New ß-lactam - Tetramic acid hybrids show promising antibacterial activities.

ß-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel ß-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin - tetramic acid, cephalosporin - tetramic acid, and cephamycin - tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25 µg/mL and 3.13 µg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ2 cephamycin - tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.

The Use of Noncarbapenem ß-Lactams for the Treatment of Extended-Spectrum ß-Lactamase Infections.

The continued rise in infections caused by extended-spectrum ß-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other ß-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem ß-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections.

Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum ß-lactamase producing Enterobacterales (ESBL-E).

STUDY OBJECTIVE: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended-spectrum ß-lactamase producing enterobacterales (ESBL-E) and investigate optimal dosing regimens for not undergoing hemodialysis (non-HD) and undergoing hemodialysis (HD) patients. DESIGN: Prospective observational study. PATIENTS: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022. MEASUREMENTS: Total and Unbound CMZ concentration was measured by high-performance liquid chromatography (HPLC) with solid-phase extraction and ultrafiltration. SETTING: Determining the CMZ dosing regimen involved modified creatinine clearance (CLCR ) with measured body weight (BW) using the Cockcroft-Gault equation. For non-HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre-HD), and 1 and 3 h after starting HD and post-HD. All blood samples were collected at steady-state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non-HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule. MAIN RESULTS: CMZ measurement methods were established. A model analysis of unbound PK in 37 non-HD patients incorporated creatinine clearance (CLCR ) using the Cockcroft-Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non-HD patients with an ESBL-E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CLCR of 60 mL/min required administration of 2 g every 6 h (1- and 3-h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL-E MIC of 4 mg/L. CONCLUSIONS: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL-E-infected patients.

Current and Ongoing Developments in Targeting Clostridioides difficile Infection and Recurrence.

Clostridioides difficile is a Gram-positive, spore-forming anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. This review provides background information on C. difficile infection and the pathogenesis and toxigenicity of C. difficile. The risk factors, causes, and the problem of recurrence of disease and current therapeutic treatments are also discussed. Recent therapeutic developments are reviewed including small molecules that inhibit toxin formation, disrupt the cell membrane, inhibit the sporulation process, and activate the host immune system in cells. Other treatments discussed include faecal microbiota treatment, antibody-based immunotherapies, probiotics, vaccines, and violet-blue light disinfection.

In vitro efficacy of cephamycins against multiple extended-spectrum ß-lactamase-producing Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae isolates from dogs and cats.

The susceptibility of 218 extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae isolates from companion animals to three cephamycins (cefmetazole, flomoxef, and latamoxef) was investigated. Phenotypic testing found 8 of 120 Klebsiella pneumoniae (KP) and 15 of 69 Enterobacter cloacae (EC) isolates were ESBL and AmpC ß-lactamase (ABL) co-producers. Isolates of KP, Proteus mirabilis, and EC that only produced ESBL exhibited susceptibility rates to cefmetazole (95.5%, 82.7%, and 9.3%), flomoxef (99.1%, 96.6%, and 74.0%), and latamoxef (99.1%, 100%, and 100%), respectively. Notably, isolates of KP and EC co-producing ESBL and ABL had significantly lower susceptibility rates to the studied drugs when compared with only ESBL producers. This implies that the in vitro activity of cephamycins against ESBL-producing bacteria can differ depending on ABL production and bacterial species.

In vitro activity of flomoxef against extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae in Korea.

To find an alternative regimen for the treatment of extended-spectrum ß-lactamase (EBSL)-producing Enterobacteriaceae infections, we examined the in vitro activity of flomoxef against Escherichia coli and Klebsiella pneumoniae having CTX-M-1 group and/or CTX-M-9 group ESBLs. Boronic acid disk methods and polymerase chain reaction amplification were used to detect for ESBL, and AmpC ß-lactamase and AmpC ß-lactamase co-producers were excluded. Minimum inhibitory concentrations (MICs) were determined for flomoxef by broth microdilution. One hundred seventy-six isolates (E. coli, n = 93 and K. pneumoniae, n = 83) were analyzed for susceptibility test. A total of 94.3% (166/176) of isolates were susceptible to flomoxef (MIC50/MIC90 were 0.5/8 µg/mL); 98.9% of the ESBL-producing E. coli (MIC50/MIC90 were 1/4 µg/mL) and 89.2% of the ESBL-producing K. pneumoniae (MIC50/MIC90 were 0.5/16 µg/mL) were susceptible to flomoxef. Flomoxef has good in vitro activity against ESBL-producing E. coli and K. pneumoniae and could be considered as an alternative for infections caused by these organisms.

Cefotetan-Induced Hemolytic Anemia: Case Series and Review.

PURPOSE: To raise awareness of cefotetan-induced hemolytic anemia, a known rare but serious side effect that occurred in 5 patients at our medical center. SUMMARY: Five cases of cefotetan-induced hemolytic anemia, which presented over the period of a single year at our center, are described. In each case, hemolytic anemia was confirmed by testing for the presence of anti-cefotetan antibodies. Each case occurred approximately 1 to 2 weeks following exposure to the drug. All five patients survived. A brief review of drug-induced immune hemolytic anemia (DIIHA) is also discussed. CONCLUSION: DIIHA may be difficult to distinguish from other causes of hemolytic anemia, but should be included in the differential in patients exposed to medications associated with DIIHA. Once suspected, antibody testing should be performed, and once diagnosed, further exposure should be avoided.

Comparative effectiveness of flomoxef versus carbapenems in the treatment of bacteraemia due to extended-spectrum ß-lactamase-producing Escherichia coli or Klebsiella pneumoniae with emphasis on minimum inhibitory concentration of flomoxef: a retrospective study.

This study compared treatment outcomes of adult patients with bacteraemia due to extended-spectrum ß-lactamase-producing Escherichia coli or Klebsiella pneumoniae (ESBL-EK) receiving flomoxef versus those receiving a carbapenem as definitive therapy. In propensity score matching (PSM) analysis, case patients receiving flomoxef shown to be active in vitro against ESBL-EK were matched with controls who received a carbapenem. The primary endpoint was 30-day crude mortality. The flomoxef group had statistically significantly higher sepsis-related mortality (27.3% vs. 10.5%) and 30-day mortality (28.8% vs. 12.8%) than the carbapenem group. Of the bacteraemic episodes caused by isolates with a MICflomoxef of ≤1 mg/L, sepsis-related mortality rates were similar between the two treatment groups (8.7% vs. 6.4%; P=0.73). The sepsis-related mortality rate of the flomoxef group increased to 29.6% and 50.0% of episodes caused by isolates with a MICflomoxef of 2-4 mg/L and 8 mg/L, respectively, which was significantly higher than the carbapenem group (12.3%). In the PSM analysis of 86 case-control pairs infected with strains with a MICflomoxef of 2-8 mg/L, case patients had a significantly higher 30-day mortality rate (38.4% vs. 18.6%). Multivariate regression analysis revealed that flomoxef therapy for isolates with a MICflomoxef of 2-8 mg/L, concurrent pneumonia or urosepsis, and a Pitt bacteraemia score ≥4 were independently associated with 30-day mortality. Definitive flomoxef therapy appears to be inferior to carbapenems in treating ESBL-EK bacteraemia, particularly for isolates with a MICflomoxef of 2-8 mg/L, even though the currently suggested MIC breakpoint of flomoxef is ≤8 mg/L.

Clinical and microbiologic characteristics of adult patients with recurrent bacteraemia caused by extended-spectrum ß-lactamase-producing Escherichia coli or Klebsiella pneumoniae.

The characteristics of patients with recurrent bacteraemia caused by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniae (EK) are rarely described. Flomoxef belongs to the cephamycins group and demonstrates in vitro activity against ESBL-producing organisms. Whether flomoxef may be used for the treatment of such infections remains controversial. This retrospective case-control study enrolled adult patients who had bacteraemia caused by ESBL-EK during 2005-2011. Case patients were those who had more than one episode of ESBL-EK bacteraemia. Controls were those who were matched for age and interval time of blood sampling and had only one episode of ESBL-EK bacteraemia with subsequent bacteraemia episodes caused by other non-ESBL-EK bacteria. Pulsed-field gel electrophoresis and microbiologic profiles of the initial and subsequent ESBL-EK isolates were analysed. During the study period, 424 patients were found to have at least one positive blood culture after the first ESBL-EK bacteraemia episode, and 67 (15.8%) had a second episode of ESBL-EK bacteraemia. Bacteraemia resulting from vascular catheter-related infection (odds ratio, 3.24; 95% confidence interval, 1.31-8.05), and definitive therapy with flomoxef (odds ratio, 2.99; 95% confidence interval, 1.10-8.15) were both independent risk factors for the recurrence. Among the 56 patients with available ESBL-EK isolates for analysis, 38 (67.8%) were infected by genetically similar strains. In three of these 38 recurrent ESBL-EK bacteraemia cases caused by an identical strain, the minimum inhibitory concentrations of carbapenem for the subsequent K. pneumoniae isolates were fourfold or higher than the initial isolates. Recurrent bacteraemia was not uncommon in our patients with ESBL-EK bacteraemia, and most of the episodes were caused by identical strains.

Efficacy of empirical therapy with non-carbapenems for urinary tract infections with extended-spectrum beta-lactamase-producing Enterobacteriaceae.

OBJECTIVES: Carbapenems are first-line agents for severe infections with extended-spectrum beta-lactamase (ESBL)-producing bacteria. The use of carbapenems, however, is associated with the emergence of resistant organisms. We investigated the effects of empirical therapy with non-carbapenems on urinary tract infections (UTIs) with ESBL-producing Enterobacteriaceae in a hospital where antimicrobial stewardship has been established. METHODS: This retrospective chart review was undertaken at a tertiary care hospital where antimicrobial stewardship and restriction of carbapenems has been established. Patients with a UTI with ESBL-producing Enterobacteriaceae were stratified into susceptible and non-susceptible therapy groups according to the susceptibility of the causative organism to the initial antimicrobial therapy. Outcome measures were the duration of antimicrobial therapy, 14-day mortality, infection-related mortality, and clinical cure. RESULTS: Of 90 patients, 30 (33.3%) exhibited susceptible therapy. However, no significant difference was observed in the duration of antimicrobial therapy, 14-day mortality, infection-related mortality, or clinical cure between the susceptible and non-susceptible groups. Multivariate analyses revealed that the independent risk factor for 14-day morality was the use of immunosuppressive agents (odds ratio 5.23, 95% confidence interval 1.26-24.04; p=0.023). CONCLUSIONS: Non-carbapenem therapy against UTIs with ESBL-producing Enterobacteriaceae does not pose a significant risk to patients who are not taking immunosuppressive agents.

Structure, evolution and virtual screening of NDM-1 strain from Kolkata.

ß-lactam antibiotics are utilised to treat bacterial infection. ß-lactamase enzymes (EC 3.5.2.6) are produced by several bacteria and are responsible for their resistance to ß-lactam antibiotics like penicillin, cephamycins and carbapenems. New Delhi Metallo-ß-lactamase (NDM-1) is a gene that makes bacteria resistant to ß-lactam antibiotics. Preparing a compound against NDM-1 will require additional investment and development by drug manufacturers as the current antibiotics will not treat patients with NDM-1 resistance. NDM-1 of Kolkata showed convergent-type evolution with other NDM-1 producing strains. The modelled structure exhibited α-ß-α barrel-type domain along with Zn metallo-ß-lactamase N-terminal domain. Compounds belonging to cephalosporins (relatively resistant to ß-lactamase) and other antibiotics ceftaroline, ceftobiprole, piperacillin, penamecillin, azidocillin, cefonicid, tigecycline and colistin have exhibited better binding affinity with the modelled NDM-1.