Efficacy and safety of ceftazidime-avibactam versus polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infection: a systematic review and meta-analysis.

OBJECTIVES: Carbapenem-resistant Enterobacteriaceae is increasingly recognised as a significant public health concern. Ceftazidime-avibactam (CAZ-AVI) and polymyxins are considered as the last therapeutic options worldwide. This is the first meta-analysis of recently published data to compare the clinical efficacy and safety of CAZ-AVI with polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infections. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase and the Cochrane Library were systematically searched, for publications in any language, from database inception to February 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies comparing the clinical efficacy and safety of CAZ-AVI with polymyxins were included. Mortality, clinical success, microbiological eradication and nephrotoxicity were assessed as the main outcomes. DATA EXTRACTION AND SYNTHESIS: Literature screening, data extraction and the quality evaluation of studies were conducted by two researchers independently, with disagreements resolved by another researcher. The Newcastle-Ottawa Scale was used to assess the bias risk for the included studies. Review Manager V.5.3 was employed for the meta-analysis. RESULTS: The meta-analysis included seven retrospective and four prospective cohort studies with 1111 patients enrolled. The CAZ-AVI groups demonstrated a lower 30-day mortality (risk ratio (RR)=0.48, 95% CI of 0.37 to 0.63, I2=10%, p<0.0001) in nine studies with 766 patients; higher clinical success (RR=1.71, 95% CI 1.33 to 2.20, I2=35%, p<0.0001) in four studies with 463 patients; and lower nephrotoxicity in seven studies with 696 patients (RR=0.42, 95% CI 0.23 to 0.77, I2=35%, p<0.05). However, no significant difference in microbiological eradication rates was observed in 249 patients from two studies (RR=1.16, 95% CI 0.97 to 1.39, I2=0, p>0.05). CONCLUSION: Available evidence suggested that CAZ-AVI treatment held a dominant position with respect to efficacy and safety compared with polymyxins in carbapenem-resistant Enterobacteriaceae infections. However, the analysis included only observational studies, and high-quality, large-scale, multicentre, double-blind randomised controlled trials are needed to confirm the advantage of CAZ-AVI.

Non-polymyxin-based combinations as potential alternatives in treatment against carbapenem-resistant Acinetobacter baumannii infections.

Due to limited therapeutic options, combination therapy has been used empirically to treat carbapenem-resistant Acinetobacter baumannii (CRAB). Polymyxin-based combinations have been widely studied and used in the clinical setting. However, the use of polymyxins is often limited due to nephrotoxicity and neurotoxicity. This study aimed to evaluate the activity of non-polymyxin-based combinations relative to polymyxin-based combinations and to identify potential synergistic and bactericidal two-drug non-polymyxin-based combinations against CRAB. In vitro activity of 14 two-drug combinations against 50 A. baumannii isolates was evaluated using the checkerboard method. Subsequently, the two best-performing non-polymyxin-based combinations from the checkerboard assay were explored in static time-kill experiments. Concentrations of antibiotics corresponding to the fractional inhibitory concentrations (FIC) and the highest serum concentration achievable clinically were tested. The most synergistic combinations were fosfomycin/sulbactam (synergistic against 37/50 isolates; 74%), followed by meropenem/sulbactam (synergistic against 28/50 isolates; 56%). No antagonism was observed for any combination. Both fosfomycin/sulbactam and meropenem/sulbactam combinations exhibited bactericidal and synergistic activity against both isolates at the highest clinically achievable concentrations in the time-kill experiments. The meropenem/sulbactam combination displayed synergistic and bactericidal activity against one of two strains at concentrations equal to the FIC. Non-polymyxin-based combinations such as fosfomycin/sulbactam and meropenem/sulbactam may have a role in the treatment of CRAB. Further in vivo and clinical studies are required to scrutinise these activities further.

Old antibiotics for multidrug-resistant pathogens: from in vitro activity to clinical outcomes.

Antimicrobial resistance is a major and emerging threat worldwide. New antimicrobials have been unable to meet the resistance challenge, and treatment options are limited for a growing number of resistant pathogens. More and more clinicians are relying on older antimicrobials for the treatment of multidrug-resistant (MDR) bacteria. Some older antimicrobials have maintained excellent in vitro activity against highly resistant pathogens. In some instances, use of older agents is limited by unfavourable pharmacokinetic/pharmacodynamic characteristics and/or toxicities. In general, clinical data pertaining to the use of older agents for the treatment of MDR pathogens are scarce. Research efforts should be focused on the evaluation of older agents for the treatment of MDR pathogens as well as evaluating how these agents perform in complex patient populations with various and multiple co-morbid conditions.

Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities.

The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy.

Polymyxins revisited.

The global emergence of multidrug-resistant gram-negative bacilli has spurred a renewed interest in polymyxins. Once discarded due to concerns regarding nephrotoxicity and neurotoxicity, polymyxins now hold an important role in the antibiotic armamentarium. However, more reliable information is needed to determine the optimal dosing of these agents. Also, unanswered questions regarding in vitro testing remain, including questions regarding the reliability of automated systems and the establishment of appropriate breakpoints for defining susceptibility. Most contemporary clinical studies examining the use of these agents have involved patients with infections due to multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii strains. It has been reassuring that polymyxin therapy for resistant bacteria has resulted in clinical responses and toxicity rates similar to those for carbapenem therapy for susceptible isolates. While most surveillance studies demonstrated high rates of susceptibility, several reports noted the emergence of polymyxin-resistant nosocomial pathogens. Polymyxins have assumed an important antibiotic niche for therapy for hospital-acquired infections; further studies defining the optimal use of these agents will likely extend the duration of their clinical usefulness.

Polymyxin antibiotics for gram-negative infections.

PURPOSE: The role of polymyxin antibiotics in the treatment of multidrug-resistant gram-negative infections is reviewed. SUMMARY: Antimicrobial resistance is an increasing problem across hospitals worldwide, especially in intensive care settings, where nosocomial infections are 5-10 times more likely to occur than on the general wards. The polymyxins, a group of basic polypeptide antibiotics, were first isolated from Bacillus species in the late 1940s and appear to have a surface detergent effect, making them active against most gram-negative organisms. Early clinical reports suggested a high rate of toxicity associated with the polymyxins, specifically nephrotoxicity (20%) and neurotoxicity (7%); thus the polymyxins had largely fallen out of favor. However, recent studies have suggested that the toxicities associated with the polymyxins may be less severe and less frequent than earlier reports. The emergence of multidrug-resistant gram-negative organisms has led to a reemergence in the use of this antibiotic class. Various clinical trials that evaluated the polymyxins for the treatment of multidrug-resistant gram-negative organisms found that these antibiotics have acceptable effectiveness and may be used if necessary. CONCLUSION: The polymyxins have become a last resort for the treatment of infections caused by multidrug-resistant gram-negative organisms. Recent studies have suggested that the frequency of polymyxin-associated nephrotoxicity and neurotoxicity may not be as high as was once thought. The polymyxins seem to be effective in treating various infections caused by multidrug-resistant gram-negative organisms but should not be used as first-line therapy until more is known about this class of antibiotics.

Effectiveness of neomycin/polymyxin bladder irrigation to treat resistant urinary pathogens in those with spinal cord injury.

Individuals with spinal cord injury (SCI) will sometimes develop bacterial organisms in the bladder that are resistant to oral antibiotics. This study evaluated the effectiveness of a 5-day course of intermittent neomycin/polymyxin bladder irrigation at eradicating or changing the bacterial sensitivity from parenteral to oral antibiotics. A chart review of individuals with SCI who were treated with neomycin/polymyxin bladder irrigations was performed. Inclusion criteria included the use of an indwelling catheter and the presence of asymptomatic bacteria resistant to oral antibiotics. The most common reason for treatment was eradication of resistant organisms prior to urologic testing. Bladder irrigation consisted of 3 rinses with 30 ml 3 times a day for 5 days. Pre- and post-urine samples were compared for white blood cells (WBCs), colony count and culture, and sensitivity. Chi-square tests were used to determine whether the proportion of changes in resistance or sensitivities was different from zero. The Wilcoxon Signed Rank Test was used to determine differences in bacteria, colony counts, and WBCs. Ten individuals were identified. A total of 12 neomycin/polymyxin irrigation treatments were evaluated because 2 individuals had a second series of irrigations at least 6 months apart. Nine of the 12 (75%) were considered to have successful irrigations because there was a change in culture sensitivity so that oral antibiotics would be effective post irrigation. This was statistically significant. There were no significant changes in colony counts or the number of WBCs. The authors concluded that while neomycin/polymyxin bladder irrigation did not change the type of organism, it was effective in changing resistance of most organisms. Individuals could then be treated with oral rather than intravenous or intramuscular antibiotics. Further work is needed to determine whether other variables, such as increased length of time of irrigation or increased frequency of irrigations, may actually eradicate the organisms.