Treatment Of Serious Infections Research Articles

Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial.

There is a need for additional therapeutic options for serious infections caused by Gram-negative pathogens. In the phase 3, descriptive REVISIT study, we investigated the safety and efficacy of aztreonam-avibactam in the treatment of complicated intra-abdominal infections or hospital-acquired pneumonia or ventilator-associated pneumonia (HAP-VAP) caused, or suspected to be caused, by Gram-negative bacteria. This prospective, multinational, open-label, central assessor-masked study enrolled adults who were hospitalised with a complicated intra-abdominal infection or HAP-VAP. Patients were randomly allocated via block randomisation using interactive response technology stratified by infection type in a 2:1 ratio to aztreonam-avibactam (with metronidazole for complicated intra-abdominal infection) or meropenem with or without colistin for 5-14 days for complicated intra-abdominal infection or 7-14 days for HAP-VAP. The primary endpoint was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population. Secondary endpoints included 28-day mortality in the ITT population and safety in patients in the ITT population who received study drug (safety analysis set). No formal hypothesis testing was planned. The study was registered with ClinicalTrials.gov (NCT03329092) and EudraCT (2017-002742-68) and is complete. Between April 5, 2018, and Feb 23, 2023, we screened 461 patients. 422 patients were enrolled and randomly allocated (282 in the aztreonam-avibactam group and 140 in the meropenem group, forming the ITT analysis set), of whom ten patients (seven in the aztreonam-avibactam group and three in the meropenem group) were randomly allocated but did not receive study treatment. 271 (64%) of 422 patients had at least one Gram-negative pathogen from an adequate specimen identified at baseline. The most frequent baseline pathogens were Enterobacterales (252 [93%] of 271). Overall, 19 (24%) of 80 isolates tested for carbapenemases were carbapenemase-positive (serine, metallo-β-lactamase, or both). 193 (68·4%) of 282 patients in the aztreonam-avibactam group and 92 (65·7%) of 140 in the meropenem group had clinical cure at the test-of-cure visit (treatment difference 2·7% [95% CI -6·6 to 12·4]). For patients with complicated intra-abdominal infection, the adjudicated clinical cure rate was 76·4% (159 of 208) for the aztreonam-avibactam group and 74·0% (77 of 104) for the meropenem group. Cure rates in patients with HAP-VAP were 45·9% (34 of 74) for aztreonam-avibactam and 41·7% (15 of 36) for meropenem. 28-day all-cause mortality rates were 4% (12 of 282) for aztreonam-avibactam and 7% (ten of 140) for meropenem; in patients with complicated intra-abdominal infection, mortality was 2% (four of 208) and 3% (three of 104) for aztreonam-avibactam and meropenem, respectively, and in patients with HAP-VAP, mortality was 11% (eight of 74) and 19% (seven of 36), respectively. Aztreonam-avibactam was generally well tolerated, and safety findings were consistent with the known safety profile of aztreonam monotherapy. There were no treatment-related serious adverse events in the aztreonam-avibactam group. These phase 3 efficacy and safety data provide support for aztreonam-avibactam as a potential therapeutic option for complicated intra-abdominal infection or HAP-VAP caused by Gram-negative bacteria. Pfizer.

In-vitro activities of essential antimicrobial agents including aztreonam/avibactam, eravacycline, colistin and other comparators against carbapenem-resistant bacteria with different carbapenemase genes: A multi-centre study in China, 2021

Carbapenem-resistant bacteria (CRB), including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Enterobacterales (CRE), pose a considerable threat to public health in China. Eravacycline, aztreonam/avibactam and colistin are important antimicrobial agents for the treatment of serious infections caused by CRB. This study aimed to evaluate the prevalence of CRB strains, and the susceptibility of commonly used clinical antimicrobial agents against strains with different carbapenemase genes. In total, 7194 gram-negative bacteria strains were collected from different regions of China, and 924 carbapenem-resistant strains were identified. All strains were from confirmed infections. Antimicrobial susceptibility testing, covering 21 antimicrobial agents including aztreonam/avibactam, eravacycline, colistin and other comparators, was performed using the broth microdilution method. Carbapenemase genes (blaKPC, blaNDM, blaOXA, blaIMP and blaVIM) were screened using polymerase chain reaction amplification and sequence analysis. All statistical analyses were performed using Statistical Package for the Social Sciences Version 23.0. The isolation rates of CRE, CRAB and CRPA were 6.31% (332/5265), 62.95% (440/699) and 15.20% (152/1000), respectively. The predominant carbapenemase in carbapenem-resistant Escherichia coli (CRECO) was NDM, while in carbapenem-resistant Klebsiella pneumoniae (CRKP), it was KPC. All CRAB produced OXA-23, and 85.52% of CRPA did not produce any of the following carbapenemases: NDM, KPC, VIM, IMP and OXA. Aztreonam/avibactam, colistin and eravacycline exhibited high antimicrobial activity against different species producing various carbapenemases. Compared with ceftazidime/avibactam, aztreonam/avibactam demonstrated superior antimicrobial activity, particularly pronounced in CRECO and strains producing metallo-beta-lactamases. In comparisons between tigecycline and eravacycline, the latter maintained higher antimicrobial activity across different species. Antimicrobial agents exhibited varying levels of activity against strains with different resistance mechanisms. Using aztreonam/avibactam, eravacycline and colistin to treat infections caused by CRB offers significant advantages. These findings will guide clinical practice and optimize antimicrobial administration.

Combination therapy with IV fosfomycin for adult patients with serious Gram-negative infections: a review of the literature.

Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a β-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a β-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of β-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.

Isavuconazole Induces Neurodevelopment Defects and Motor Behaviour Impairment in Zebrafish Larvae.

Isavuconazole is a broad-spectrum antifungal drug used for the treatment of serious infections caused by invasive aspergillosis and mucormycosis in adults. With the continuous use of this drug, its safety and environmental impact have received increasing attention. However, information on the adverse effects of the drug is very limited. Fish is a particularly important model for assessing environmental risks. In this study, the aquatic vertebrate zebrafish was used as a model to study the toxic effects and mechanisms of isavuconazole. We exposed zebrafish embryos to 0.25, 0.5, and 1mg/L of isavuconazole 6h after fertilization. The results showed that at 72 hpf, isavuconazole exposure reduced heart rate, body length, and survival of zebrafish embryos compared to controls. Secondly, when isavuconazole reached a certain dose level (0.25mg/L), it caused morphological changes in the Tg(elavl3:eGFP) transgenic fish line, with the head shrunk, the body bent, the fluorescence intensity becoming weaker, the abnormal motor behaviour, etc. At the same time, exposure of zebrafish embryos to isavuconazole downregulated acetylcholinesterase (AchE) and adenosine triphosphate (ATPase) activities but upregulated oxidative stress, thereby disrupting neural development and gene expression of neurotransmitter pathways. In addition, astaxanthin partially rescued the neurodevelopmental defects of zebrafish embryos by downregulating oxidative stress. Thus, our study suggests that isavuconazole exposure may induce neurodevelopment defects and behavioural disturbances in larval zebrafish.

Safety and Treatment Outcomes of Infants and Children Treated With Daptomycin: Six-Year Experience From a Pediatric Academic Medical Center.

Daptomycin is a common treatment for serious infections caused by gram-positive bacteria in adult patients; however, data regarding its safety and efficacy in the pediatric population are limited. This was a retrospective chart review of adverse reactions and treatment outcomes associated with daptomycin use in children <13 years old who received at least 1 dose of daptomycin. At least 1 dose of daptomycin was received by 147 patients. Seventy-two patients received daptomycin for 5 or more days. New-onset loose stools on daptomycin initiation were reported for 14 (9.5%) patients, elevations in creatine kinase in 3 (2%) patients, and elevated aspartate transaminase and alanine transaminase in 13 (8.8%) and 9 (6.1%) patients, respectively. Two patients (1.4%) had daptomycin discontinued due to specific concerns for adverse drug reactions. Daptomycin was found to be safe and effective in this pediatric cohort that included young children and infants with a variety of types and severities of infections.

Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight carbapenem-resistant Klebsiella pneumoniae

BackgroundCarbapenems represent the first line treatment of serious infections caused by drug-resistant Klebsiella pneumoniae. Carbapenem-resistant K. pneumoniae (CRKP) is one of the urgent threats to human health worldwide. The current study aims to evaluate the carbapenemase inhibitory potential of coumarin and to test its ability to restore meropenem activity against CRKP. Disk diffusion method was used to test the antimicrobial susceptibility of K. pneumoniae clinical isolates to various antibiotics. Carbapenemase genes (NDM-1, VIM-2, and OXA-9) were detected using PCR. The effect of sub-MIC of coumarin on CRKP isolates was performed using combined disk assay, enzyme inhibition assay, and checkerboard assay. In addition, qRT-PCR was used to estimate the coumarin effect on expression of carbapenemase genes. Molecular docking was used to confirm the interaction between coumarin and binding sites within three carbapenemases.ResultsK. pneumoniae clinical isolates were found to be multi-drug resistant and showed high resistance to meropenem. All bacterial isolates harbor at least one carbapenemase-encoding gene. Coumarin significantly inhibited carbapenemases in the crude periplasmic extract of CRKP. The checkerboard assay indicated that coumarin-meropenem combination was synergistic exhibiting a fractional inhibitory concentration index ≤ 0.5. In addition, qRT-PCR results revealed that coumarin significantly decreased carbapenemase-genes expression. Molecular docking revealed that the binding energies of coumarin to NDM1, VIM-2, OXA-48 and OXA-9 showed a free binding energy of -7.8757, -7.1532, -6.2064 and − 7.4331 Kcal/mol, respectively.ConclusionCoumarin rendered CRKP sensitive to meropenem as evidenced by its inhibitory action on hydrolytic activity and expression of carbapenemases. The current findings suggest that coumarin could be a possible solution to overcome carbapenems resistance in CRKP.

Win Ratio Analyses of Piperacillin-Tazobactam Versus Meropenem for Ceftriaxone-Nonsusceptible Escherichia coli or Klebsiella pneumoniae Bloodstream Infections: Post Hoc Insights From the MERINO Trial.

Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii.

ANT3310 is a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii (n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) (n = 252) or Klebsiella pneumoniae carbapenemase (KPC) (n = 180) carbapenemases, and Pseudomonas aeruginosa (n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii. This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other β-lactam/β-lactamase combinations.

A New Case of Fournier's Gangrene Caused by Actinotignum schaalii

Actinotignum schaalii (formerly known as Actinobaculum schaalii) is an anaerobic or facultative anaerobic gram-positive bacillus that can be found commensally in the urogenital region. It can be overlooked because it grows slowly and is difficult to identify with classical microbiology laboratory techniques. Colonies become visible after 48-72 hours of incubation on blood agar in anaerobic or CO₂-rich media. While it typically causes urinary tract infection in older individuals, cases of bacteremia, vertebral osteomyelitis, endocarditis and cellulitis have been reported. Fournier's gangrene caused by A.schaalii has been reported very rarely so far. Fournier's gangrene has been defined as necrotizing fasciitis of the external genitalia, perineal and perianal region. Diabetes, immunosuppression, peripheral vascular disease, urethral anomalies, chronic alcoholism and smoking are important predisposing factors. In addition, approximately 25% of the cases have no known or identifiable etiology. The bacteria causing the infection may originate from skin, urogenital or intestinal microbiota. In this case report, a new case of Fournier's gangrene caused by A.schaalii was presented. A 65-year-old male patient admitted to the emergency department with the complaints of pain, swelling, redness in the left testis and also nausea, vomiting and chills that started three days ago. Physical examination revealed increased diameter of the scrotum, intense hyperemia of the skin and foci of necrosis. It was learned that the patient had no known chronic disease other than benign prostatic hyperplasia. The patient reported smoking of 25 packs of cigarettes per year. Routine laboratory tests revealed leukocyte= 32.41 x 109/L, neutrophil= 89.9%, procalcitonin= 1.62 ug/L, CRP= 265.07 mg/L and the patient was operated with the diagnosis of Fournier's gangrene. Gram staining of the abscess specimen obtained during the operation showed gram-positive bacilli both inside and outside the leukocytes. After 24 hours, grampositive bacilli were detected in the Gram staining of thin, transparent/gray colonies grown on 5% sheep blood and chocolate agar. The isolate was identified as A.schaalii by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) VITEK® MS (bioMérieux, France) microbial identification system. VITEK®2 ID ANC (bioMérieux, France) bacterial identification card was also used for comparison but the bacteria could be identified. As a result of the sequence analysis performed for confirmation, it was shown to be 100% homologous with Actinobaculum schaalii (GenBank accession no: FJ711193.1). For susceptibility tests, 5% sheep blood Schaedler agar was used and incubated in anaerobic environment. According to the minimal inhibitory concentration (MIC) results evaluated after 48 hours, penicillin was found to be 0.032 mg/L, clindamycin 0.125 mg/L, ciprofloxacin 0.19 mg/L, ceftazidime 4 mg/L, and amoxicillin 0.19 mg/L. The primary cause that initiated the infection in the case could not be identified, but it was thought that the presence of prostatic hyperplasia and smoking history may have contributed to the occurence or the progress of the disease. It is noteworthy that the ciprofloxacin MIC result was quite low compared to other studies. In addition, this study revealed the value of MALDI-TOF MS based methods in identification. In conclusion, it is thought that a significant proportion of A.schaalii infections may be overlooked due to the difficulty in growth and identification. Increasing the diagnostic power of clinical microbiology laboratories for poorly identified bacteria and renewing the databases of commercial identification systems are important for the early and accurate diagnosis and treatment of serious infections that may occur with such agents.

EE34 Cost-Effectiveness Analysis of Aztreonam-Avibactam (ATM-AVI) Versus Meropenem for the Treatment of Serious Infections Due to Gram-Negative Bacteria for Which There Are Limited Treatment Options (LTO) in Italy

EE34 Cost-Effectiveness Analysis of Aztreonam-Avibactam (ATM-AVI) Versus Meropenem for the Treatment of Serious Infections Due to Gram-Negative Bacteria for Which There Are Limited Treatment Options (LTO) in Italy

Epidemiology of vancomycin-resistant enterococci in the United Arab Emirates: a retrospective analysis of 12 years of national AMR surveillance data.

Enterococci are usually low pathogenic, but can cause invasive disease under certain circumstances, including urinary tract infections, bacteremia, endocarditis, and meningitis, and are associated with peritonitis and intra-abdominal abscesses. Increasing resistance of enterococci to glycopeptides and fluoroquinolones, and high-level resistance to aminoglycosides is a concern. National antimicrobial resistance (AMR) surveillance data for enterococci from the Middle East and North Africa (MENA) and the Gulf region is scarce. A retrospective 12-year analysis of N = 37,909 non-duplicate diagnostic Enterococcus spp. isolates from the United Arab Emirates (UAE) was conducted. Data was generated by routine patient care during 2010-2021, collected by trained personnel and reported by participating surveillance sites to the UAE National AMR Surveillance program. Data analysis was conducted with WHONET. Enterococcus faecalis was the most commonly reported species (81.5%), followed by Enterococcus faecium (8.5%), and other enterococci species (4.8%). Phenotypically vancomycin-resistant enterococci (VRE) were found in 1.8% of Enterococcus spp. isolates. Prevalence of VRE (%VRE) was highest for E. faecium (8.1%), followed by E. faecalis (0.9%). A significant level of resistance to glycopeptides (%VRE) for these two species has been observed in the majority of observed years [E. faecalis (0-2.2%), 2010: 0%, 2021: 0.6%] and E. faecium (0-14.2%, 2010: 0%, 2021: 5.8%). Resistance to fluoroquinolones was between 17 and 29% (E. faecalis) and was higher for E. faecium (between 42 and 83%). VRE were associated with higher patient mortality (RR: 2.97), admission to intensive care units (RR: 2.25), and increased length of stay (six excess inpatient days per VRE case), as compared to vancomycin-susceptible Enterococcus spp. Published data on Enterococcus infections, in particular VRE-infections, in the UAE and MENA region is scarce. Our data demonstrates that VRE-enterococci are relatively rare in the UAE, however showing an increasing resistance trend for several clinically important antibiotic classes, causing a concern for the treatment of serious infections caused by enterococci. This study also demonstrates that VRE were associated with higher mortality, increased intensive care unit admission rates, and longer hospitalization, thus poorer clinical outcome and higher associated costs in the UAE. We recommend the expansion of current surveillance techniques (e.g., local VRE screening), stricter infection prevention and control strategies, and better stewardship interventions. Further studies on the molecular epidemiology of enterococci are needed.

A Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneously Determining Meropenem and Linezolid in Blood and Cerebrospinal Fluid.

Antibiotic therapy requires appropriate dosage of drugs for effective treatment. Too low antibiotic concentrations may lead to treatment failure and the development of resistant pathogens, whereas overdosing may cause neurological side effects or hemolytic diseases. Meropenem and linezolid are used only in the treatment of serious infections or when other antibiotics are no longer effective as well as for treating central nervous system infections. It is difficult or sometimes even impossible to predict the relation between dosing of antibiotics and its cerebrospinal fluid (CSF) concentration; thus, a method of determining antibiotics not only in the blood but also in the CSF is needed. Analytical method validation is an integral part of good laboratory practice and ensures high accuracy of the results. We performed complete validation process according to the Food and Drug Administration and European Medicine Agency, covering the aspects precision, specificity, accuracy, recovery, limit of detection, limit of quantification, stability, carry-over, and matrix effects. Our liquid chromatography-tandem mass spectrometry method for the simultaneous measurement of meropenem and linezolid in different matrix meets all the acceptance criteria. The method was successfully applied to determine meropenem and linezolid concentrations in serum and CSF samples obtained from children treated with these antibiotics.

Effectiveness and Adverse Events of Generic and Original Imipenem/Cilastatin in Hospitalized Patients: The First Multicenter Non-Inferiority Study in Thailand

Objective: Imipenem/cilastatin, a broad-spectrum antibacterial, is reserved for treatment of serious infections caused by multidrug-resistant Gram-negative bacteria. The present study was aimed to compare the effectiveness and adverse events of generic and original imipenem/cilastatin. Materials and Methods:A retrospective, multicenter, cohort, non-inferiority study of generic imipenem/cilastatin (Sianem®), and original imipenem/cilastatin (Tienam®) was carried on between November 2017 and September 2020. The centers included Srinagarind Hospital, Taksin Hospital, Nakornping Hospital, Nakhonpathom Hospital, and King Chulalongkorn Memorial Hospital. The clinically relevant data were retrieved from the medical records on day 3, 7, and 14 after enrollment. A sample size of 260 patients per arm was needed. Results: There were 214 and 227 medical and surgical patients enrolled in generic and original imipenem/cilastatin groups, respectively. Baseline characteristics of the two groups were not significantly different. Most patients were male and elderly. Comorbidity was observed in 86.6%. The average length of hospital stay was 17 days. At day 14 after enrollment, the favorable outcome in generic and original imipenem/cilastatin groups were 83.1% and 90.0%, respectively, with no statistical difference. The mortality rates were 3.4% and 2.0% in generic and original imipenem/ cilastatin groups, respectively, with no statistic difference. Serious adverse events were also not significantly different between the two groups at 0.9% and 0.4%. Conclusion: The generic imipenem/cilastatin was non-inferior to the original imipenem/cilastatin in terms of effectiveness and adverse events for the treatment of serious bacterial infections in hospitalized adult patients. Keywords: Effectiveness; Safety; Adverse events; Generic drug; Imipenem/cilastatin

Cefepime in vivo activity against carbapenem-resistant Enterobacterales that test as cefepime susceptible or susceptible-dose dependent in vitro: implications for clinical microbiology laboratory and clinicians.

Carbapenem-resistant Enterobacterales (CRE) are a public health concern. Among these isolates, there are reports of isolates that test as cefepime susceptible or susceptible-dose dependent (SDD) in vitro despite presence of a carbapenemase. This study aimed to evaluate the pharmacokinetic/pharmacodynamic profile of cefepime against carbapenemase-producing (CP-CRE) and non-producing (non-CP-CRE) isolates with a range of cefepime MICs. Reference broth microdilution and modified carbapenem inactivation method (mCIM) were performed on genotypically characterized clinical CRE isolates. Ultimately, CP-CRE (n = 21; blaKPC) and non-CP-CRE (n = 19) isolates with a distribution of cefepime MICs (≤0.5 to >256 mg/L) were utilized in the murine thigh infection model. Mice were treated with cefepime human-simulated regimens (HSRs) representative of a standard dose (1 g q12h 0.5 h infusion) or the SDD dose (2 g q8h 0.5 h infusion). Efficacy was assessed as the change in bacterial growth at 24 h compared with 0 h control, where ≥1 log bacterial reduction is considered translational value for clinical efficacy. Among both cohorts of CRE isolates, i.e. CP-CRE and non-CP-CRE, that tested as SDD to cefepime in vitro, 1 log bacterial reduction was not attainable with cefepime. Further blunting of cefepime efficacy was observed among CP-CRE isolates compared with non-CP-CRE across both susceptible and SDD categories. Data indicate to avoid cefepime for the treatment of serious infections caused by CRE isolates that test as cefepime susceptible or SDD. Data also provide evidence that isolates with the same antibiotic MIC may have different pharmacokinetic/pharmacodynamic profiles due to their antimicrobial resistance mechanism.

The effects of daptomycin on cell wall biosynthesis in Enterococcal faecalis

Daptomycin is a cyclic lipodepsipeptide antibiotic reserved for the treatment of serious infections by multidrug-resistant Gram-positive pathogens. Its mode of action is considered to be multifaceted, encompassing the targeting and depolarization of bacterial cell membranes, alongside the inhibition of cell wall biosynthesis. To characterize the daptomycin mode of action, 15N cross-polarization at magic-angle spinning NMR measurements were performed on intact whole cells of Staphylococcus aureus grown in the presence of a sub-inhibitory concentration of daptomycin in a chemically defined media containing l-[ϵ-15N]Lys. Daptomycin-treated cells showed a reduction in the lysyl-ε-amide intensity that was consistent with cell wall thinning. However, the reduced lysyl-ε-amine intensity at 10 ppm indicated that the daptomycin-treated cells did not accumulate in Park’s nucleotide, the cytoplasmic peptidoglycan (PG) precursor. Consequently, daptomycin did not inhibit the transglycosylation step of PG biosynthesis. To further elucidate the daptomycin mode of action, the PG composition of daptomycin-susceptible Enterococcus faecalis grown in the presence of daptomycin was analyzed using liquid chromatography-mass spectrometry. Sixty-nine muropeptide ions correspond to PG with varying degrees of modifications including crosslinking, acetylation, alanylation, and 1,6-anhydrous ring formation at MurNAc were quantified. Analysis showed that the cell walls of daptomycin-treated E. faecalis had a significant reduction in PG crosslinking which was accompanied by an increase in lytic transglycosylase activities and a decrease in PG-stem modifications by the carboxypeptidases. The changes in PG composition suggest that daptomycin inhibits cell wall biosynthesis by impeding the incorporation of nascent PG into the cell walls by transpeptidases and maturation by carboxypeptidases. As a result, the newly formed cell walls become highly susceptible to degradation by the autolysins, resulting in thinning of the cell wall.

Low-Generation Cationic Phosphorus Dendrimers: Novel Approach to Tackle Drug-Resistant S. aureus In Vitro and In Vivo.

The incessant, global increase in antimicrobial resistance (AMR) is a very big challenge for healthcare systems. AMR is predicted to grow at an alarming pace, with a dramatic increase in morbidity, mortality, and a 100 trillion US$ loss to the global economy by 2050. The mortality rate caused by methicillin-resistant S. aureus (MRSA) is much higher as compared to infections caused by drug-susceptible S. aureus. Additionally, there is a big paucity of therapeutics available for treatment of serious infections caused by MRSA. Thus, the discovery and development of novel therapies is an urgent, unmet medical need. In this context, we synthesized AE4G0, a low-generation cationic-phosphorus dendrimer expressing potent antimicrobial activity against S. aureus and Enterococcus sp., and demonstrating a broad selectivity index against eukaryotic cells. AE4G0 exhibits concentration-dependent, bactericidal activity and synergizes with gentamicin, especially against gentamicin-resistant MRSA NRS119. Fluorescence and scanning electron microscopy demonstrate that treatment with AE4G0 led to the utter destruction of S. aureus ATCC 29213 without inducing resistance, despite repeated exposure. When tested in vivo, AE4G0 demonstrates significant efficacy against S. aureus ATCC 29213, alone and in combination with gentamicin against gentamicin-resistant S. aureus NRS119 in the murine skin model of infection. Taken together, AE4G0 demonstrates the potential to be translated as a novel therapeutic option for the treatment of topical, drug-resistant S. aureus infections.

Snapshots of ID Week 2022

Snapshots of ID Week 2022

Antibacterial Activity of Eravacycline Against Carbapenem-Resistant Gram-Negative Isolates in China: An in vitro Study.

Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, with a broad-spectrum antimicrobial activity, including against carbapenem-resistant gram-negative bacteria (CRGNB). However, the in vitro activity of eravacycline against CRGNB has not been well known in China. In this study, we analysed the antibacterial activity of eravacycline against CRGNB isolates in order to provide a theoretical basis for the clinical treatment. A total of 346 isolates of CRGNB were collected from two different tertiary care hospitals in Zhejiang, China. Carbapenem resistance genes of all isolates were detected by polymerase chain reaction. And we analysed the in vitro activity of eravacycline against CRGNB by antimicrobial susceptibility tests. In addition, the time-kill curves were generated to evaluate the antibacterial effect of tigecycline and eravacycline. Four different types of carbapenem-resistant isolates were collected, including 50 Escherichia coli isolates, 160 Klebsiella pneumoniae isolates, 42 Enterobacter cloacae complex isolates, and 94 Acinetobacter baumannii isolates. The carbapenem resistance genes were identified in 346 isolates, including bla KPC-2 (48.0%), bla OXA-23 (27.2%), bla NDM-1 (23.1%), and bla NDM-16 (0.3%). The antimicrobial susceptibility testing results showed that the minimum inhibitory concentration (MIC) values of 346 isolates were within the sensitivity range (≤0.0625~16 mg/L) and that the MIC50 or MIC90 of eravacycline was generally approximately 2-fold lower than tigecycline. In addition, the time-kill curves showed that the bactericidal effect of eravacycline was stronger than that of tigecycline against four different types of isolates. Our research indicated that eravacycline had a good antibacterial effect on CRGNB, which could provide a theoretical basis for the clinical treatment of drug-resistant bacterial infections in the future.

Piperacillin/tazobactam versus cefepime or carbapenems for cefoxitin-non-susceptible Enterobacter cloacae, Klebsiella aerogenes, Citrobacter freundii, Serratia marcescens and Morganella morganii bacteraemia in immunocompromised patients.

The role of piperacillin/tazobactam for treatment of serious infections due to AmpC-producing organisms remains debatable, particularly in immunocompromised patients. This was a retrospective cohort study in immunocompromised patients that investigated the effect of definitive treatment with either piperacillin/tazobactam versus cefepime or carbapenems for bacteraemia caused by cefoxitin-non-susceptible Enterobacterales. The primary endpoint was a composite of clinical and microbiological failure. A logistic regression model was constructed to assess the impact of definitive treatment choice on the primary endpoint. A total of 81 immunocompromised patients with blood cultures positive for cefoxitin-non-susceptible Enterobacterales were included for analysis. There was more microbiological failure in the piperacillin/tazobactam arm compared with the cefepime/carbapenem arm (11.4% versus 0.0%, P = 0.019). Definitive treatment with cefepime or a carbapenem was associated with a decreased odds of clinical or microbiological failure (OR 0.303, 95% CI 0.093-0.991, P = 0.048) when controlling for baseline characteristics. In immunocompromised patients with bacteraemia due to cefoxitin-non-susceptible Enterobacterales, definitive treatment with piperacillin/tazobactam was associated with an increased risk of microbiological failure and higher odds of clinical or microbiological failure compared with cefepime or carbapenems.

1684. Antimicrobial Activity of Aztreonam-Avibactam Against a Large Collection of Stenotrophomonas maltophilia and Burkholderia cepacia Species Complex Causing Infections in United States (US) Medical Centers (2016-2021)

Abstract Background S. maltophilia has become a major cause of hospital-associated pneumonia. Aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs), including those intrinsically produced by S. maltophilia. Avibactam (AVI) is a non-β-lactam β-lactamase inhibitor that inhibits serine β-lactamases such as ESBLs, KPCs, AmpCs, and some OXAs. ATM-AVI is being developed for treatment of serious infections caused by Gram-negative bacteria, including MBL producers. We evaluated the activity of ATM-AVI against S. maltophilia and B. cepacia from US hospitals. Methods 1,565 S. maltophilia and 219 B. cepacia were consecutively collected (1/patient) in 77 US medical centers in 2016-2021 and susceptibility tested by CLSI broth microdilution method. Only isolates determined to be the probable cause of infection were included. CLSI/US FDA breakpoints were applied when available. Results The isolate collection were recovered mainly from patients with pneumonia (73.3%) and bloodstream infection (BSI; 10.1%). ATM-AVI was very active against S. maltophilia, with MIC50/90s of 2/4 mg/L and 98.3% of isolates inhibited at ≤8 mg/L, including 100.0% of isolates from BSI and 97.9% of isolates from pneumonia. Trimethoprim-sulfamethoxazole (TMP-SMX; MIC50/90, ≤0.5/1 mg/L; 95.7% susceptible [S]) and minocycline (MIC50/90, 0.5/2 mg/L; 99.2%S) also were very active against S. maltophilia, while ceftazidime and levofloxacin were active against 21.3% and 76.2% of isolates per CLSI criteria, respectively (Table). ATM-AVI was also very active against B. cepacia, with MIC50/90s of 4/16 mg/L and 88.1% inhibited at ≤8 mg/L, including 93.3% and 87.3% of isolates from BSI and pneumonia, respectively. The most active comparators tested against B. cepacia were ceftazidime (84.9%S), meropenem (84.5%S), TMP-SMX (83.5%S), and minocycline (80.0%S). Conclusion ATM-AVI demonstrated potent in vitro activity against S. maltophilia and B. cepacia from US hospitals and may represent a valuable option to treat infections caused by these organisms. Clinical studies are urgently warranted to evaluate the efficacy of ATM-AVI as well as reevaluate the susceptibility breakpoints for antibiotics currently used to treat infections caused by these organisms. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.