Search

The aim of this project was to develop a synthetic protocol for the preparation of a cephamycin scaffold that would readily allow the synthesis of its analogues with variations at the C-7 amino group and the C-3′ position. We also aimed to develop a method that avoided the use of toxic and potentially explosive diphenyldiazomethane. These aims were achieved via the synthesis of the novel α-bromo acetamide 18 which allowed functionalization at the α-bromo acetamide position by azide and then the introduction of a 4-phenyl-1H-1,2,3-triazol-1-yl moiety via a Cu(I)-catalysed azide–alkyne cycloaddition reaction with phenylacetylene. Palladium-catalyzed arylthioallylation reactions then allowed the introduction of 3′-arylthiol substituents. We also report for the first time the synthesis of the 4-methoxybenzyl ester of (6R,7S)-3-[(acetyloxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and the use of diphenyl trichloroacetimidate, instead of diphenyldiazomethane, and 4-methoxybenzyl trichloroacetimidate to prepare related 4-methoxybenzyl esters. The chemistry described, and several of the synthetic intermediates reported here, are potentially valuable methods and scaffolds, respectively, for further development of β-lactam antibiotics. [ABSTRACT FROM AUTHOR]

Carbapenems are frequently used to treat infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), but carbapenem-resistant Enterobacteriaceae bacteria are a clinical concern. Although cephamycins (cefmetazole; CMZ) have been shown to be effective against mild cases of ESBL-E infection, data on their use for severe ESBL-E infections with sepsis or septic shock remain scarce. Herein, we discuss a de-escalation therapy to CMZ that could be used after empiric antibiotic therapy in ICU patients with sepsis or septic shock caused by ESBL-E bacteremia. A sequence of 25 cases diagnosed with sepsis or septic shock caused by ESBL-E bacteria was evaluated. The attending infectious disease specialist physicians selected the antibiotics and decided the de-escalation timing. The median SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) severity scores were 8 and 30; the rate of septic shock was 60%. Infections originated most frequently with urinary tract infection (UTI) (56%) and Escherichia coli (85%). Eleven patients were de-escalated to CMZ after vital signs were stable, and all survived. No patients died of UTI regardless of with or without de-escalation. The median timing of de-escalation antibiotic therapy after admission was 4 days (range, 3-6 days). At the time of de-escalation, the median SOFA score fell from 8 to 5, the median APACHE II score from 28 to 22, and the rate of septic shock from 55% to 0%. We conclude that for sepsis in UTI caused by ESBL-E bacteremia, de-escalation therapy from broad-spectrum antibiotics to CMZ is a potential treatment option when vital signs are stable. [ABSTRACT FROM AUTHOR]

Cefoxitin has demonstrated good in vitro activity against extended spectrum beta-lactamase (ESBL)–producing Escherichia coli (ESBL-Ec) and is regarded as a carbapenem-sparing beta-lactam alternative in urinary tract infections. Its efficacy has never been compared to carbapenems in male UTIs. Our study aimed to compare the clinical and microbiological efficacy of cefoxitin (FOX) and carbapenems (CP) in febrile M-UTI due to ESBL-Ec (F-M-UTI). We conducted a multicenter retrospective cohort study of patients with F-M-UTI treated with FOX or CP as definitive therapy, between January 2013 and June 2015, in six French acute care teaching hospitals. The clinical and microbiological efficacies of FOX and CP were compared using multivariable logistic regression models, adjusting for propensity scores. Of the 66 patients included, 23 patients in FOX group and 27 in CP group had clinical assessment at follow-up. Median follow-up after end of treatment was 63 days (interquartile range 26–114). Clinical success was observed for 17/23 (73.9%) and 22/27 (81.5%) patients and microbiological success for 11/19 (57.9%) and for 6/12 (50.0%) patients in FOX and CP groups respectively. We did not find any significant difference for clinical (OR = 0.90, 95% CI [0.12; 6.70]) neither microbiological (OR = 0.85, 95% CI [0.05; 14.00]) success between CP and FOX groups in univariate and multivariable models. In the FOX group, high dose with use of continuous infusion was associated with clinical success. These results add evidence that FOX is an effective alternative treatment to carbapenems for M-UTI caused by ESBL-Ec, particularly when high doses and continuous infusion are used. [ABSTRACT FROM AUTHOR]

Objective: Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to public and clinical health because of their high levels of resistance to various antibiotics. We assessed the efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) against Imipenemase (IMP)-producing CRE, using the checkerboard method and time-killing assay on 13 Enterobacteriaceae isolates harboring blaIMP-1 (4 Enterobacter hormaechei, 5 Escherichia coli, and 4 Klebsiella pneumoniae isolates) and 13 isolates harboring blaIMP-6 (8 E. coli and 5 K. pneumoniae isolates). Results: Minimum inhibitory concentrations (MICs) of MEM and CMZ ranged from 2 to 64 and 64 to 2048 μg/mL, respectively. Checkerboard method demonstrated the synergy of the MEM/CMZ combination in all the tested IMP-producing CRE isolates, and the time-kill assay indicated a bactericidal effect for both blaIMP-1 and blaIMP-6 positive CRE when MEM/CMZ combination was used. In vitro, the MEM/CMZ combination was potentially effective against IMP-1- or IMP-6-producing CRE. Further investigations including in vivo animal studies and clinical studies are warranted to corroborate the clinical utility of the novel combination therapy. [ABSTRACT FROM AUTHOR]

Purpose: Optimal treatment regimens are yet to be established for carbapenemase-producing Enterobacteriaceae (CPE). We assessed the in vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination treatment against blaKPC-2-positive Enterobacteriaceae, in comparison with that of double-carbapenem therapy using ertapenem (ERT). Materials and Methods: We performed checkerboard assay for 10 blaKPC-2-positive clinical isolates and Klebsiella pneumoniae BAA-1705 (possessing blaKPC-2), with synergistic effect being defined by a fractional inhibitory concentration index of ≤0.5. Subsequently, we conducted time–kill assays using K. pneumoniae BAA-1705 with an initial inoculum of 104–107 colony forming unit (CFU)/mL. Bactericidal effect was defined as the reduction of initial bacterial count by ≥103 CFU/mL in 24 hr. Finally, we applied scanning electron microscopy to observe morphological changes induced by the combination of MEM and CMZ. Results: Checkerboard assays revealed a synergistic effect in 7 out of 11 blaKPC-2 -positive Enterobacteriaceae when the MEM and CMZ combination was used, and no effect when the MEM and ERT combination was used. The minimum inhibitory concentration of MEM decreased 4–8-fold when combined with CMZ. Time–kill assays with an initial inoculum of 5 × 105 CFU/mL revealed regrowth under the combination of MEM and ERT (0.25 × minimum inhibitory concentration [MIC] each), whereas the combination of 0.25 × MIC each of MEM and CMZ exhibited bactericidal effect. Scanning electron microscopy results demonstrated that the combination of 0.5 × MIC MEM and 0.5 × MIC CMZ facilitated bacterial cell lysis compared with each antibiotic alone. Conclusion: The combination therapy using MEM and CMZ potentially has bactericidal effect against KPC-producing Enterobacteriaceae. [ABSTRACT FROM AUTHOR]

Background: Pyelonephritis caused by extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacteriaceae is an urgent problem in pediatrics. Although carbapenem is the standard therapy for infections caused by ESBL‐producing Enterobacteriaceae, some cephamycins, including cefmetazole, are stable against hydrolysis by ESBL. There are few reports, however, on the use of cefmetazole in children. The aim of this study was to evaluate the therapeutic effect of cefmetazole in pediatric pyelonephritis caused by ESBL‐producing Enterobacteriaceae. Methods: Children with pyelonephritis caused by ESBL‐producing Enterobacteriaceae were enrolled between April 2010 and November 2016 at Tokyo Metropolitan Children's Medical Center. Presence of ESBL was tested for using the disk diffusion method. Medical records were reviewed for a past history of bacterial infection. The outcomes were clinical cure rate at 4 weeks and the duration of therapy in the cefmetazole and non‐cefmetazole groups. Results: Fifty‐five patients met the criteria for pyelonephritis caused by ESBL‐producing Enterobacteriaceae. The most common causative organisms were Escherichia coli (n = 51; 92.7%), Klebsiella pneumoniae (n = 3; 5.5%), and K. oxytoca (n = 1; 1.8%). Thirty‐six and 19 patients were treated with cefmetazole and with other antibiotics as definitive therapy, respectively. There was no difference in the clinical cure rate (86.1% vs 89.5%; P = 0.72) or duration of therapy (median, 7.0 vs 7.0 days; P = 0.73) between the cefmetazole and non‐cefmetazole groups. Conclusions: Cefmetazole was not inferior to the other antibiotics in the treatment of pyelonephritis caused by ESBL‐producing Enterobacteriaceae in children. Cefmetazole is a valuable therapeutic alternative to carbapenems for treating pyelonephritis caused by ESBL‐producing Enterobacteriaceae. [ABSTRACT FROM AUTHOR]

Background: ESBL (Extended spectrum beta-lactamase) producing enterobacteriaceae are challenging organisms with little treatment options. Carbapenems are frequently used, but the emergence of carbapenem resistant enterobacteriaceae is a concerning issue, which may hinder the use of carbapenems. Although cephamycins such as cefoxitin, cefmetazole or cefotetan are effective against ESBL-producers in vitro, there are few clinical data demonstrating effects against bacteremia caused by these organisms.Methods: We performed a retrospective observational study on cases of bacteremia caused by ESBL-producers to investigate the efficacy of cefmetazole compared with carbapenems. We also evaluated whether the trend of antibiotic choice changed over years.Results: Sixty-nine patients (male 34, age 69.2 ± 14.4), including two relapse cases, were reviewed for this analysis. The most common causative organisms were Escherichia coli (64, 93 %), followed by Klebsiella pneumoniae and K. oxytoca (2 each, 4 %). The group that received carbapenem therapy (43, 62 %) had increased severity in the Pittsburgh Bacteremic score than the group that received cefmetazole therapy, (1.5 ± 1.5 vs 2.5 ± 2.1, p = 0.048), while analysis of other factors didn't reveal any statistical differences. Five patients in the carbapenem group and one patient in the cefmetazole group died during the observation period (p = 0.24). CTX-M-9 were predominant in this series (59 %). Infectious disease physicians initially recommended carbapenems at the beginning of the current research period, which gradually changed over time favoring the use of cefmetazole instead (p = 0.002).Conclusion: Cefmetazole may be safely given to patients with bacteremia caused by ESBL-producers as a definitive therapy, if one can select out relatively stable patients. [ABSTRACT FROM AUTHOR]

To investigate the in vitro activities of cephamycins (cefmetazole and flomoxef) for extended-spectrum β-lactamase (ESBL)– and plasmid-mediated AmpC β-lactamase (pAmpC)–producing Enterobacteriaceae, a total of 574 third-generation cephalosporin-resistant clinical isolates were collected at a Japanese multicenter study. PCR and sequencing identified 394 isolates with only ESBL genes, 63 isolates with only pAmpC genes, and 6 isolates with both ESBL and pAmpC genes. bla CTX-M types predominated 95.5% of the ESBL genes, and bla CMY-2 predominated 91.3% of the pAmpC genes. The MIC 50/90 values of cefmetazole and flomoxef were ≤1/4 and ≤1/≤1 μg/mL for isolates with only ESBL genes, respectively, and 16/>16 and 8/16 μg/mL for isolates with only pAmpC genes, respectively. Flomoxef ≥4 μg/mL had the best screening performance for the detection of isolates with pAmpC genes. Flomoxef had better in vitro activities against ESBL-producing Enterobacteriaceae and provided a clearer distinction between ESBL and pAmpC-producing Enterobacteriaceae compared to cefmetazole. [ABSTRACT FROM AUTHOR]

OBJECTIVE:To probe into the participation of clinical pharmacists in treatment of one patient with severe pneumonia .METHODS:The clinical pharmacists participated in the medication treatment process of one patient with severe pneumonia , analyzed the change of disease , summarized the program with different kinds of antibiotics and the efficacy , and provided pharmaceutical services for the patient .RESULTS:The efficacy of cefoxitin , as one of cephamycin , in primary treatment of respiratory tract infection was poorer than the basic drugs---high dose of penicillin.CONCLUSIONS:It is necessary to conduct the pharmacodynamics evaluation on the antibiotics of cephamycin , and take effective management measures and medication education , so as to improve the medical quality . The clinical pharmacists go into the clinic and provide pharmaceutical services can assist the clinicians to formulate the safe and effective medication treatment program and promote ration drug use . [ABSTRACT FROM AUTHOR]

• Therapeutic strategy is very limited for severe infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. • In vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination assessed against NDM-producing Enterobacteriaceae. • Synergistic effect of MEM/CMZ for all tested isolates of NDM-producing Enterobacteriaceae: 2- to 8-fold MIC reduction of MEM. • Kinetic studies indicated CMZ may be an antagonist for NDM-1. • In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms. Limited treatment options complicate management of infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. The efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) was assessed against NDM-producing Enterobacteriaceae. Twelve Escherichia coli clinical isolates harbouring bla NDM-1 and a positive control E. coli BAA-2469 harbouring bla NDM-1 were studied. Minimum inhibitory concentrations (MICs) of MEM, ertapenem (ERT) and CMZ were determined by broth microdilution. Checkerboard and time-kill assays were performed to confirm the in vitro efficacy of the MEM/CMZ combination. Scanning electron microscopy, kinetic studies and whole-genome sequence analysis were used to determine the antimicrobial resistance mechanisms. MICs of MEM, ERT and CMZ in monotherapy ranged from 8 to 32, 16 to 128, and 32 to 512 µg/mL, respectively. In the checkerboard assay, MEM/ERT resulted in no synergy, whereas MEM/CMZ showed a synergistic effect in all the tested isolates. Furthermore, the MIC of MEM in combination decreased by 2- to 8-fold compared with that of MEM alone. The time-kill study revealed a bactericidal effect in 4 of 13 isolates at 24 h. Scanning electron microscopy showed spheroidisation of the bacterial cell in the MEM/CMZ combination; this was not observed in single antibiotic conditions. Kinetic studies indicated CMZ was a better antagonist for NDM-1 than ERT. Whole-genome sequence analysis did not reveal any explainable differences between isolates susceptible and those non-susceptible to combination therapy. In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are on the increase. Although cefmetazole is stable in vitro against the hydrolyzing activity of ESBLs, no clinical study has ever evaluated its role in infections caused by these organisms. We therefore evaluated the efficacy of cefmetazole compared to carbapenems against pyelonephritis caused by ESBL-producing Enterobacteriaceae. Methods: A retrospective chart review was conducted at a tertiary care hospital from August 2008 to July 2010. Chart reviews were done for patients with ESBL-producing organisms in urine identified in the microbiology database. Patients who were treated with cefmetazole were compared to those treated with carbapenems. The clinical and bacteriological cure rates at 4 weeks after completion of therapy were evaluated. Results: Two hundred and fifty-six urine cultures growing ESBL-producing organisms were identified during the study period. Ten patients treated with cefmetazole and 12 patients treated with carbapenems were evaluated. There was no difference in clinical (9/10 vs. 12/12, p =0.46) or bacteriological cure rate (5/7 vs. 6/7, p =1.00) at 4 weeks after the completion of therapy. There was no difference in the incidence of adverse effects (2/10 vs. 2/12, p =1.00). Conclusions: Cefmetazole may be a useful option for the treatment of UTIs caused by ESBL-producing organisms. Prospective and larger sized studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]