Cefpirome Treatment Results in Limited Selection of Stable Derepressed Enterobacter cloacae Mutants in the Intestinal Flora of Rats Treated for an Experimental Klebsiella pneumoniae Pulmonary Infection.

Background: Fourth-generation cephalosporins have been developed to improve their potency, that is, low minimal inhibitory concentrations (MICs) and to prevent resistance selection of derepressed AmpC-producing mutants in comparison to third-generation cephalosporins as ceftazidime. Objectives: We investigated the role of the administered cefpirome dose on the efficacy of treatment of a Klebsiella pneumoniae lung infection as well as in the selection of resistant Enterobacter cloacae isolates in the intestines of rats treated for a K. pneumoniae lung infection. Materials and Methods: Rats with K. pneumoniae lung infection received therapy with cefpirome doses of 0.4 to 50 mg/kg/day b.i.d. for 18 days. Resistance selection in intestinal E. cloacae was monitored during 43 days. Mutants were checked for ß-lactamase activity, mutations in their structural ampC gene, ampD gene, and omp39-40 gene. Results: A 45% and 100% rat survival rate was obtained by administration of 3.1 and 12.5 mg/kg b.i.d. of cefpirome. A significant correlation was demonstrated in the reduction of the susceptible E. cloacae isolates with %fT>MIC at days 7, 14, 22, and 29. Cefpirome E. cloacae mutants, with increased cefpirome MICs, were obtained in only four rats. Conclusions: The treatment with cefpirome resulted in less selection of derepressed mutants in comparison to ceftazidime as shown by their low number per gram of feces and in a limited number of animals.

Randomized controlled trial of cefazolin monotherapy versus cefazolin plus azithromycin single dose prophylaxis for cesarean deliveries: A developing country's perspective.

AIM: To compare the efficacy of pre-incision intravenous single doses of cefazolin versus cefazolin plus azithromycin as an antibiotic prophylaxis in cesarean delivery (CD). METHODS: This was a single-center, double blind, randomized controlled trial conducted in the PGIMER, Chandigarh. 200 women undergoing elective/emergency cesarean section were randomized. Group A received single dose of cefazolin plus placebo while Group B received single dose of cefazolin plus azithromycin. Primary outcome evaluated was occurrence of surgical site infections (SSI); secondary outcomes included incidence of febrile morbidity, UTI, endometritis, neonatal outcome, total cost of antibiotics, and duration of hospital stay in both the study arms. Descriptive statistics and χ2 tests were used for analysis of the data. RESULT: There was an overall significant reduction in the incidence of SSI (15% vs 3%; P = 0.03), endometritis (8% vs 2%; P = 0.048), and post-operative febrile morbidity (17% vs 3%; P = 0.001) with the addition of azithromycin to cefazolin. Duration of hospital stay was almost two days lesser for the cefazolin plus azithromycin group. Subgroup analysis of patients with SSI showed the age, duration of ruptured membranes, and type of anesthesia as important predictors of infection rate. Study observed statistically significant reduction in requirement of additional post operative antibiotics, phototherapy for neonates, hospital stay and cost of therapy in cefazolin plus azithromycin group (P < 0.05). CONCLUSION: Tertiary care hospitals in developing countries such as India can opt for the cefazolin plus azithromycin as antimicrobial prophylaxis during CD to maximize the efficacy as well as for decreasing the cost burden of postoperative infections.

Evaluation of evidence for pharmacokinetics-pharmacodynamics-based dose optimization of antimicrobials for treating Gram-negative infections in neonates.

BACKGROUND & OBJECTIVES: Neonates present a special subgroup of population in whom optimization of antimicrobial dosing can be particularly challenging. Gram-negative infections are common in neonates, and inpatient treatment along with critical care is needed for the management of these infections. Dosing recommendations are often extrapolated from evidence generated in older patient populations. This systematic review was done to identify the knowledge gaps in the pharmacokinetics-pharmacodynamics (PK-PD)-based optimized dosing schedule for parenteral antimicrobials for Gram-negative neonatal infections. METHODS: Relevant research questions were identified. An extensive electronic and manual search methodology was used. Potentially eligible articles were screened for eligibility. The relevant data were extracted independently in a pre-specified data extraction form. Pooling of data was planned. RESULTS: Of the 340 records screened, 24 studies were included for data extraction and incorporation in the review [carbapenems - imipenem and meropenem (n=7); aminoglycosides - amikacin and gentamicin (n=9); piperacillin-tazobactam (n=2); quinolones (n=2); third- and fourth-generation cephalosporins (n=4) and colistin nil]. For each of the drug categories, the information for all the questions that the review sought to answer was incomplete. There was a wide variability in the covariates assessed, and pooling of results could not be undertaken. INTERPRETATION & CONCLUSIONS: There is a wide knowledge gap for determining the doses of antimicrobials used for Gram-negative infections in neonates. A different profile of newborns in the developing countries could affect the disposition of antimicrobials for Gram negative infections, necessitating the generation of PK-PD data of antimicrobials in neonates from developing countries. Further, guidelines for treatment of neonatal conditions may incorporate the evidence-based PK-PD-guided dosing regimens.