Herein, we describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against carbapenem-resistant Acinetobacter baumannii strains in a neutropenic murine thigh infection model. Five of the six isolates examined expressed OXA-23 or OXA-24.

Background and Objectives: The increase in antimicrobial resistance (AMR) across countries has seriously impacted the effective management of infectious diseases, with subsequent impact on morbidity, mortality and costs. This includes Pakistan. Antimicrobial surveillance activities should be mandatory to continually assess the extent of multidrug-resistant bacteria and the implications for future empiric prescribing. The objective of this retrospective observational study was to monitor the susceptibility pattern of microbes in Pakistan. Materials and Methods: Clinical samples from seven laboratories in Punjab, Pakistan were collected between January 2018 and April 2019, with Punjab being the most populous province in Pakistan. The isolates were identified and their antimicrobial susceptibility was tested using the Kirby-Bauer disc diffusion assay and micro broth dilution methods. The antibiotics assessed were those typically prescribed in Pakistan. Results: In total, 2523 bacterial cultural reports were studied. The most frequently isolated pathogens were Staphylococcus aureus (866, 34.3%), followed by Escherichia coli (814, 32.2%), Pseudomonas aeruginosa (454, 18.0%) and Klebsiella pneumoniae (269, 10.7%). Most pathogens were isolated from pus (1464, 58.0%), followed by urine (718, 28.5%), blood (164, 6.5%) and sputum (81, 3.2%). Conclusions: The findings suggest that current antimicrobial options are severally restricted in Pakistan due to the emergence of multidrug-resistant pathogens. This calls for urgent actions including initiating antimicrobial stewardship programs to enhance prudent prescribing of antibiotics. This includes agreeing on appropriate empiric therapy as part of agreed guidelines, in line with the WHO EML and AWaRe book, whilst awaiting culture reports. This is alongside other measures to reduce inappropriate antimicrobial prescribing and reverse the threat of rising AMR.

Colistin is considered a last treatment option for multi-drug and extensively resistant Gram-negative infections. We aimed to assess the available data on the dosing strategy of colistin. A systematic review was performed to identify all published studies on the dose optimization of colistin. Grey literature and electronic databases were searched. Data were collected in a specified form and the quality of the included articles was then assessed using the Newcastle-Ottawa scale for cohort studies, the Cochrane bias tool for randomized clinical trials (RCT), and the Joanna Briggs Institute (JBI) critical checklist for case reports. A total of 19 studies were included, of which 16 were cohort studies, one was a RCT, and two were case reports. A total of 18 studies proposed a dosing regimen for adults, while only one study proposed a dosing schedule for pediatric populations. As per the available evidence, a loading dose of 9 million international units (MIU) of colistin followed by a maintenance dose of 4.5 MIU every 12 h was considered the most appropriate dosing strategy to optimize the safety and efficacy of treatment and improve clinical outcomes. This review supports the administration of a loading dose followed by a maintenance dose of colistin in severe and life-threatening multi-drug Gram-negative bacterial infections.

Combination therapy is an attractive option for the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections; however, limited data are available on combinations with ceftolozane-tazobactam (C-T). The in vitro pharmacodynamic chemostat model was employed to compare human-simulated exposures of C-T at 3 g every 8 h alone or in combination with amikacin at 25 mg/kg of body weight daily or colistin at 360 mg daily against four MDR P. aeruginosa isolates. C-T alone resulted in 24-h changes in the number of CFU of −0.02 ± 0.21, −1.81 ± 0.55, −1.44 ± 0.40, and +0.62 ± 0.05 log ₁₀ CFU/ml against isolates with C-T MICs of 4, 4, 8, and 16 μg/ml, respectively. Amikacin and colistin monotherapy displayed various results. The addition of amikacin to C-T resulted in −2.00 ± 0.23 ( P < 0.001, additive)-, −1.50 ± 0.83 ( P = 0.687, indifferent)-, −2.84 ± 0.08 ( P = 0.079, indifferent)-, and −2.67 ± 0.54 ( P < 0.001, synergy)-log ₁₀ CFU/ml reductions, respectively. The addition of colistin to C-T resulted in −3.02 ± 0.22 ( P < 0.001, additive)-, −3.21 ± 0.24 ( P > 0.05, indifferent)-, −4.6 ± 0.11 ( P = 0.002, synergy)-, and −3.01 ± 0.28 ( P < 0.001, synergy)-log ₁₀ CFU/ml reductions, respectively, against the MDR P. aeruginosa isolates with these MICs. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 h, with C-T plus amikacin or colistin were observed against 3 out of 4 MDR P. aeruginosa strains tested, particularly those strains that were intermediate or resistant to C-T. Further studies assessing combination regimens containing C-T against MDR P. aeruginosa are warranted.

Purpose The results of a study to determine the physical compatibility of ZTI-01 (fosfomycin for injection) in 0.9% sodium chloride or 5% dextrose during simulated Y-site administration with 37 i.v. antimicrobials and 58 nonantimicrobials are reported. Methods Fosfomycin, an epoxide antibiotic with broad-spectrum activity against multidrug-resistant bacteria, is marketed in the United States only in an oral formulation with limited bioavailability, but an i.v. formulation is in development. Fosfomycin for injection and other evaluated drugs were reconstituted according to manufacturer recommendations and further diluted with 0.9% sodium chloride or 5% dextrose to the final desired concentrations. Y-site administration was simulated in glass culture tubes. Incompatibility was defined as changes in visual characteristics or a change in turbidity of >0.5 nephelometric turbidity units over the 120-minute observation period. Results Of the 95 drugs tested, 16 were incompatible with fosfomycin in 0.9% sodium chloride, and 18 were incompatible with fosfomycin in 5% dextrose; incompatibility was observed with 10 of 37 antimicrobials, including the 3 commercially available amphotericin B products, anidulafungin, caspofungin, ceftaroline, ciprofloxacin, daptomycin, doxycycline, and isavuconazonium sulfate. Conclusion Fosfomycin for injection at a concentration of 30 mg/mL was physically compatible with 73 of 95 (77%) of the i.v. drugs tested at concentrations used clinically in both 0.9% sodium chloride injection and 5% dextrose injection. Twenty-two drugs were deemed incompatible in at least 1 of the 2 diluents.