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Clinical Infectious Diseases : An... May 2023Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other... (Review)
Review
Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed β-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors' perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.
Topics: Humans; Sulbactam; Acinetobacter baumannii; Carbapenems; Acinetobacter Infections; Anti-Bacterial Agents; Colistin; Microbial Sensitivity Tests
PubMed: 37125467
DOI: 10.1093/cid/ciad094 -
Journal of Global Antimicrobial... Mar 2021This study aimed to compare the efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for treating... (Meta-Analysis)
Meta-Analysis Review
Comparative efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for multiple drug-resistant and extensively drug-resistant Acinetobacter baumannii infections: A systematic review and network meta-analysis.
OBJECTIVES
This study aimed to compare the efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for treating multidrug-resistant or extensively drug-resistant Acinetobacter baumannii (MDR-AB or XDR-AB) infections.
METHODS
We systematically searched PubMed, Embase, Cochrane, and Web of Science (through March 30, 2020) for studies that examined high-dose sulbactam or colistin with additional antibacterial agents as therapy for patients with infections with MDR-AB and XDR-AB. Through a network meta-analysis (NMA), using both direct and indirect evidence, we determined risk ratios and 95% confidence intervals. Primary outcomes included clinical improvement, clinical cure, microbiological eradication, and mortality from any cause. Secondary outcomes included nephrotoxicity.
RESULTS
The NMA included 18 studies and 1835 patients. We found that high-dose sulbactam (≥6 g per day), combined with another single antibacterial agent (levofloxacin or tigecycline), which were the highest ranking in clinical improvement and clinical cure. Still colistin-based combination in drug-resistant Acinetobacter baumannii therapy occupied the main position (the number of studies and patients) in most studies. Colistin combined with additional antibacterial agents was associated with a higher risk of nephrotoxicity.
CONCLUSIONS
Therapeutic regimens including high-dose sulbactam in combination with additional antibacterial agents (including colistin) might be one of the promising options for the treatment of MDR-AB or XDR-AB infections and high-quality study will be needed to confirm clinical efficacy.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Minocycline; Network Meta-Analysis; Pharmaceutical Preparations; Sulbactam
PubMed: 32889142
DOI: 10.1016/j.jgar.2020.08.021 -
Antimicrobial Agents and Chemotherapy Sep 2022Sulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii complex (ABC) infections, including...
Sulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii complex (ABC) infections, including carbapenem-non-susceptible and multidrug-resistant (MDR) isolates. The current study characterized the activity of sulbactam-durlobactam against a collection of 5,032 ABC clinical isolates collected in 33 countries across the Asia/South Pacific region, Europe, Latin America, the Middle East, and North America from 2016 to 2021. The sulbactam-durlobactam MIC and MIC were 1 and 2 μg/mL, respectively, for all ABC isolates tested. The addition of durlobactam (at a fixed concentration of 4 μg/mL) to sulbactam decreased its MIC by 8-fold (from 8 to 1 μg/mL) and its MIC by 32-fold (from 64 to 2 μg/mL) for all ABC isolates. The activity of sulbactam-durlobactam was maintained across individual ABC species, years, global regions of collection, specimen sources, and resistance phenotypes, including MDR and extensively drug-resistant (XDR) isolates. At 4 μg/mL (preliminary sulbactam-durlobactam susceptible MIC breakpoint), sulbactam-durlobactam inhibited 98.3% of all ABC isolates and >96% of sulbactam-, imipenem-, ciprofloxacin-, amikacin-, and minocycline-non-susceptible isolates; as well as colistin-resistant, MDR, and XDR isolates. Most imipenem-non-susceptible ABC isolates (96.8%, 2,488/2,570) were carbapenem-resistant A. baumannii (CRAB); 96.9% (2,410/2,488) of CRAB isolates were sulbactam-durlobactam-susceptible. More than 80% of ABC isolates had sulbactam-durlobactam MIC values that were ≥2 doubling-dilutions (4-fold) lower than sulbactam alone. Only 1.7% (84/5,032) of ABC isolates from 2016 to 2021 had sulbactam-durlobactam MIC values of >4 μg/mL. Of the 84 isolates, 94.0% were A. baumannii, 4.8% were A. pittii, and 1.2% were A. nosocomialis. In summary, sulbactam-durlobactam demonstrated potent antibacterial activity against a 2016 to 2021 collection of geographically diverse clinical isolates of ABC isolates, including carbapenem-non-susceptible and MDR isolates.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Amikacin; Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Ciprofloxacin; Colistin; Drug Combinations; Humans; Imipenem; Microbial Sensitivity Tests; Minocycline; Sulbactam; beta-Lactamase Inhibitors
PubMed: 36005804
DOI: 10.1128/aac.00781-22 -
Journal of Postgraduate Medicine 2023Drug-induced hemolytic anemia (DIHA) is a rare complication of drug therapy and usually underdiagnosed. Cefoperazone/sulbactam is a compound prepared from the third...
Drug-induced hemolytic anemia (DIHA) is a rare complication of drug therapy and usually underdiagnosed. Cefoperazone/sulbactam is a compound prepared from the third generation of cephalosporin and β-lactamase inhibitor. There are limited data of DIHA induced from cefoperazone/sulbactam. A 93-year-old female patient, who had an operation on the biliary tract 3 months ago, was admitted to our hospital with an abdominal infection. After cefoperazone/sulbactam was given as anti-infection treatment, the patient developed hemolytic anemia on the third day. Cefoperazone/sulbactam was discontinued and replaced with meropenem. Subsequently the level of red blood cells, hemoglobin, and hematocrit returned to normal. Clinicians should pay attention to monitoring the possible adverse reactions during the use of cefoperazone/sulbactam and should be aware of the occurrence of DIHA, so as to give timely treatment.
Topics: Female; Humans; Aged, 80 and over; Cefoperazone; Sulbactam; Anti-Bacterial Agents; Meropenem; Anemia, Hemolytic; Microbial Sensitivity Tests
PubMed: 34528516
DOI: 10.4103/jpgm.JPGM_1335_20 -
Antibiotics (Basel, Switzerland) Dec 2022Infections caused by carbapenem-resistant (CRAB) have limited therapeutic options. Sulbactam-durlobactam is a combination of two βlactamase inhibitors with activity... (Review)
Review
Infections caused by carbapenem-resistant (CRAB) have limited therapeutic options. Sulbactam-durlobactam is a combination of two βlactamase inhibitors with activity against CRAB under phase 3 clinical investigation. We performed a systematic review on in vitro studies reporting resistances against sulbactam/durlobactam. We considered "resistant" species to be those with MIC ≥ 8 mg/L. Ten studies were included in the review (9754 tested isolates). Overall, 2.3% of were resistant to sulbactam/durlobactam, and this percentage rose to 3.4% among CRAB subgroups and to 3.7% among colistin-resistant strains. Resistance was 100% among metallo β-lactamase-producing strains. Overall, in 12.5% of cases, sulbactam/durlobactam resistance was associated with the production of NDM-1, in 31.7% of cases with the substitutions in the PBP3 determinants, and in the remaining cases the resistance mechanism was unknown. In conclusion, resistance towards sulbactam/durlobactam is limited, except for MBL-producing strains.
PubMed: 36551450
DOI: 10.3390/antibiotics11121793 -
Clinical Pharmacokinetics Apr 2023The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e.,...
BACKGROUND
The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e., < 60 mL/min).
OBJECTIVE
This study investigated the population pharmacokinetics of ampicillin and sulbactam in patients with a wide range of renal functions and sought to define dosing approaches that have a high likelihood for optimising drug exposure.
METHODS
Serial blood samples were collected from 16 adult patients receiving intravenous ampicillin-sulbactam in general wards. Total ampicillin and sulbactam concentrations were measured by chromatographic assay and pharmacokinetic parameters were estimated using Pmetrics. Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) of free ampicillin and sulbactam concentrations exceeding the minimum inhibitory concentration (MIC) for 60% and 100% of the dosing interval. Fractional target attainment (FTA) was calculated against MIC distributions of common hospital pathogens. A threshold of ≥ 90% and ≥ 95% was used to define both optimal PTA and FTA, respectively.
RESULTS
The median (range) age, weight, and serum creatinine of the study population was 68 (40-82) years, 62 (40-82) kg, and 1.4 (0.6-6.4) mg/dL, respectively. The pharmacokinetics of ampicillin and sulbactam were best described by a two-compartment model with serum creatinine most closely associated with clearance for both drugs. The estimated ampicillin and sulbactam clearances were 5.58 L/h and 4.79 L/h, respectively, while the volumes of distribution were 12.6 L and 15.36 L, respectively. Approved dosing regimens of ampicillin-sulbactam were sufficient against MICs ≤ 8 and ≤ 4 mg/L, respectively. A 4-h infusion enabled optimal PTA at higher MICs. For both dosing targets, optimal FTAs were obtained against Streptococcus pneumoniae.
CONCLUSION
Optimal FTAs were obtained against the susceptible MIC distributions of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Applying a 4-h infusion will enhance PTA and FTA, particularly at higher MICs.
Topics: Humans; Adult; Aged; Aged, 80 and over; Sulbactam; Anti-Bacterial Agents; Creatinine; Ampicillin; Microbial Sensitivity Tests
PubMed: 36853585
DOI: 10.1007/s40262-023-01219-5 -
Bone Concentration of Ampicillin/Sulbactam: A Pilot Study in Patients with Osteonecrosis of the Jaw.International Journal of Environmental... Nov 2022Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to...
Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam. The poor blood supply in particular raises the question as to whether this form of antibiosis can achieve sufficient concentrations in the bone. Therefore, we investigated the antibiotic concentration in plasma and bone samples in a prospective study. Bone samples were collected from the necrosis core and in the vital surrounding bone. The measured concentrations in plasma for ampicillin and sulbactam were 126.3 ± 77.6 and 60.2 ± 35.0 µg/mL, respectively. In vital bone and necrotic bone samples, the ampicillin/sulbactam concentrations were 6.3 ± 7.8/1.8 ± 2.0 µg/g and 4.9 ± 7.0/1.7 ± 1.7 µg/g, respectively. These concentrations are substantially lower than described in the literature. However, the concentration seems sufficient to kill most bacteria, such as and , which are mostly present in the biofilm of ONJ. We, therefore, conclude that intravenous administration of ampicillin/sulbactam remains a valuable treatment in the therapy of ONJ. Nevertheless, increasing resistance of towards beta-lactam antibiotics have been reported and should be considered.
Topics: Humans; Sulbactam; Pilot Projects; Prospective Studies; Ampicillin; Anti-Bacterial Agents; Osteonecrosis; Escherichia coli
PubMed: 36429636
DOI: 10.3390/ijerph192214917 -
The Journal of International Medical... Jun 2021Eosinophilic peritonitis (EP) is a well-described complication of peritoneal dialysis that occurs because of an overreaction to constituents that are related to the... (Review)
Review
Eosinophilic peritonitis (EP) is a well-described complication of peritoneal dialysis that occurs because of an overreaction to constituents that are related to the catheter or tubing, peritoneal dialysate, pathogenic infection, or intraperitoneal drug use. EP caused by antibiotic use is rare. We present the case of a patient with cefoperazone and sulbactam-related EP. A 59-year-old woman who was undergoing peritoneal dialysis presented with peritonitis with abdominal pain and turbid peritoneal dialysis. Empiric intraperitoneal cefazolin in combination with cefoperazone and sulbactam was started after peritoneal dialysis effluent cultures were performed. Her peritonitis achieved remission in 2 days with the help of cephalosporin, but she developed EP 1 week later, when her dialysate eosinophil count peaked at 49% of the total dialysate white blood cells (absolute count, 110/mm). We excluded other possible causes and speculated that cefoperazone and sulbactam was the probable cause of EP. The patient continued treatment with cefoperazone and sulbactam for 14 days. EP resolved within 48 hours after stopping cefoperazone and sulbactam. Thus, EP can be caused by cefoperazone and sulbactam use. Physicians should be able to distinguish antibiotic-related EP from refractory peritonitis to avoid technique failure.
Topics: Anti-Bacterial Agents; Cefoperazone; Female; Humans; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Sulbactam
PubMed: 34162261
DOI: 10.1177/03000605211025367 -
The Brazilian Journal of Infectious... 2013A number of studies have reported on the effectiveness of sulbactam-based therapies for Acinetobacter baumannii infection; however, there is little evidence that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A number of studies have reported on the effectiveness of sulbactam-based therapies for Acinetobacter baumannii infection; however, there is little evidence that sulbactam-based therapies are more or less effective than alternative therapies. Unfortunately, there is a distinct lack of high quality data (i.e., from randomized controlled trials) available on this issue. Therefore, we conducted a systematic review and meta-analysis comparing the efficacy of sulbactam-based and non-sulbactam-based regimens in the treatment of A. baumannii infection.
METHODS
We searched PubMed, MEDLINE, Biomedical Central, Google Scholar, the China National Knowledge Infrastructure, the Cochrane library, and the Directory of Open Access using the terms "sulbactam and baumannii" or "maxtam and baumannii". Randomized controlled trials, controlled clinical studies, and cohort studies were considered for inclusion. The primary outcome was the clinical response rate for sulbactam-based therapy vs comparator therapies.
RESULTS
Four studies (1 prospective, 3 retrospective) were included in the meta-analysis. Sulbactam was given in combination with ampicillin, carbapenem, or cefoperazone (n=112 participants). Comparator drugs included colistin, cephalosporins, anti-pseudomonas penicillins, fluoroquinolones, minocycline/doxycycline, aminoglycosides, tigecycline, polymyxin, imipenem/cilastatin, and combination therapy (n=107 participants). The combined clinical response rate odds ratio did not significantly favor sulbactam-based therapy over comparator therapy (odds ratio=1.054, 95% confidence interval=0.550-2.019, p=0.874), nor did any of the individual study odds ratios.
CONCLUSIONS
The available evidence suggests that sulbactam-based therapy may be similarly efficacious to alternative antimicrobial therapies for the treatment of A. baumannii infection. Further research on this issue is warranted given the limited availability of data from high quality/randomized controlled trials.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Drug Therapy, Combination; Humans; Sulbactam; Treatment Outcome
PubMed: 23602463
DOI: 10.1016/j.bjid.2012.10.029