Effectiveness and safety of meropenem-vaborbactam versus ceftazidime-avibactam in multidrug-resistant Gram-negative infections: a systematic review and meta-analysis with trial sequential analysis.

Background: Multidrug-resistant (MDR) Gram-negative infections, particularly those caused by carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat Pseudomonas aeruginosa (DTR-Pa), present a growing global healthcare challenge, especially in critically ill populations. Imipenem-relebactam (I/R), a novel β-lactam/β-lactamase inhibitor combination, has shown efficacy in clinical trials, but real-world data remain limited. Methods: We conducted a multicenter, retrospective-prospective observational study across tertiary-care hospitals in Italy between January 2020 and May 2025. Adult patients (≥18 years) treated with I/R for ≥48 h for suspected or confirmed MDR Gram-negative infections were included. Primary endpoints were clinical success at the end of therapy and 30-day all-cause mortality. Secondary endpoints included microbiological eradication, recurrence, safety, and predictors of treatment failure. Statistical analysis involved descriptive methods and correlation analysis for mortality predictors. Results: Twenty-nine patients were included (median age 66 years; 58.6% ICU admission; 71.4% mechanical ventilation). Clinical success was achieved in 22/29 patients (75.9%), while 30-day mortality was 24.1% (7/29). The most common pathogen was Klebsiella pneumoniae (62.1%), with 41.4% of infections being polymicrobial. Microbiological eradication was confirmed in all the BSIs. Parenteral nutrition (p = 0.016), sepsis at presentation (p = 0.04), candidemia (p = 0.036), and arterial catheter use (p = 0.029) were significantly more frequent in non-survivors. Survivors showed significant reductions in CRP, PCT, and bilirubin at 48 h, while non-survivors did not. Parenteral nutrition (rho = 0.427, p = 0.023), sepsis (rho = 0.378, p = 0.043), and arterial catheter use (rho = 0.384, p = 0.04) were significantly correlated with mortality. Conclusions: In this Italian multicenter cohort of critically ill patients, imipenem-relebactam demonstrated high clinical success and acceptable mortality rates in the treatment of severe MDR Gram-negative infections, particularly those caused by KPC-producing K. pneumoniae. Early biomarker dynamics may aid in monitoring treatment response. Larger prospective studies are needed to confirm these findings and define optimal treatment strategies.

The growing prevalence of antimicrobial resistance poses a grave threat to human health. Among the most difficult bacterial infections to treat are those caused by multidrug-resistant (MDR) Gram-negative pathogens because few effective regimens are available. One approach to this problem is to find ways to increase the activity of old antimicrobials that had seen limited application. Bicyclomycin, an inhibitor of transcription termination, is an example in which the additional inhibition of protein or RNA synthesis increases bicyclomycin-mediated lethality against Gram-negative bacteria. To examine the potential of bicyclomycin for the treatment of MDR bacterial pathogens, we first measured the MICs of bicyclomycin and other widely used antimicrobials against more than 100 multidrug-resistant Gram-negative clinical isolates. Bicyclomycin showed good coverage of carbapenem-resistant Enterobacteriaceae (CRE) and Escherichia coli (MIC50/MIC90 of 25/50 μg/mL for both bacteria) and moderate activity against Klebsiella pneumoniae (MIC50/MIC90 of 50/200 μg/mL). Bicyclomycin also exhibited synergy (e.g., fractional inhibitory concentration [FIC] index of <0.5) with doxycycline for the inhibition of bacterial growth by a checkerboard assay. Although bicyclomycin exhibited very weak lethality by itself, it showed synthetic lethality with doxycycline against K. pneumoniae: the combination killed 100- to 1,000-fold more bacteria than either agent alone. In a murine model of infection, the bicyclomycin-doxycycline combination showed better efficacy than either agent alone, and the combination treatment largely eliminated histopathological manifestations caused by infection. Thus, bicyclomycin, which has largely been limited to the treatment of Gram-negative digestive tract infections, can now be considered for the combination treatment of systemic multidrug-resistant infections caused by CRE, E. coli, and K. pneumoniae. IMPORTANCE As antimicrobial resistance continues to increase, options for effectively treating multidrug-resistant (MDR) Gram-negative infections are declining. Finding ways to enhance the lethality of old agents that have unique molecular targets is important because developing new antimicrobials is becoming increasingly difficult. The present work showed that the old antibiotic bicyclomycin has good bacteriostatic activity against multiple clinical isolates of three significant types of MDR Gram-negative pathogens frequently encountered in hospital infections, as required for the consideration of expanded indications. More significant is the synergistic growth-inhibitory effect and the enhancement of killing by the additional presence of doxycycline since this increases the in vivo efficacy. These data demonstrate that bicyclomycin-containing regimens have potential as new treatment options for MDR Gram-negative infections such as those caused by CRE, E. coli, and K. pneumoniae.

The increasing prevalence of antibiotic-resistant pathogens exerts a substantial burden on the healthcare infrastructure worldwide. The World Health Organization (WHO) has declared that multidrug-resistant (MDR) Gram-negative pathogens, especially, carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii, and Pseudomonas aeruginosa as the topmost priority while developing newer antimicrobials. The increasing prevalence of infectious diseases caused by MDR Gram-negative bacteria also poses a challenge when choosing the empiric antimicrobial therapy for seriously ill hospitalized patients. The infections caused by MDR Gram-negative organisms ultimately result in increased mortality, morbidity, prolonged hospital stay, and increased cost of management. To tackle these challenges, newer antimicrobials like ceftazidime-avibactam were explored. The article also discusses the in vitro activity and therapeutic efficacy of ceftazidime-avibactam along with its pharmacokinetic properties and the role it will play in the management of MDR Gram-negative organisms in the Indian setting. Several studies have highlighted the role of early and appropriate antibiotic use in the reduction of mortality in patients with Gram-negative infections. Timely initiation of appropriate antibiotic therapy for serious infections leads to favorable clinical outcomes. Early and appropriate use of ceftazidime-avibactam while treating MDR Gram-negative infections has been associated with improved clinical outcomes. The aim of this review is to highlight the efficacy of ceftazidime-avibactam in the treatment of MDR Gram-negative infections. We have also summarized the information on outcomes achieved by early and appropriate use of ceftazidime-avibactam.

Multidrug-resistant gram-negative bacterial infections after liver transplantation – Spectrum and risk factors

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.

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

Objective:To describe the clinical and laboratory characteristics of Gram-negative neonatal infections and to identify risk factors associated with multidrug-resistant (MDR) Gram-negative infections at the Pediatric Center, Bach Mai Hospital, during 2023–2025. Methods:A cross-sectional study combined with a case–control design was conducted among neonates (&lt;28 days old) diagnosed with neonatal sepsis. The case group included 60 infants with culture-confirmed MDR Gram-negative infections, and the control group consisted of 180 infants with negative cultures. Clinical manifestations, laboratory findings, and potential risk factors were collected and statistically analyzed. Results:Among 60 cases of Gram-negative neonatal infections, late-onset sepsis accounted for 78.9%, while early-onset sepsis accounted for 21.1%. Klebsiella pneumoniae was the most common pathogen (42.3%). The predominant clinical features were respiratory distress (83.3%), tachypnea ≥60 breaths/min (75%), chest retraction (73.3%), SpO₂ &lt;90% (56.7%), poor feeding (56.7%), and jaundice (35%). Laboratory abnormalities included leukocytosis (43.3%), thrombocytopenia (40%), hypoalbuminemia (66.7%), elevated CRP (78.3%), and coagulopathy(70%).Significant risk factors for MDR Gram-negative infection (p &lt;0.05) included age at admission ≥7 days, late-onset sepsis, bag-mask ventilation or re-intubation, blood transfusion, parenteral nutrition, umbilical or central line catheterization, invasive mechanical ventilation ≥7 days, use of vasopressors, and exposure to ≥2 antibiotics or antibiotic regimen changes during treatment. Conclusion:Gram-negative neonatal infections, particularly those caused by Klebsiella pneumoniae, are common and mainly associated with late-onset sepsis. Respiratory symptoms predominate, often accompanied by hematologic, biochemical, and coagulation abnormalities. Early identification and close monitoring of high-risk neonates, adherence to aseptic techniques, effective infection control, and rational antibiotic use are essential to improve outcomes and reduce mortality.

BackgroundInfections caused by multi-drug resistant gram-negative bacterial infections are the principle threats to the critically ill patients of intensive care units. Increasing reports of these infections from the Nepalese intensive care unit underline the clinical importance of these pathogens. However, the impact of these infections on the patient’s clinical outcome has not yet been clearly evaluated. The objective of our study was to determine the incidence and associated clinical outcome of multi-drug resistant gram-negative bacterial infections in intensive care unit from a tertiary care center of Nepal.MethodsA prospective cohort study was conducted among adult patients admitted in intensive care unit of B. P Koirala Institute of Health Sciences from July to December 2017. Patients infected with multi-drug resistant gram-negative bacteria, non-multi-drug resistant gram-negative bacteria and those without infection were included. Identification of gram-negative bacteria and their antibiotic susceptibility pattern was performed with standard microbiological methods. Demographic, clinical profiles and outcomes (in-hospital-mortality, intensive care unit and hospital length of stay) were documented.ResultsThe incidence rate of multi-drug resistant gram-negative bacteria infections was 47 per 100 admitted patients (64/137) with 128 episodes. Acinetobacter species (41%, 52/128) was the commonest followed by Klebsiella pneumoniae (28%, 36/128) and Pseudomonas spp (21%, 27/128). Patients with multi-drug resistant gram-negative bacteria in comparison to non-multi-drug resistant gram-negative bacteria had high healthcare-associated infections (95%, 61/64 versus 20%, 2/10; p = < 0.001). In-hospital-mortality was 38% (24/64), 20% (2/10) and 10% (4/41) in multi-drug resistant, non-multi-drug resistant and uninfected group respectively (p = 0.007). After adjustment for independent risk factors, compared to uninfected patients, the odds ratio (CI) for in-hospital-mortality in multi-drug resistant and non-multi-drug resistant group was (4.7[1.4–15.5], p = 0.01) and 2.60 [0.38–17.8], p = 0.32) respectively. Multi-drug resistant patients also had longer intensive care unit and hospital stay, however, it was statistically insignificant.ConclusionThe incidence of multi-drug resistant gram-negative bacterial infections was remarkably high in our intensive care unit and showed a significant association with healthcare-associated infections and in-hospital-mortality.

Background: The global burden of multi-drug resistant gram-negative bacterial (MDR-GNB) infections has been increasing. Neonates are at a particularly high-risk and there is limited treatment option. The use of colistin has been re-introduced for this population. However, data on its use in neonates is scarce. Objectives: To determine the effectiveness and adverse effects of intravenous colistin in neonates with multidrug-resistant gram-negative infections. Design: This is a retrospective cohort study of the clinical profile and outcome of neonates with MDR-GNB infections given colistin for a minimum of 3 days conducted from April 2015 to April 2019. Results: A total of 175 pediatric patients had MDR-GNB infections. 75 (43%) neonates met the inclusion criteri a and received intravenous colistin. Of the 75 patients with MDRGNB infections- that included sepsis, pneumonia, urinary tract infection and abscess, 37 (49.3%) were alive and 38 (50.7%) patients died. Nephrotoxicity was seen in 4% if patients and 2.6% patients had hypersensitivity reaction. MDROs isolated were Acinetobacter baumanii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Conclusions: Intravenous colistin is 50% effective and is relatively safe to use in neonates.

BackgroundCOVID-19 is a rapidly spreading disease that has caused extensive burden toindividuals, families, countries, and the world. Effective treatments ofCOVID-19 are urgently needed. This is the second edition of a livingsystematic review of randomized clinical trials assessing the effects of alltreatment interventions for participants in all age groups withCOVID-19.Methods and findingsWe planned to conduct aggregate data meta-analyses, trial sequentialanalyses, network meta-analysis, and individual patient data meta-analyses.Our systematic review was based on PRISMA and Cochrane guidelines, and oureight-step procedure for better validation of clinical significance ofmeta-analysis results. We performed both fixed-effect and random-effectsmeta-analyses. Primary outcomes were all-cause mortality and serious adverseevents. Secondary outcomes were admission to intensive care, mechanicalventilation, renal replacement therapy, quality of life, and non-seriousadverse events. According to the number of outcome comparisons, we adjustedour threshold for significance to p = 0.033. We used GRADEto assess the certainty of evidence. We searched relevant databases andwebsites for published and unpublished trials until November 2, 2020. Tworeviewers independently extracted data and assessed trial methodology. Weincluded 82 randomized clinical trials enrolling a total of 40,249participants. 81 out of 82 trials were at overall high risk of bias.Meta-analyses showed no evidence of a difference between corticosteroidsversus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidenceinterval [CI] 0.79 to 1.00; p = 0.05; I2 =23.1%; eight trials; very low certainty), on serious adverse events (RR0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%;eight trials; very low certainty), and on mechanical ventilation (RR 0.86;95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; twotrials; very low certainty). The fixed-effect meta-analyses showedindications of beneficial effects. Trial sequential analyses showed that therequired information size for all three analyses was not reached.Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31;I2 = 0%; four trials; moderate certainty) and trialsequential analysis (boundary for futility crossed) showed that we couldreject that remdesivir versus control reduced the risk of death by 20%.Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05;I2 = 38.9%; four trials; very low certainty) and trialsequential analysis (required information size not reached) showed noevidence of difference between remdesivir versus control on serious adverseevents. Fixed-effect meta-analysis showed indications of a beneficial effectof remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19to 0.87; p = 0.02; I2 = 0%; two trials; very lowcertainty) showed evidence of a beneficial effect of intravenousimmunoglobulin versus control on all-cause mortality, but trial sequentialanalysis (required information size not reached) showed that the result wasseverely underpowered to confirm or reject realistic intervention effects.Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12;I2 = 77.4%; five trials; very low certainty) and trialsequential analysis (required information size not reached) showed noevidence of a difference between tocilizumab versus control on seriousadverse events. Fixed-effect meta-analysis showed indications of abeneficial effect of tocilizumab on serious adverse events. Meta-analysis(RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 =0%; three trials; very low certainty) showed evidence of a beneficial effectof tocilizumab versus control on mechanical ventilation, but trialsequential analysis (required information size not reached) showed that theresult was severely underpowered to confirm of reject realistic interventioneffects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p< 0.00; I2 = 0%; two trials; very low certainty) showedevidence of a beneficial effect of bromhexine versus standard care onnon-serious adverse events, but trial sequential analysis (requiredinformation size not reached) showed that the result was severelyunderpowered to confirm or reject realistic intervention effects.Meta-analyses and trial sequential analyses (boundary for futility crossed)showed that we could reject that hydroxychloroquine versus control reducedthe risk of death and serious adverse events by 20%. Meta-analyses and trialsequential analyses (boundary for futility crossed) showed that we couldreject that lopinavir-ritonavir versus control reduced the risk of death,serious adverse events, and mechanical ventilation by 20%. All remainingoutcome comparisons showed that we did not have enough information toconfirm or reject realistic intervention effects. Nine single trials showedstatistically significant results on our outcomes, but were underpowered toconfirm or reject realistic intervention effects. Due to lack of data, itwas not relevant to perform network meta-analysis or possible to performindividual patient data meta-analyses.ConclusionsNo evidence-based treatment for COVID-19 currently exists. Very low certaintyevidence indicates that corticosteroids might reduce the risk of death,serious adverse events, and mechanical ventilation; that remdesivir mightreduce the risk of serious adverse events; that intravenous immunoglobinmight reduce the risk of death and serious adverse events; that tocilizumabmight reduce the risk of serious adverse events and mechanical ventilation;and that bromhexine might reduce the risk of non-serious adverse events.More trials with low risks of bias and random errors are urgently needed.This review will continuously inform best practice in treatment and clinicalresearch of COVID-19.Systematic review registrationPROSPERO CRD42020178787.

Glucocorticosteroids for people with alcoholic hepatitis.

Infection with multidrug-resistant (MDR) Gram-negative organisms leads to poorer outcomes in the critically ill burn patient. The aim of this study was to identify the risk factors for MDR Gram-negative pathogen infection in critically ill burn patients admitted to a major tertiary referral intensive care unit (ICU) in Australia. A retrospective case-control study of all adult burn patients admitted over a 7-year period was conducted. Twenty-one cases that cultured an MDR Gram-negative organism were matched with 21 controls of similar age, gender, burn size and ICU stay. Multivariable conditional logistic regression was used to individually assess risk factors after adjusting for Acute Burn Severity Index. Adjusted odds ratios (ORs) were reported. P-values < 0.25 were considered as potentially important risk factors. Factors increasing the risk of MDR Gram-negative infection included superficial partial thickness burn size (OR: 1.08; 95% confidence interval (CI): 1.01-1.16; P-value: 0.034), prior meropenem exposure (OR: 10.39; 95% CI: 0.96-112.00; P-value: 0.054), Gram-negative colonization on admission (OR: 9.23; 95% CI: 0.65-130.15; P-value: 0.10) and escharotomy (OR: 2.66; 95% CI: 0.52-13.65; P-value: 0.24). For cases, mean age was 41 (SD: 13) years, mean total body surface area burned was 47% (SD: 18) and mean days in ICU until MDR specimen collection was 17 (SD: 10) days. Prior meropenem exposure, Gram-negative colonization on admission, escharotomy and superficial partial thickness burn size may be potentially important factors for increasing the risk of MDR Gram-negative infection in the critically ill burn patient.

Re: real world clinical outcome of cefiderocol for treatment of multidrug-resistant non-fermenting gram-negative bacilli infections: author's response

Multidrug resistant Gramnegative (MDRGN) infections are an increasing problem in neonatal intensive care units. The objective of this study was to establish the epidemiological, clinical, microbiological, and evolutionary characteristics of carbapenem-resistant MDRGN infections and the risk factors for them at the Division of Neonatology of a tertiary care hospital. A retrospective cohort study was done in this Division in patients with a documented MDRGN infection between 4/24/2013 and 4/29/2015. Twenty-one patients were included. Their median gestational age and birth weight were 35 weeks and 2070 g, respectively. Eighteen patients (86 %) had a positive blood culture; the most commonly isolated microorganism was Acinetobacter baumannii (17 patients, 81 %), followed by carbapenemase-producing Klebsiella pneumoniae (3 patients, 14 %) and Enterobacter cloacae (1 patient, 5 %).The median age at diagnosis was 28 days and all patients had risk factors for infection, including surgery, assisted mechanical ventilation, parenteral nutrition, central venous line, and antibiotics. The definite antibiotic therapy included colistin in all cases; in combination, in 84 %. Five patients (24 %) died due to the infection. Prematurity and a birth weight < 2000 g were statistically significant risk factors associated with mortality (p = 0.03 and 0.01, respectively). MDRGN infections were observed in patients with predisposing factors. Acinetobacter baumannii was the main etiologic agent. Mortality was high and related to prematurity and a low birth weight.

The resurgence of colistin as a last-resort antibiotic has become pivotal in managing multidrug-resistant (MDR) Gram-negative infections in neonatal intensive care units. Despite its life-saving potential, colistin use in neonates remains controversial due to limited pharmacokinetic data, variable dosing strategies, and substantial risks of nephrotoxicity and neurotoxicity. Globally, MDR Gram-negative infections account for nearly half of late-onset neonatal sepsis cases, contributing to high mortality and prolonged hospitalization. The emergence of mcr-mediated colistin resistance and inconsistent adherence to antimicrobial stewardship protocols further complicate management. Evidence reveals that a significant proportion of neonatal colistin use is empiric rather than culture-driven, underscoring the gap between guidelines and clinical practice. Strengthening stewardship frameworks, integrating therapeutic drug monitoring, and adopting real-time resistance surveillance are essential to safeguard colistin efficacy and mitigate resistance spread among vulnerable neonatal populations.