the mainstay drug for treatment; however, nephrotoxicity and neurotoxicity make this drug less desirable. Thus, mortality may be higher among patients treated with alternative antimicrobials that are potentially less efficacious than colistin. We assessed mortality in patients with CRE bacteremia treated with colistin-based therapy compared to colistin-sparing therapy. METHODS: We conducted a cross-sectional study using secondary data from a South African national laboratory-based CRE bacteremia surveillance system from January 2015 to December 2020. Patients hospitalized at surveillance sentinel sites with CRE isolated from blood cultures were included. Multivariable logistic regression modeling, with multiple imputations to account for missing data, was conducted to determine the association between in-hospital mortality and colistin-based therapy versus colistin-sparing therapy. RESULTS: We included 1 607 case-patients with a median age of 29 years (interquartile range [IQR], 0-52 years) and 53% (857/1 607) male. Klebsiella pneumoniae caused most of the infections (82%, n=1 247), and the most common carbapenemase genes detected were blaOXA-48-like (61%, n=551), and blaNDM (37%, n=333). The overall in-hospital mortality was 31% (504/1 607). Patients treated with colistin-based combination therapy had a lower case fatality ratio (29% [152/521]) compared to those treated with colistin-sparing therapy 32% [352/1 086]) (p=0.18). In our imputed model, compared to colistin-sparing therapy, colistin-based therapy was associated with similar odds of mortality (adjusted odds ratio [aOR] 1.02; 95% confidence interval [CI] 0.78-1.33, p=0.873). CONCLUSION: In our resource-limited setting, the mortality risk in patients treated with colistin-based therapy was comparable to that of patients treated with colistin-sparing therapy. Given the challenges with colistin treatment and the increasing resistance to alternative agents, further investigations into the benefit of newer antimicrobials for managing CRE infections are needed.

Intravenous fosfomycin for treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: A multi-centre clinical experience.

BACKGROUND: Severe infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have been reported increasingly over the past few years. Many in-vivo and in-vitro studies have suggested a possible role of intravenous fosfomycin for the treatment of CRAB infections. METHODS: This multi-centre, retrospective study included patients treated with intravenous fosfomycin for severe infections caused by CRAB admitted consecutively to four hospitals in Italy from December 2017 to December 2022. The primary goal of the study was to evaluate the risk factors associated with 30-day mortality in the study population. A propensity score matched analysis was added to the model. RESULTS: One hundred and two patients with severe infections caused by CRAB treated with an intravenous fosfomycin-containing regimen were enrolled in this study. Ventilator-associated pneumonia (VAP) was diagnosed in 59% of patients, primary bacteraemia in 22% of patients, and central-venous-catheter-related infection in 16% of patients. All patients were treated with a regimen containing intravenous fosfomycin, mainly in combination with cefiderocol (n=54), colistin (n=48) or ampicillin/sulbactam (n=18). Forty-eight (47%) patients died within 30 days. Fifty-eight (57%) patients experienced clinical therapeutic failure. Cox regression analysis showed that diabetes, primary bacteraemia and a colistin-containing regimen were independently associated with 30-day mortality, whereas adequate source control of infection, early 24-h active in-vitro therapy, and a cefiderocol-containing regimen were associated with survival. A colistin-based regimen, A. baumannii colonization and primary bacteraemia were independently associated with clinical failure. Conversely, adequate source control of infection, a cefiderocol-containing regimen, and early 24-h active in-vitro therapy were associated with clinical success. CONCLUSIONS: Different antibiotic regimens containing fosfomycin in combination can be used for treatment of severe infections caused by CRAB.

Using host-mimicking conditions and a murine cutaneous abscess model to identify synergistic antibiotic combinations effective against Pseudomonas aeruginosa.

Antibiotic drug combination therapy is critical for the successful treatment of infections caused by multidrug resistant pathogens. We investigated the efficacy of ß-lactam and ß-lactam/ß-lactamase inhibitor combinations with other antibiotics, against the hypervirulent, ceftazidime/avibactam resistant Pseudomonas aeruginosa Liverpool epidemic strain (LES) B58. Although minimum inhibitory concentrations in vitro differed by up to eighty-fold between standard and host-mimicking media, combinatorial effects only marginally changed between conditions for some combinations. Effective combinations in vitro were further tested in a chronic, high-density murine infection model. Colistin and azithromycin demonstrated combinatorial effects with ceftazidime and ceftazidime/avibactam both in vitro and in vivo. Conversely, while tobramycin and tigecycline exhibited strong synergy in vitro, this effect was not observed in vivo. Our approach of using host-mimicking conditions and a sophisticated animal model to evaluate drug synergy against bacterial pathogens represents a promising approach. This methodology may offer insights into the prediction of combination therapy outcomes and the identification of potential treatment failures.

Treatment of infections caused by multidrug-resistant Gram-negative bacilli: A practical approach by the Italian (SIMIT) and French (SPILF) Societies of Infectious Diseases.

INTRODUCTION: The emergence of multidrug-resistant Gram-negative bacilli and the development of new antibiotics have complicated the selection of optimal regimens. International guidelines are valuable tools, but are limited by the scarcity of high-quality randomized trials in many situations. METHODS: A panel of experts from the French and Italian Societies of Infectious Diseases aimed to address unresolved issues in clinical practice based on their experience, an updated literature review and open discussions. RESULTS: The panel reached consensus for the following 'first choices': (i) cefepime for ventilator-acquired pneumonia due to AmpC ß-lactamase-producing Enterobacterales; (ii) the ß-lactam/ß-lactamase inhibitor combination most active in vitro, or cefiderocol combined with fosfomycin, and aerosolized colistin or aminoglycosides, for severe pneumonia due to Pseudomonas aeruginosa resistant to ceftolozane-tazobactam; (iii) high-dose piperacillin-tazobactam (including loading dose and continuous infusion) for complicated urinary tract infections (cUTIs) caused by extended-spectrum ß-lactamase-producing Enterobacterales with piperacillin-tazobactam minimum inhibitory concentration (MIC) ≤8 mg/L; (iv) high-dose cefepime for cUTIs due to AmpC ß-lactamase-producing Enterobacterales other than Enterobacter spp. if cefepime MIC ≤2 mg/L; (v) ceftolozane-tazobactam or ceftazidime-avibactam plus metronidazole for intra-abdominal infections (IAIs) due to third-generation cephalosporin-resistant Enterobacterales; (vi) ceftazidime-avibactam plus aztreonam plus metronidazole for IAIs due to metallo-ß-lactamase-producing Enterobacterales; (vii) ampicillin-sulbactam plus colistin for bloodstream infections (BSIs) caused by carbapenem-resistant Acinetobacter baumannii; (viii) meropenem-vaborbactam for BSIs caused by Klebsiella pneumoniae carbapenemase-producing Enterobacterales; and (ix) ceftazidime-avibactam plus fosfomycin for neurological infections caused by carbapenem-resistant P. aeruginosa. CONCLUSIONS: These expert choices were based on the necessary balance between antimicrobial stewardship principles and the need to provide optimal treatment for individual patients in each situation.

Characterization of Acinetobacter baumannii-calcoaceticus complex isolates and microbiological outcome for patients treated with sulbactam-durlobactam in a phase 3 trial (ATTACK).

Acinetobacter baumannii-calcoaceticus complex (ABC) causes severe, difficult-to-treat infections that are frequently antibiotic resistant. Sulbactam-durlobactam (SUL-DUR) is a targeted ß-lactam/ß-lactamase inhibitor combination antibiotic designed to treat ABC infections, including those caused by multidrug-resistant strains. In a global, pathogen-specific, randomized, controlled phase 3 trial (ATTACK), the efficacy and safety of SUL-DUR were compared to colistin, both dosed with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. Results from ATTACK showed that SUL-DUR met the criteria for non-inferiority to colistin for the primary efficacy endpoint of 28-day all-cause mortality with improved clinical and microbiological outcomes compared to colistin. This report describes the characterization of the baseline ABC isolates from patients enrolled in ATTACK, including an analysis of the correlation of microbiological outcomes with SUL-DUR MIC values and the molecular drivers of SUL-DUR resistance.

Clinical effectiveness of cefiderocol for the treatment of bloodstream infections due to carbapenem-resistant Acinetobacter baumannii during the COVID-19 era: a single center, observational study.

BACKGROUND: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). MATERIALS/METHODS: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). RESULTS: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. CONCLUSIONS: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided.

A challenging case of carbapenem resistant Klebsiella pneumoniae-related pyogenic liver abscess with capsular polysaccharide hyperproduction: a case report.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are a major public health problem, necessitating the administration of polymyxin E (colistin) as a last-line antibiotic. Meanwhile, the mortality rate associated with colistin-resistant K. pneumoniae infections is seriously increasing. On the other hand, importance of administration of carbapenems in promoting colistin resistance in K. pneumoniae is unknown. CASE PRESENTATION: We report a case of K. pneumoniae-related pyogenic liver abscess in which susceptible K. pneumoniae transformed into carbapenem- and colistin-resistant K. pneumoniae during treatment with imipenem. The case of pyogenic liver abscess was a 50-year-old man with diabetes and liver transplant who was admitted to Abu Ali Sina Hospital in Shiraz. The K. pneumoniae isolate responsible for community-acquired pyogenic liver abscess was isolated and identified. The K. pneumoniae isolate was sensitive to all tested antibiotics except ampicillin in the antimicrobial susceptibility test and was identified as a non-K1/K2 classical K. pneumoniae (cKp) strain. Multilocus sequence typing (MLST) identified the isolate as sequence type 54 (ST54). Based on the patient's request, he was discharged to continue treatment at another center. After two months, he was readmitted due to fever and progressive constitutional symptoms. During treatment with imipenem, the strain acquired blaOXA-48 and showed resistance to carbapenems and was identified as a multidrug resistant (MDR) strain. The minimum inhibitory concentration (MIC) test for colistin was performed by broth microdilution method and the strain was sensitive to colistin (MIC < 2 µg/mL). Meanwhile, on blood agar, the colonies had a sticky consistency and adhered to the culture medium (sticky mucoviscous colonies). Quantitative real-time PCR and biofilm formation assay revealed that the CRKP strain increased capsule wzi gene expression and produced slime in response to imipenem. Finally, K. pneumoniae-related pyogenic liver abscess with resistance to a wide range of antibiotics, including the last-line antibiotics colistin and tigecycline, led to sepsis and death. CONCLUSIONS: Based on this information, can we have a theoretical hypothesis that imipenem is a promoter of resistance to carbapenems and colistin in K. pneumoniae? This needs more attention.

Enhancing colistin efficacy against Salmonella infections with a quinazoline-based dual therapeutic strategy.

Colistin remains one of the last-resort therapies for combating infections caused by multidrug-resistant (MDR) Enterobacterales, despite its adverse nephro- and neuro-toxic effects. This study elucidates the mechanism of action of a non-antibiotic 4-anilinoquinazoline-based compound that synergistically enhances the effectiveness of colistin against Salmonella enterica. The quinazoline sensitizes Salmonella by deactivating intrinsic, mutational, and transferable resistance mechanisms that enable Salmonella to counteract the antibiotic impact colistin, together with an induced disruption to the electrochemical balance of the bacterial membrane. The attenuation of colistin resistance via the combined treatment approach also proves efficacious against E. coli, Klebsiella, and Acinetobacter strains. The dual therapy reduces the mortality of Galleria mellonella larvae undergoing a systemic Salmonella infection when compared to individual drug treatments. Overall, our findings unveil the potential of the quinazoline-colistin combined therapy as an innovative strategy against MDR bacteria.

Sub-inhibitory concentrations of colistin and imipenem impact the expression of biofilm-associated genes in Acinetobacter baumannii.

Acinetobacter baumannii is an opportunistic pathogen that is responsible for nosocomial infections. Imipenem and colistin are drugs that are commonly used to treat severe infections caused by A. baumannii, such as sepsis, ventilator-associated pneumonia, and bacteremia. However, some strains of A. baumannii have become resistant to these drugs, which is a concern for public health. Biofilms produced by A. baumannii increase their resistance to antibiotics and the cells within the inner layers of biofilm are exposed to sub-inhibitory concentrations (sub-MICs) of antibiotics. There is limited information available regarding how the genes of A. baumannii are linked to biofilm formation when the bacteria are exposed to sub-MICs of imipenem and colistin. Thus, this study's objective was to explore this relationship by examining the genes involved in biofilm formation in A. baumannii when exposed to low levels of imipenem and colistin. The study found that exposing an isolate of A. baumannii to low levels of these drugs caused changes in their drug susceptibility pattern. The relative gene expression profiles of the biofilm-associated genes exhibited a change in their expression profile during short-term and long-term exposure. This study highlights the potential consequences of overuse and misuse of antibiotics, which can help bacteria become resistant to these drugs.

Comparative effectiveness and mortality of colistin monotherapy versus colistin-fosfomycin combination therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections: A propensity score analysis.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infections pose a significant threat to global health due to limited treatment options and high mortality rates. Colistin-based regimens have emerged as a primary treatment approach, but the effectiveness and mortality outcomes of colistin monotherapy versus colistin-fosfomycin combination therapy remain uncertain. This study aims to compare the effectiveness and mortality of colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. Notably, our study is the first to undertake a comprehensive examination of the effectiveness and mortality outcomes between colistin monotherapy and colistin-fosfomycin combination therapy in the context of CRE infections. METHODS: A retrospective cohort study was conducted using data from patients diagnosed with carbapenem-resistant Enterobacteriaceae (CRE) infections at Nakornping Hospital during 2015 to 2022. Inverse probability weighting (IPW) was employed to create balanced cohorts of patients receiving either colistin monotherapy or colistin-fosfomycin combination therapy. The primary outcome measure was treatment effectiveness, assessed by 30-day mortality. Secondary outcome measures included clinical response, mortality at the end of treatment, and microbiologic response. Univariate and multivariate logistic regression analysis were employed after applying propensity score weighting using inverse probability of weighting (IPW). RESULTS: A total of 220 patients were included in the analysis, with 67 receiving colistin monotherapy and 153 receiving colistin-fosfomycin combination therapy. Propensity score weighting using IPW balanced the baseline characteristics between the two groups. The effectiveness of treatment, as measured by 30-day mortality, was not significantly different between the colistin monotherapy group and the colistin-fosfomycin combination therapy group (adjusted odds ratio [aOR] = 1.51, 95% confidence interval [CI]: 0.60-3.78, p = 0.383). Similarly, no significant difference was observed in the mortality at the end of treatment between the two groups (aOR = 1.26, 95% CI: 0.55-2.90, p = 0.576). The clinical response (aOR = 1.48, 95% CI: 0.61-3.59, p = 0.383) and microbiologic response (aOR = 0.66, 95% CI: 0.18-2.38, p = 0.527) were similar between the colistin monotherapy and colistin-fosfomycin combination therapy groups. CONCLUSION: The propensity score analysis among 220 matched patients showed comparable treatment effectiveness and mortality between colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. These results suggest that colistin monotherapy may be as effective as combination therapy. More prospective randomized controlled trials are needed to confirm these findings and establish optimal CRE treatment strategies.

Ineffectiveness of colistin monotherapy in treating carbapenem-resistant Acinetobacter baumannii Pneumonia: A retrospective single-center cohort study.

BACKGROUND: Acinetobacter baumannii, a common carbapenem-resistant gram-negative bacillus, usually causes nosocomial infections. Colistin has been used for carbapenem-resistant A. baumannii (CRAB) infections; however, only a few studies have evaluated colistin as a treatment option compared to appropriate controls. We investigated the effectiveness of colistin monotherapy in treating CRAB pneumonia compared to those treated without an active drug. METHODS: Adult patients (≥ 18 years) with CRAB isolated from respiratory specimens were screened from September 2017 to August 2022. Only patients with pneumonia treated with colistin monotherapy (colistin group) were included and compared to those without any active antibiotics (no active antibiotics [NAA] group). The primary and secondary outcomes were 30-day all-cause mortality and acute kidney injury within 30 days. The inverse probability of the treatment-weighted Cox proportional hazard model was used to compare mortality between groups. RESULTS: Among the 826 adult patients with CRAB in their respiratory specimens, 45 and 123 patients were included in the colistin and NAA groups, respectively. Most of the CRAB pneumonia (91.1%) cases were hospital-acquired pneumonia. The 30-day all-cause mortality rates in the colistin and NAA groups were 58.3% and 56.1%, respectively, and no difference was observed after adjustments (adjusted hazard ratio, 0.74; 95% CI, 0.47-1.17). The incidence of acute kidney injury was higher in the colistin group (65.3%) compared to the NAA group (39.0%) (P = 0.143). CONCLUSIONS: Colistin monotherapy did not significantly improve treatment outcomes for CRAB pneumonia. The development and evaluation of new antimicrobials for CRAB pneumonia should be advocated in clinical practice.

Post Trauma Acinetobacter Baumanii Meningitis Treatment Approach.

A. baumannii, which is said to be associated with nosocomial infections is considered a significant mortality risk if not adequately addressed. A. baumannii infections typically occur in the aftermath of surgery or trauma. Our patient developed complicated A. baumannii meningitis with lateral ventriculitis and a lumbar abscess post surgery after suffering from a fall. The patient was treated with a 21-day regimen of intrathecally administered colistin and polymyxin B. Following this therapeutic period, the patient's condition improved, ultimately leading to successful recovery and subsequent discharge. This case report serves to highlight the ability of intrathecal administration of antibiotics, that normally have limited potential of crossing the blood-brain-barrier, to lead to improved survival outcomes in multi-drug resistant nosocomial meningitis.

An Intra-Hospital Spread of Colistin-Resistant K. pneumoniae Isolates-Epidemiological, Clinical, and Genetic Analysis.

Background and Objective: Klebsiella pneumoniae appears to be a significant problem due to its ability to accumulate antibiotic-resistance genes. After 2013, alarming colistin resistance rates among carbapenem-resistant K. pneumoniae have been reported in the Balkans. The study aims to perform an epidemiological, clinical, and genetic analysis of a local outbreak of COLr CR-Kp. Material and Methods: All carbapenem-resistant and colistin-resistant K. pneumoniae isolates observed among patients in the ICU unit of Military Medical Academy, Sofia, from 1 January to 31 October 2023, were included. The results were analyzed according to the EUCAST criteria. All isolates were screened for blaVIM, blaIMP, blaKPC, blaNDM, and blaOXA-48. Genetic similarity was determined using the Dice coefficient as a similarity measure and the unweighted pair group method with arithmetic mean (UPGMA). mgrB genes and plasmid-mediated colistin resistance determinants (mcr-1, mcr-2, mcr-3, mcr-4, and mcr-5) were investigated. Results: There was a total of 379 multidrug-resistant K. pneumoniae isolates, 88% of which were carbapenem-resistant. Of these, there were nine (2.7%) colistin-resistant isolates in six patients. A time and space cluster for five patients was found. Epidemiology typing showed that two isolates belonged to clone A (pts. 1, 5) and the rest to clone B (pts. 2-4) with 69% similarity. Clone A isolates were coproducers of blaNDM-like and blaOXA-48-like and had mgrB-mediated colistin resistance (40%). Clone B isolates had only blaOXA-48-like and intact mgrB genes. All isolates were negative for mcr-1, -2, -3, -4, and -5 genes. Conclusions: The study describes a within-hospital spread of two clones of COLr CR-Kp with a 60% mortality rate. Clone A isolates were coproducers of NDM-like and OXA-48-like enzymes and had mgrB-mediated colistin resistance. Clone B isolates had only OXA-48-like enzymes and intact mgrB genes. No plasmid-mediated resistance was found. The extremely high mortality rate and limited treatment options warrant strict measures to prevent outbreaks.

One Health surveillance of colistin-resistant Enterobacterales in Belgium and the Netherlands between 2017 and 2019.

BACKGROUND: Colistin serves as the last line of defense against multidrug resistant Gram-negative bacterial infections in both human and veterinary medicine. This study aimed to investigate the occurrence and spread of colistin-resistant Enterobacterales (ColR-E) using a One Health approach in Belgium and in the Netherlands. METHODS: In a transnational research project, a total of 998 hospitalized patients, 1430 long-term care facility (LTCF) residents, 947 children attending day care centres, 1597 pigs and 1691 broilers were sampled for the presence of ColR-E in 2017 and 2018, followed by a second round twelve months later for hospitalized patients and animals. Colistin treatment incidence in livestock farms was used to determine the association between colistin use and resistance. Selective cultures and colistin minimum inhibitory concentrations (MIC) were employed to identify ColR-E. A combination of short-read and long-read sequencing was utilized to investigate the molecular characteristics of 562 colistin-resistant isolates. Core genome multi-locus sequence typing (cgMLST) was applied to examine potential transmission events. RESULTS: The presence of ColR-E was observed in all One Health sectors. In Dutch hospitalized patients, ColR-E proportions (11.3 and 11.8% in both measurements) were higher than in Belgian patients (4.4 and 7.9% in both measurements), while the occurrence of ColR-E in Belgian LTCF residents (10.2%) and children in day care centres (17.6%) was higher than in their Dutch counterparts (5.6% and 12.8%, respectively). Colistin use in pig farms was associated with the occurrence of colistin resistance. The percentage of pigs carrying ColR-E was 21.8 and 23.3% in Belgium and 14.6% and 8.9% in the Netherlands during both measurements. The proportion of broilers carrying ColR-E in the Netherlands (5.3 and 1.5%) was higher compared to Belgium (1.5 and 0.7%) in both measurements. mcr-harboring E. coli were detected in 17.4% (31/178) of the screened pigs from 7 Belgian pig farms. Concurrently, four human-related Enterobacter spp. isolates harbored mcr-9.1 and mcr-10 genes. The majority of colistin-resistant isolates (419/473, 88.6% E. coli; 126/166, 75.9% Klebsiella spp.; 50/75, 66.7% Enterobacter spp.) were susceptible to the critically important antibiotics (extended-spectrum cephalosporins, fluoroquinolones, carbapenems and aminoglycosides). Chromosomal colistin resistance mutations have been identified in globally prevalent high-risk clonal lineages, including E. coli ST131 (n = 17) and ST1193 (n = 4). Clonally related isolates were detected in different patients, healthy individuals and livestock animals of the same site suggesting local transmission. Clonal clustering of E. coli ST10 and K. pneumoniae ST45 was identified in different sites from both countries suggesting that these clones have the potential to spread colistin resistance through the human population or were acquired by exposure to a common (food) source. In pig farms, the continuous circulation of related isolates was observed over time. Inter-host transmission between humans and livestock animals was not detected. CONCLUSIONS: The findings of this study contribute to a broader understanding of ColR-E prevalence and the possible pathways of transmission, offering insights valuable to both academic research and public health policy development.

In vitro antimicrobial susceptibility data of global meropenem-resistant Acinetobacter baumannii isolates causing pneumonia: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2014-2021, and re-estimations of susceptibility breakpoints and appropriate dosages of important antibiotics for pneumonia treatment.

OBJECTIVES: To evaluate the susceptibility of globally pneumonia-causing meropenem-resistant (MEM-R) Acinetobacter baumannii isolates against important antibiotics and estimate appropriate dosages of indicated antibiotics. METHODS: We extracted the 2014-2021 Antimicrobial Testing of Leadership Surveillance database regarding the susceptibility of MEM-R A. baumannii isolates causing pneumonia against important antibiotics. The susceptibility and carbapenemase-encoding gene (CPEG) data of pneumonia-causing MEM-R A. baumannii isolates from patients hospitalized in intensive care units of five major regions were analyzed. The susceptibility breakpoints (SBP) recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2022, other necessary criteria [SBP of MIC for colistin, 2 mg/L, in the CLSI 2018; and cefoperazone-sulbactam (CFP-SUL), 16 mg/L], and the pharmacokinetic and pharmacodynamic data of indicated antibiotics were employed. RESULTS: Applying the aforementioned criteria, we observed the susceptible rates of colistin, minocycline, and CFP-SUL against the pneumonia-causing MEM-R A. baumannii isolates globally (n = 2905) were 93.2%, 69.1%, and 26.3%, respectively. Minocycline was significantly more active in vitro (MIC ≤4 mg/L) against the pneumonia-causing MEM-R A. baumannii isolates collected from North and South America compared to those from other regions (>90% vs. 58-72%). Additionally, blaOXA-23 and blaOXA-72 were the predominant CPEG in pneumonia-causing MEM-R A. baumannii isolates. CONCLUSIONS: After deliberative estimations, dosages of 200 mg minocycline intravenously every 12 h (SBP, 8 mg/L), 100 mg tigecycline intravenously every 12 h (SBP, 1 mg/L), and 160 mg nebulized colistin methanesulphonate every 8 h (SBP, 2 mg/L) are needed for the effective treatment of pneumonia-causing MEM-R A. baumannii isolates.

Prevalence of colistin resistance in clinical isolates of Acinetobacter baumannii: a systematic review and meta-analysis.

INTRODUCTION: The development of colistin resistance in Acinetobacter baumannii during treatment has been identified in certain patients, often leading to prolonged or recurrent infections. As colistin, is the last line of therapy for A. baumannii infections that are resistant to almost all other antibiotics, colistin-resistant A. baumannii strains currently represent a significant public health threat, particularly in healthcare settings where there is significant selective pressure. AIM: The aim of this study was to comprehensively determine the prevalence of colistin resistance in A. baumannii from clinical samples. Regional differences in these rates were also investigated using subgroup analyses. METHOD: The comprehensive search was conducted using "Acinetobacter baumannii", "Colistin resistant" and all relevant keywords. A systematic literature search was performed after searching in PubMed, Embase, Web of Science, and Scopus databases up to April 25, 2023. Statistical analysis was performed using Stata software version 17 and sources of heterogeneity were evaluated using I2. The potential for publication bias was explored using Egger's tests. A total of 30,307 articles were retrieved. After a thorough evaluation, 734 studies were finally eligible for inclusion in the present systematic review and meta-analysis. RESULT: According to the results, the prevalence of resistance to colistin among A. baumannii isolates was 4% (95% CI 3-5%), which has increased significantly from 2% before 2011 to 5% after 2012. South America had the highest resistance rate to this antibiotic. The broth microdilution method had the highest level of resistance, while the agar dilution showed the lowest level. CONCLUSIONS: This meta-analysis found a low prevalence of colistin resistance among A. baumannii isolates responsible for infections worldwide from 2000 to 2023. However, there is a high prevalence of colistin-resistant isolates in certain countries. This implies an urgent public health threat, as colistin is one of the last antibiotics available for the treatment of infections caused by XDR strains of A. baumannii.

Comparison of in vitro synergy between polymyxin B or colistin in combination with 16 antimicrobial agents against multidrug-resistant Acinetobacter baumannii isolates.

PURPOSES: This study determined the synergy of polymyxin B (POLB) and colistin (COL) with 16 other tested antimicrobial agents in the inhibition of multidrug-resistant Acinetobacter baumannii (MDR-AB). METHODS: We used chequerboard assays to determine synergy between the drugs against 50 clinical MDR-AB from a tertiary hospital in the Zhejiang province in 2019, classifying combinations as either antagonistic, independent, additive, or synergistic. The efficacy of hit combinations which showed highest synergistic rate were confirmed using time-kill assays. RESULTS: Both POLB and COL displayed similar bactericidal effects when used in combination with these 16 tested drugs. Antagonism was only observed for a few strains (2%) exposed to a combination of POLB and cefoperazone/sulbactam (CSL). A higher percentage of synergistic combinations with POLB and COL were observed with rifabutin (RFB; 90%/96%), rifampicin (RIF; 60%/78%) and rifapentine (RFP; 56%/76%). Time-kill assays also confirmed the synergistic effect of POLB and rifamycin class combinations. 1/2 MIC rifamycin exposure can achieve bacterial clearance when combined with 1/2 MIC POLB or COL. CONCLUSION: Nearly no antagonism was observed when combining polymyxins with other drugs by both chequerboard and time-kill assays, suggesting that polymyxins may be effective in combination therapy. The combinations of POLB/COL with RFB, RIF, and RFP displayed neat synergy, with RFB showing the greatest effect.