Severe Gram-negative Infections Research Articles

Ceftazidime with avibactam for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of ceftazidime-avibactam in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. The health benefit of ceftazidime-avibactam was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. Patient-level costs and health-related quality of life of ceftazidime-avibactam under various usage scenarios compared with alternative management strategies in the high-value clinical scenarios were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population in quality-adjusted life-years using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for ceftazidime-avibactam. The clinical effectiveness of ceftazidime-avibactam relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. In the base case, ceftazidime-avibactam was associated with a statistically significantly higher susceptibility relative to colistin (odds ratio 7.24, 95% credible interval 2.58 to 20.94). The remainder of the treatments were associated with lower susceptibility than colistin (odds ratio < 1). The results were sensitive to the definition of resistance and the studies included in the analysis. In the base case, patient-level benefit of ceftazidime-avibactam was between 0.08 and 0.16 quality-adjusted life-years, depending on the site of infection and the usage scenario. There was a high degree of uncertainty surrounding the benefits of ceftazidime-avibactam across all subgroups, and the results were sensitive to assumptions in the meta-analysis used to estimate susceptibility. There was substantial uncertainty in the number of infections that are suitable for treatment with ceftazidime-avibactam, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time, and rates of emergence of resistance. The population-level benefit varied substantially across the scenarios, from 531 to 2342 quality-adjusted life-years over 20 years. This work has provided quantitative estimates of the value of ceftazidime-avibactam within its areas of expected usage within the NHS. Given existing evidence, the estimates of the value of ceftazidime-avibactam are highly uncertain. Future evaluations of antimicrobials would benefit from improvements to NHS data linkages, research to support appropriate synthesis of susceptibility studies, and application of routine data and decision modelling to assess enablement value. No registration of this study was undertaken. This award was funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme (NIHR award ref: NIHR135592), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 73. See the NIHR Funding and Awards website for further award information.

Cefiderocol for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. No registration of this study was undertaken. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.

Polymyxins with Potent Antibacterial Activity against Colistin-Resistant Pathogens: Fine-Tuning Hydrophobicity with Unnatural Amino Acids.

In view of the increased prevalence of antimicrobial resistance among human pathogens, antibiotics against multidrug-resistant (MDR) bacteria are in urgent demand. In particular, the rapidly emerging resistance to last-resort antibiotic colistin, used for severe Gram-negative MDR infections, is critical. Here, a series of polymyxins containing unnatural amino acids were explored, and some analogues exhibited excellent antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Hydrophobicity of the compounds within this series (as measured by retention in reversed-phase analytical HPLC) exhibited a discernible correlation with their antimicrobial activity. This trend was particularly pronounced for colistin-resistant pathogens. The most active compounds demonstrated competitive activity against a panel of Gram-negative pathogens, while exhibiting low in vitro cytotoxicity. Importantly, most of these hits also retained (or even had increased) potency against colistin-susceptible strains. These findings infer that fine-tuning hydrophobicity may enable the design of polymyxin analogues with favorable activity profiles.

Therapeutic Effect of Chitosan-Zinc Oxide Nanoparticles on Acute Kidney Injury Induced by Gentamicin in Wistar Rats

Background: Gentamicin (GM) is an antibiotic frequently used to treat severe gram-negative infections. However, due to nephrotoxicity, its clinical application is restricted. Several lines of evidence indicate that free radicals are important mediators of gentamicin nephrotoxicity. Therefore, the purpose of this research was to examine the potential antioxidant therapeutic value of ZnO-chitosan nanoparticles on gentamicin-induced nephrotoxicity. Methods: Twenty-four rats were divided into four groups (6 rats/group). All groups except group 1 were injected with gentamicin (100 mg/kg body weight i.p.) for eight days. On day 9, rats of groups 1 and 2 were administrated distilled water, and those of groups 3 and 4 were administrated 1/10 and 1/20 LD50 of ZnO-CS-NPs continuously for 30 days. Results: Treatment with ZnO-CS NPs caused a significant decrease in urea, creatinine, uric acid, sodium, potassium, chloride, microalbumin, and malondialdehyde levels; this was accompanied by a significant increase in kidney glutathione reduced, nitric oxide, superoxide dismutase, glutathione S-transferase, and catalase. Conclusion: The findings of the current study revealed that ZnO-CS NP ameliorated kidney injury against gentamicin induced-acute kidney injury in rats by its antioxidant properties.

Capturing Value Attributes in the Economic Evaluation of Ceftazidime with Avibactam for Treating Severe Aerobic Gram-Negative Bacterial Infections in the United Kingdom.

Antimicrobial resistance remains a serious and growing threat to public health, both globally and in the UK, leading to diminishing effectiveness of antimicrobials. Despite a clear need for new antimicrobials, the clinical pipeline is insufficient, driven by high research and development costs and limited expected returns on investment. To counteract this, National Institute for Health and Care Excellence (NICE) and National Health Service (NHS) England have launched a reimbursement mechanism, de-linked from volume of sales, that aims to reduce economic risk by recognising the broader population-level value of antimicrobials. The objective of this study was to quantify the value of ceftazidime-avibactam for treating gram-negative infections in the UK considering some of these broader value elements unique to antimicrobials. A previously developed dynamic disease transmission and cost-effectiveness model was applied to assess the value of introducing ceftazidime-avibactam to UK treatment practice in the management of gram-negative hospital-acquired infections in line with the licenced indications for ceftazidime-avibactam. Model inputs were parameterised using sources aligned to the UK perspective. The introduction of ceftazidime-avibactam into a two-line treatment sequence saved over 2300 lives, leading to a gain of 27,600 life years and 22,000 quality-adjusted life years (QALY) at an additional cost of £17 million, over a ten-year transmission period. Ceftazidime-avibactam was associated with a net monetary benefit of £642 million at willingness to pay threshold of £30,000 per QALY; even at a lower threshold of £20,000 per QALY, the net monetary benefit is £422 million. Increasing the diversity of antimicrobial treatments through the introduction of an additional antimicrobial, in this instance ceftazidime-avibactam, was associated with substantial clinical and economic benefits, when considering broader population-level value. Despite revealing considerable benefits, the value of ceftazidime-avibactam is only partially reflected in this analysis. Further efforts are required to fully operationalise the spectrum, transmission, enablement, diversity and insurance (STEDI) value framework and accurately reflect the population-level value of antimicrobials.

Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections.

To explore the relationship between real-time therapeutic drug monitoring (TDM)-guided pharmacodynamic target attainment of continuous infusion (CI) beta-lactam monotherapy and microbiological outcome in the treatment of critically ill children with severe documented Gram-negative infections. Observational, monocentric, retrospective study of critically ill patients receiving CI piperacillin-tazobactam, ceftazidime, or meropenem in monotherapy for documented Gram-negative infections optimized by means of a real-time TDM-guided strategy. Average steady-state beta-lactam concentrations (Css) were calculated for each patient, and the beta-lactam Css/minimum inhibitory concentration (MIC) ratio was selected as a pharmacodynamic parameter of efficacy. The Css/MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between Css/MIC and microbiological outcome was assessed. Forty-six TDM assessments were carried out in 21 patients [median age 2 (interquartile range: 1-8) years]. Css/MIC ratios were optimal in 76.2% of cases. Patients with optimal Css/MIC ratios had both a significantly higher microbiological eradication rate (75.0% vs. 0.0%; P = 0.006) and lower resistance development rate (25.0% vs. 80.0%; P = 0.047) than those with quasi-optimal or suboptimal Css/MIC ratios. Quasi-optimal/suboptimal Css/MIC ratio occurred more frequently when patients had infections caused by pathogens with MIC values above the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint (100.0% vs. 6.3%; P < 0.001). Real-time TDM-guided pharmacodynamic target attainment of CI beta-lactam monotherapy allowed to maximize treatment efficacy in most critically ill children with severe Gram-negative infections. Attaining early optimal Css/MIC ratios of CI beta-lactams could be a key determinant associated with microbiological eradication during the treatment of Gram-negative infections. Larger prospective studies are warranted for confirming our findings.

First Detection of mcr-9 in a Multidrug-Resistant Escherichia coli of Animal Origin in Italy Is Not Related to Colistin Usage on a Pig Farm.

The emergence of colistin resistance raises growing concerns because of its use as a last-resort antimicrobial for the treatment of severe gram-negative bacterial infections in humans. Plasmid-borne mobile colistin resistance genes (mcr) are particularly worrisome due to their high propensity to spread. An mcr-9-positive Escherichia coli was isolated from a piglet in Italy, representing the first isolation of this gene from an E. coli of animal origin in the country. Whole genome sequencing (WGS) revealed that mcr-9 was borne by an IncHI2 plasmid carrying several other resistance genes. The strain was indeed phenotypically resistant to six different antimicrobial classes, including 3rd and 4th generation cephalosporins. Despite the presence of mcr-9, the isolate was susceptible to colistin, probably because of a genetic background unfavourable to mcr-9 expression. The lack of colistin resistance, coupled with the fact that the farm of origin had not used colistin in years, suggests that mcr-9 in such a multidrug-resistant strain can be maintained thanks to the co-selection of neighbouring resistance genes, following usage of different antimicrobials. Our findings highlight how a comprehensive approach, integrating phenotypical testing, targeted PCR, WGS-based techniques, and information on antimicrobial usage is crucial to shed light on antimicrobial resistance.

4F-Indole Enhances the Susceptibility of Pseudomonas aeruginosa to Aminoglycoside Antibiotics.

Infections caused by multidrug-resistant bacteria are becoming increasingly serious. The aminoglycoside antibiotics have been widely used to treat severe Gram-negative bacterial infections. Here, we reported that a class of small molecules, namely, halogenated indoles, can resensitize Pseudomonas aeruginosa PAO1 to aminoglycoside antibiotics such as gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribosomalin sulfate, and cisomicin. We selected 4F-indole as a representative of halogenated indoles to investigate its mechanism and found that the two-component system (TCS) PmrA/PmrB inhibited the expression of multidrug efflux pump MexXY-OprM, allowing kanamycin to act intracellularly. Moreover, 4F-indole inhibited the biosynthesis of several virulence factors, such as pyocyanin, type III secretion system (T3SS), and type VI secretion system (T6SS) exported effectors, and reduced the swimming and twitching motility by suppressing the expression of flagella and type IV pili. This study suggests that the combination of 4F-indole and kanamycin can be more effective against P. aeruginosa PAO1 and affect its multiple physiological activities, providing a novel insight into the reactivation of aminoglycoside antibiotics. IMPORTANCE Infections caused by Pseudomonas aeruginosa have become a major public health crisis. Its resistance to existing antibiotics causes clinical infections that are hard to cure. In this study, we found that halogenated indoles in combination with aminoglycoside antibiotics could be more effective than antibiotics alone against P. aeruginosa PAO1 and preliminarily revealed the mechanism of the 4F-indole-induced regulatory effect. Moreover, the regulatory effect of 4F-indole on different physiological behaviors of P. aeruginosa PAO1 was analyzed by combined transcriptomics and metabolomics. We explain that 4F-indole has potential as a novel antibiotic adjuvant, thus slowing down the further development of bacterial resistance.

One-stage revision using intra-articular carbapenem infusion effectively treats chronic periprosthetic joint infection caused by Gram-negative organisms.

Gram-negative periprosthetic joint infection (PJI) has been poorly studied despite its rapidly increasing incidence. Treatment with one-stage revision using intra-articular (IA) infusion of antibiotics may offer a reasonable alternative with a distinct advantage of providing a means of delivering the drug in high concentrations. Carbapenems are regarded as the last line of defense against severe Gram-negative or polymicrobial infection. This study presents the results of one-stage revision using intra-articular carbapenem infusion for treating Gram-negative PJI, and analyzes the characteristics of bacteria distribution and drug sensitivity. We retrospectively reviewed 32 patients (22 hips and 11 knees) who underwent single-stage revision combined with IA carbapenem infusion between November 2013 and March 2020. The IA and intravenous (IV) carbapenem infusions were administered for a single Gram-negative infection, and IV vancomycin combined with IA carbapenems and vancomycin was applied for polymicrobial infection including Gram-negative bacteria. The bacterial community distribution, drug sensitivity, infection control rate, functional recovery, and complications were evaluated. Reinfection or death caused by PJI was regarded as a treatment failure. Gram-negative PJI was mainly caused by Escherichia coli (8/34), Enterobacter cloacae (7/34), and Klebsiella pneumoniae (5/34). Seven cases (7/32) involved polymicrobial PJIs. The resistance rates of penicillin, cephalosporin, quinolones, and sulfonamides were > 10%, and all penicillin and partial cephalosporins (first and second generation) were > 30%. Of 32 cases, treatment failed to eradicate infection in only three cases (9.4%), at a mean follow-up of 55.1 months (SD 25 to 90). The mean postoperative Harris Hip Score and Hospital for Special Surgery knee score at the most recent follow-up were 81 (62 to 91) and 79 (56 to 89), respectively. One patient developed a fistula, and another presented with a local rash on an infected joint. The use of IA carbapenem delivered alongside one-stage revision effectively controlled Gram-negative infection and obtained acceptable clinical outcomes with few complications. Notably, first- and second-generation cephalosporins and penicillin should be administrated with caution, due to a high incidence of resistance.

Measuring Creatinine Clearance Is the Most Accurate Way for Calculating the Proper Continuous Infusion Meropenem Dose for Empirical Treatment of Severe Gram-Negative Infections among Critically Ill Patients

Assessment of glomerular filtration rate (GFR) is necessary for dose adjustments of beta-lactam that are excreted by the kidneys, such as meropenem. The aim of this study was to compare the daily dose of 24 h-continuous infusion (CI) meropenem when GFR was calculated by means of measured creatinine clearance (mCLCR) or estimated by the CKDEPI (eGFRCKDEPI), Cockcroft-Gault (eGFRCG), and MDRD (eGFRMDRD) equations. Adult critically ill patients who underwent therapeutic drug monitoring (TDM) for the assessment of 24 h-CI meropenem steady state concentration (Css) and for whom a 24 h-urine collection was performed were retrospectively enrolled. Meropenem clearance (CLM) was regressed against mCLCR, and meropenem daily dose was calculated based on the equation infusion rate = daily dose/CLM. eGFRCKDEPI, eGFRCG, and eGFRCKDEPI were regressed against mCLCR in order to estimate CLM. Forty-six patients who provided 133 meropenem Css were included. eGFRCKDEPI overestimated mCLCR up to 90 mL/min, then mCLCR was underestimated. eGFRCG and eGFRMDRD overestimated mCLCR across the entire range of GFR. In critically ill patients, dose adjustments of 24 h-CI meropenem should be based on mCLCR. Equations for estimation of GFR may lead to gross under/overestimates of meropenem dosages. TDM may be highly beneficial, especially for critically ill patients with augmented renal clearance.

618. Pharmacokinetic/pharmacodynamic analysis of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating documented carbapenem-resistant Gram-negative bloodstream infections and/or hospital-acquired pneumonia: a case series

Abstract Background To describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour and the microbiological outcome of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating severe carbapenem-resistant Gram-negative (CR-GN) infections. Methods Single-center retrospective study of patients who were treated with CI fosfomycin plus EI or CI beta-lactams for severe CR-GN infections and who underwent therapeutic drug monitoring (TDM), from 01 April 2021 to 31 January 2022. Concentrations of CI fosfomycin, meropenem and ceftazidime-avibactam were determined at steady-state (Css), while those of EI cefiderocol were measured at trough (Cmin). The desired joint PK/PD targets of combination therapy were considered as optimal when simultaneously the area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio for fosfomycin was &amp;gt; 83 and the Css/MIC for meropenem or for ceftazidime-avibactam or the Cmin/MIC ratio for cefiderocol was &amp;gt; 4 (quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). Relationship between the joint PK/PD targets and microbiological failure (MF) defined as isolation of the same pathogens from follow-up blood cultures or BAL and assessed within 30 days of treatment onset, was investigated. Results Among the 16 retrieved patients with documented CR-GN infections, 12 underwent TDM of both fosfomycin and beta-lactams, and seven out of these (3 HAP, 3 BSI+HAP, and one BSI) had determination of fosfomycin MIC determined by agar-dilution (see Table). The joint PK/PD targets were optimal in 4 cases and quasi-optimal in the other 3y. MF occurred in two patients (29%) who were affected by HAP, received combination therapy with ceftazidime-avibactam, and achieved only quasi-optimal joint PK/PD targets (with fosfomycin AUC/MIC &amp;lt; 83). No MF occurred in patients with optimal joint PK/PD targets. Summary of the relationship between PK/PD targets and microbiological failure in patients receiving combination therapy with CI fosfomycin plus EI/CI beta-lactams Conclusion CI fosfomycin in combination with EI/CI beta-lactams may allow for the achievement of optimal joint PK/PD targets in most patients with CR-GN infections, and may represent a potential strategy for minimizing the risk of MF. Disclosures All Authors: No reported disclosures.

New antimicrobial treatment options for severe Gram-negative infections.

This review will provide rationale for the development of new antibiotics to treat severe or multidrug-resistant (MDR) Gram-negative infections. It will also provide an overview of recently approved and pipeline antibiotics for severe/MDR Gram-negative infections. MDR Gram-negative infections are recognized as critical threats by global and national organizations and carry a significant morbidity and mortality risk. Increasing antibiotic resistance amongst Gram-negative bacteria, including carbapenem-resistant Acinetobacter baumannii , extended-spectrum β-lactamase-producing Enterobacterales, carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa , with difficult-to-treat-resistance has made both empiric and definitive treatment of these infections increasingly problematic. In recent years, several antibiotics have been approved for treatment of MDR Gram-negative infections and ongoing clinical trials are poised to provide additional options to clinicians' armamentarium. These agents include various β-lactam/β-lactamase inhibitor combinations, eravacycline, plazomicin and cefiderocol. Severe/MDR Gram-negative infections continue to be important infections due to their impact on patient outcomes, especially in critically ill and immunocompromised hosts. The availability of new antibiotics offers an opportunity to improve empiric and definitive treatment of these infections.

A Survey of Current Activities and Technologies Used to Detect Carbapenem Resistance in Bacteria Isolated from Companion Animals at Veterinary Diagnostic Laboratories-United States, 2020.

Carbapenems are antimicrobial drugs reserved for the treatment of severe multidrug-resistant Gram-negative bacterial infections. Carbapenem-resistant organisms (CROs) are an urgent public health threat and have been made reportable to public health authorities in many jurisdictions. Recent reports of CROs in companion animals and veterinary settings suggest that CROs are a One Health problem. However, standard practices of U.S. veterinary diagnostic laboratories (VDLs) to detect CROs are unknown. We assessed the capacity of VDLs to characterize carbapenem resistance in isolates from companion animals. Among 74 VDLs surveyed in 42 states, 23 laboratories (31%) from 22 states responded. Most (22/23, 96%) included ≥1 carbapenem on their primary antimicrobial susceptibility testing panel, and approximately one-third (9/23, 39%) performed phenotypic carbapenemase production testing or molecular identification of carbapenemase genes. Overall, 35% (8/23) of VDLs across eight states reported they would notify public health if a CRO was detected. Most (17/21, 81%) VDLs were not aware of CRO reporting mandates, and some expressed uncertainty about whether the scope of known mandates included CROs from veterinary sources. Although nearly all surveyed VDLs tested for carbapenem resistance, fewer had the capacity for mechanism testing or awareness of public health reporting requirements. Addressing these gaps is critical to monitoring CRO incidence and trends in veterinary medicine, preventing spread in veterinary settings, and mounting an effective One Health response. Improved collaboration and communication between public health and veterinary medicine is critical to inform infection control practices in veterinary settings and conduct a public health response when resistant isolates are detected.

Dose Optimization of Colistin: A Systematic Review

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.

Utilization of Colistin Versus β-Lactam and β-Lactamase Inhibitor Agents in Relation to Acute Kidney Injury in Patients with Severe Gram-Negative Infections.

IntroductionColistin is used to treat severe antibiotic-resistant Gram-negative infections (GNIs). With the rise of antibiotic resistance, colistin has been used increasingly as a ‘last-line’ therapy for multidrug-resistant GNIs. We evaluated the incidence of acute kidney injury (AKI) and mortality among patients receiving colistin or one of the new β-lactam/β-lactamase inhibitors (βL + βLI) (ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem/vaborbactam).MethodsThis retrospective cohort study used data from the Premier Healthcare Database. The cohort included propensity score-matched adults with an inpatient stay between January 2016 and December 2018. Patients given both colistin and BL + BLI as treatment for ≥ 72 h were excluded. AKI was defined as acute renal failure or dialysis during hospitalization with antibiotic administration. Propensity score matching was used to control for selection bias and confounding. Logistic regression evaluated associations between treatment, AKI, and in-hospital mortality.ResultsThe total number of patients in the matched cohorts were 256 in each. Overall, 23.8% and 13.3% of patients receiving colistin or new βL + βLI agents, respectively, experienced AKI during hospitalization (p = 0.002); odds of AKI for colistin were 3.0 (95% CI 1.71, 5.21). Following propensity score-matching, patients without baseline renal disease experienced AKI during hospitalization to a higher degree in the colistin group compared to the βL + βLI group (17.1% vs. 6.8%); colistin use was associated with 3.7 times higher odds (95% CI 1.84, 7.42) of AKI compared to βL + βLI agents. The odds of mortality in patients on colistin developing AKI were more than three times that of patients receiving a BL + BLI agent who developed AKI. Among patients receiving colistin, incident AKI was associated with 6.1 times higher odds (95% CI 2.53, 14.71) of mortality.ConclusionsPatients receiving colistin for GNIs had significantly higher odds of AKI and mortality than those receiving βL + βLI.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00556-x.

Сочетание карбапенемрезистентности и колистинрезистентности возбудителей тяжелых грамотрицательных нозокомиальных инфекций: первые признаки наступления постантибиотической эры

В статье обозначена современная ситуация с полиантибиотикорезистентностью, которая возникает у тяжелых больных в условиях отделения интенсивной терапии (ОИТ), в мире и в Украине, отмечаются различия в осознании этой проблемы. Акцентировано внимание на распространении карбапенемрезистентности и возникновении колистинрезистентности «проблемных» грамотрицательных возбудителей нозокомиальных инфекций, таких как P.аeruginosa и K.рneumoniae. Именно P.аeruginosa недавно считалась наиболее опасным (распространенным и наиболее резистентным) возбудителем, тогда как на сегодняшний день на ведущие позиции выходит именно K.рneumoniae. В статье приведены основные механизмы резистентности этих возбудителей по фенотипическим проявлениям, а также подчеркнуты перспективы молекулярно-генетического определения механизмов резистентности «проблемного» возбудителя и отслеживания того, чтобы он не распространялся. В работе представлены также собственные данные, свидетельствующие, что распространенность карбапенемрезистентных штаммов в ОИТ неуклонно растет. Определены основные направления и пути предупреждения и преодоления антибиотикорезистентности, которые доказали свою эффективность в развитых странах, а также указаны проблемы и перспективы в этом направлении в ОИТ в Украине.

Clinical Pharmacokinetics and Pharmacodynamics of Cefiderocol.

Cefiderocol is a new broad-spectrum cephalosporin antibiotic with promising activity against various Gram-negative bacteria including carbapenem-resistant strains. A chlorocatechol group in the C-3 side chain provides cefiderocol with a siderophore activity, improving its stability against β-lactamases and facilitating the transportation of cefiderocol across outer bacterial membranes. Cefiderocol shows linear pharmacokinetics over a broad range of clinically relevant doses, with unchanged renal excretion constituting the main route of elimination. Geometric means (coefficient of variation) of the volume of distribution and clearance in individuals with normal kidney function were 15.8 (15%) L and 4.70 (27%) L/h, respectively. In patients with end-stage renal disease, clearance was 1.10 (24%) L/h. Time above the minimum inhibitory concentration is the main predictor of efficacy. There is no evidence for clinically relevant interactions of cefiderocol with other drugs mediated by metabolizing enzymes or drug transporters. Simulations based on population pharmacokinetic modeling suggest that dosing regimens should be adjusted based on kidney function to optimize therapeutic exposure to cefiderocol. Clinical efficacy trials indicated that cefiderocol is non-inferior to imipenem/cilastatin in the treatment of complicated urinary tract infections and acute uncomplicated pyelonephritis, and to meropenem in the treatment of nosocomial pneumonia. In the one study currently available, cefiderocol performed similarly to the best available therapy in the treatment of severe carbapenem-resistant Gram-negative infections regarding clinical and microbiological efficacy. In summary, cefiderocol shows favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol might be a viable option to treat infections with bacteria resistant to other antibiotics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01063-5.

Prevalence of ESBL-producing Escherichia coli in adults with and without HIV presenting with urinary tract infections to primary care clinics in Zimbabwe.

BackgroundPeople living with HIV may be at increased risk for infections with resistant organisms. Infections with ESBL-producing organisms are of particular concern because they limit treatment options for severe Gram-negative infections in low-resource settings.ObjectivesTo investigate the association between HIV status and urinary tract infections (UTIs) with ESBL-producing Escherichia coli.Patients and methodsCross-sectional study enrolling adults presenting with UTI symptoms to primary care clinics in Harare, Zimbabwe. Demographic and clinical data were collected during interviews and a urine sample was collected for culture from each participant. Antimicrobial susceptibility testing was performed according to EUCAST recommendations.ResultsOf the 1164 who were enrolled into the study, 783 (64%) were female and 387 (33%) were HIV infected. The median age was 35.8 years. Urine cultures were positive in 338 (29.0%) participants, and the majority of bacterial isolates were E. coli (n = 254, 75.2%). The presence of ESBL was confirmed in 49/254 (19.3%) E. coli. Participants with HIV had a 2.13 (95% CI 1.05–4.32) higher odds of infection with ESBL-producing E. coli than individuals without HIV. Also, the prevalence of resistance to most antimicrobials was higher among participants with HIV.ConclusionsThis study found an association between HIV and ESBL-producing E. coli in patients presenting with symptoms suggestive of UTI to primary care in Harare. HIV status should be considered when prescribing empirical antimicrobial treatment.

Serious adverse events with novel beta-lactam/beta-lactamase inhibitor combinations: a large-scale pharmacovigilance analysis

The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.

Amelioration of renal cortex histological alterations by aqueous garlic extract in gentamicin induced renal toxicity in albino rats: a histological and immunohistochemical study

ABSTRACT Background: Aminoglycosides, particularly gentamicin, endure crucial antibiotics in the armamentarium for severe Gram-negative bacterial infections through their significant risk for nephrotoxicity. Co-administration of several applicant nephroprotective agents has been investigated at the preclinical level. Garlic was proved to be an oxidative stress combatant with unique antioxidant potential. Aim of the work: To assess renal cortex structural changes due to gentamicin treatment and the role of the aqueous garlic extract (AGE) in ameliorating these changes. Material and methods: Thirty-two male albino rats were assigned into four equal groups. Group I (Control group) received 0.9% NaCl solution through oral gavage in the same volume as in AGE-treated group. Group II (AGE treated group) received AGE by oral gavage at 250 mg/kg/day. Group III (Gentamicin treated group) received Gentamicin at 80 mg/kg/day intraperitoneally. Group IV (Gentamicin and AGE cotreated group) received both gentamicin and AGE. The duration of the treatment was 21 days. Specimens of renal cortex of all groups were processed for light microscopic examination. Specimens were additionally prepared for electron microscopic examination. Morphometric study and statistical analysis were performed. Results: Examination of the renal cortex in the gentamicin treated rats showed both proximal and distal tubular necrosis, vacuolation, desquamation and interstitial mononuclear cell infiltration. Masson’s trichrome staining revealed intense deposition of collagen fibers. Strong positive immunoreaction for caspase-3 was observed. Ultrastructurally, the glomerulus showed thickened basement membrane, destructed endothelium. Proximal and distal convoluted tubular cells exhibited vacuolations, distorted mitochondria and nuclear chromatin condensation with loss of microvilli. AGE ameliorated these changes. Conclusion: Aqueous garlic extract ameliorates the histological changes caused by gentamicin in the rat renal cortex.