Broad-spectrum Beta-lactam Research Articles

Empirical fluoroquinolones versus broad-spectrum beta-lactams for Gram-negative bloodstream infections in the absence of antimicrobial resistance risk factors

ObjectivesIncreasing antimicrobial resistance rates limit empirical antimicrobial treatment options for Gram-negative bloodstream infections (GN-BSI). However, antimicrobial resistance may be predicted based on patient-specific risk factors using precision medicine concepts. This retrospective, 1:2 matched cohort examined clinical outcomes in hospitalized adults without major risk factors for antimicrobial resistance receiving empirical fluoroquinolones or broad-spectrum beta-lactams (BSBL) for GN-BSI at Prisma Health-Midlands hospitals in Columbia, SC, USA from January 2010 through June 2015. MethodsMultivariable logistic regression was used to examine early treatment failure at 72–96 h from GN-BSI. Cox proportional hazards regression was used to examine 28-day mortality and hospital length of stay (HLOS). ResultsAmong 74 and 148 patients receiving empirical fluoroquinolones and BSBL for GN-BSI, respectively, median age was 68 years, 159 (72%) were women, and 152 (68%) had a urinary source of infection. Early treatment failure rates were comparable in fluoroquinolone and BSBL groups (27% vs. 30%, respectively, odds ratio 0.82, 95% confidence intervals [CI] 0.43–1.54, P = 0.53), as well as 28-day mortality (8.9% vs. 9.7%, respectively, hazards ratio [HR] 0.74, 95% CI 0.26–1.90, P = 0.54). Median HLOS was 6.1 days in the fluoroquinolone group and 7.1 days in the BSBL group (HR 0.73, 95% CI 0.54–0.99, P = 0.04). Transition from intravenous to oral therapy occurred sooner in the fluoroquinolone group than in the BSBL group (3.0 vs. 4.9 days, P < 0.001). ConclusionsIn the absence of antimicrobial resistance risk factors, fluoroquinolones provide an additional empirical treatment option to BSBL for GN-BSI. Shorter HLOS in the fluoroquinolone group may be due to earlier transition from intravenous to oral antimicrobial therapy.

Trends in and Predictors of Carbapenem Consumption across North American Hospitals: Results from a Multicenter Survey by the MAD-ID Research Network.

We sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013. Consumption was tabulated as defined daily doses (DDD) or as days of therapy (DOT) per 1,000 patient days (PD). Multivariate mixed-effects models were explored, and final model goodness of fit was assessed by regressions of observed versus predicted values and residual distributions. A total of 20 acute-care hospitals responded. The centers treated adult patients (n = 19/20) and pediatric/neonatal patients (n = 17/20). The majority of the centers were nonprofit (n = 17/20) and not affiliated with medical/teaching institutions (n = 11/20). The median (interquartile range [IQR]) carbapenem consumption rates were 38.8 (17.4 to 95.7) DDD/1,000 PD and 29.7 (19.2 to 40.1) DOT/1,000 PD overall. Carbapenem consumption was well described by a multivariate linear mixed-effects model (fixed effects, R2 = 0.792; fixed plus random effects, R2 = 0.974). Carbapenem consumption increased by 1.91-fold/quarter from 48.6 DDD/1,000 PD (P = 0.004) and by 0.056-fold/quarter from 45.7 DOT/1,000 PD (P = 0.93) over the study period. Noncarbapenem consumption was independently related to increasing carbapenem consumption (beta = 0.31 for increasing noncarbapenem beta-lactam consumption; P < 0.001). Regular antibiogram publication and promotion of conversion from intravenous (i.v.) to oral (p.o.) administration independently affected carbapenem consumption rates. In the final model, 58.5% of the observed variance in consumption was attributable to between-hospital differences. Rates of carbapenem consumption across 20 North American hospitals differed greatly, and the observed differences were correlated with hospital-specific demographics. Additional studies focusing on the drivers of hospital-specific carbapenem consumption are needed to determine whether these rates are justifiable.

Probabilistic chemotherapy in knee and hip replacement infection: the place of linezolid.

Prosthetic joint infection (PJI) can occur with a wide range of microorganisms and clinical features. After replacement surgery of prosthetic joint, prescription of probabilistic broad-spectrum antimicrobial therapy is usual, while awaiting microbial culture results. The aim of our study was to describe the antibiotic susceptibility of microorganisms isolated from hip and knee PJI. The data were collected to determine the best alternative to the usual combination of piperacillin-tazobactam (TZP) or cefotaxime (CTX) and vancomycin (VAN). Based on a French prospective, multicenter study, we analyzed microbiological susceptibility to antibiotics of 183 strains isolated from patients with confirmed hip or knee PJI. In vitro susceptibility was evaluated: TZP+VAN, TZP+linezolid (LZD), CTX+VAN, and CTX+LZD. We also analyzed resistance to different antibiotics commonly used as oral alternatives. Among the 183 patients with PJI, 62 (34%) had a total knee prosthesis, and 121 (66%) a hip prosthesis. The main identified bacteria were Staphylococcus aureus (32.2% of isolates), coagulase-negative staphylococci (27.3%), Enterobacteriaceae (14.2%), and Streptococcus (13.7%). Infections were polymicrobial for 28 (15.3%) patients. All combinations were highly effective: CTX+VAN, CTX+LZD, TZP+VAN, and TZP+LZD (93.4%, 94%, 98.4%, and 98.9% of all cases respectively). Use of LZD instead of VAN in combination with a broad-spectrum beta-lactam covers almost all of the bacteria isolated in PJI. This association should be considered in probabilistic chemotherapy, as it is particularly easy to use (oral administration and no vancomycin monitoring).

Novel insights into the chemistry of an old medicine: A general degradative pathway for penicillins from a piperacillin/tazobactam stability study

Piperacillin is a broad spectrum beta-lactam antibiotic used in combination with tazobactam for hospital-related bacterial infections. The reconstituted solutions must respect the sub-visible and visible particles specifications. It was claimed that the reformulation containing EDTA/sodium citrate was able to control the formation of an insoluble impurity responsible for the formation of particulate matter observed using Ringer Lactate as diluent. The nature of the impurities formed during the degradative process of piperacillin/tazobactam combination has been herein investigated, by exploring the effect of added excipients and pH variations. The exact structure of the isolated dimeric impurity, the penicilloic acid-piperacillin dimer, was determined through complete characterization, allowing to propose a novel degradative general pathway for beta-lactam antibiotics. The presence of EDTA resulted unnecessary to contain the formation of the insoluble impurity, since the use of sodium citrate alone allowed to avoid this drawback. Finally, the proposed mechanism was successfully applied to the design of a novel, easy and high purity procedure for the synthesis of the acetylated penicilloic acid, known related substance of piperacillin.

Impact of Levofloxacin for the Prophylaxis of Bloodstream Infection on the Gut Microbiome in Patients With Hematologic Malignancy

BackgroundWe evaluated the differential impact of levofloxacin administered for the prophylaxis of bloodstream infections compared with broad-spectrum beta-lactam (BSBL) antibiotics used for the treatment of neutropenic fever on the gut microbiome in patients with hematologic malignancy.MethodsStool specimens were collected from patients admitted for chemotherapy or stem cell transplant in the setting of the evaluation of diarrhea from February 2017 until November 2017. Microbiome characteristics were compared among those exposed to levofloxacin prophylaxis vs those who received BSBL antibiotics.ResultsSixty patients were included, most with acute myeloid leukemia (42%) or multiple myeloma (37%). The gut microbiome of patients with BSBL exposure had significantly reduced Shannon’s alpha diversity compared with those without (median [interquartile range {IQR}], 3.28 [1.73 to 3.71] vs 3.73 [3.14 to 4.31]; P = .01). However, those with levofloxacin exposure had increased alpha diversity compared with those without (median [IQR], 3.83 [3.32 to 4.36] vs 3.32 [2.35 to 4.02]; P = .03). Levofloxacin exposure was also associated with a trend toward lower risk of dominance of non-Bacteroidetes genera compared with those without levofloxacin exposure (3 [14%] vs 15 [38%]; P = .051).ConclusionsThe impact of antibiotics on the gut microbiome varies by class, and levofloxacin may disrupt the gut microbiome less than BSBLs in this patient population.

Prospective Cohort Study of the Tolerability of Prosthetic Joint Infection Empirical Antimicrobial Therapy.

The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011 to 2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis. The EAT of the 333 included patients (median age, 69.8 years; interquartile range [IQR], 59.3 to 79.1 years) mostly relies on vancomycin (n = 229, 68.8%), piperacillin-tazobactam (n = 131, 39.3%), and/or third-generation cephalosporins (n = 50, 15%). Forty-two patients (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥ 3). The use of vancomycin (odds ratio [OR], 6.9; 95% confidence interval [95%CI], 2.1 to 22.9), piperacillin-tazobactam (OR, 3.7; 95%CI, 1.8 to 7.2), or the combination of both (OR, 4.1; 95%CI, 2.1 to 8.2) were the only AE predictors. Acute kidney injury (AKI) was the most common AE (n = 25; 51.0% of AE) and was also associated with the use of the vancomycin and piperacillin-tazobactam combination (OR, 6.7; 95%CI, 2.6 to 17.3). A vancomycin plasma overexposure was noted in nine (37.5%) of the vancomycin-related AKIs only. Other vancomycin-based therapies were significantly less at risk for AE and AKI. The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and the piperacillin-tazobactam combination. These results corroborate recent findings suggesting a synergic toxicity of these drugs in comparison to vancomycin-cefepime, which remains to be evaluated in PJI. (This study has been registered at ClinicalTrials.gov under identifier NCT03010293.).

Evaluation of broad-spectrum beta-lactam prescriptions (except carbapenems) in a French teaching hospital

ObjectivesWe aimed to assess broad-spectrum beta-lactam prescriptions (except carbapenems) in a French teaching hospital and the impact of controlled dispensing, antimicrobial management team, and antibiotic treatment reassessment on Day 2–3. Patients and methodsWe performed a point-prevalence study in all hospital units and analyzed curative antibiotic broad-spectrum beta-lactam prescriptions. The assessment focused on indication, dosing, combinations, revaluation on Day 2–3, and treatment duration. ResultsSixty-seven broad-spectrum beta-lactam prescriptions were identified. The main prescriptions were amoxicillin-clavulanic acid (37%, n=25), ceftriaxone (36%, n=24), and piperacillin-tazobactam (16%, n=11). Indications, doses, combinations, and reassessment on Day 2–3 were appropriate, respectively 90% (n=60), 96% (n=64), 94% (33/35 combinations), and 88% (n=59). However, appropriate treatment durations amounted to only 63% (n=42). The benefit of controlled dispensing was observed in terms of overall antibiotic treatment duration: 86% versus 51% adequacy for uncontrolled dispensing of beta-lactams (P=0.02). The antimicrobial management team improved the antibiotic treatment duration: 73% of appropriate durations versus 44% for beta-lactams not monitored by the team, but this difference was not significant. ConclusionBroad-spectrum beta-lactams were usually well prescribed but the adequacy of treatment duration could be improved, especially by reinforcing the monitoring of prescriptions.

Faecal colonization of E. coli and Klebsiella spp. producing extended-spectrum beta-lactamases and plasmid-mediated AmpC in Mozambican university students

BackgroundIn recent years, the world has seen a surge in Enterobacteriaceae resistant to broad-spectrum beta-lactam antibiotics due to the production of extended-spectrum beta-lactamases (ESBLs) or plasmid-mediated AmpC (pAmpC) enzymes. Data on the epidemiology of cephalosporin-resistant Enterobacteriaceae in Sub-Saharan Africa are still limited.MethodsTwo hundred seventy-five non-repetitive stool samples were collected from Mozambican university students of both sexes. Samples were cultured on MacConkey agar with and without ceftriaxone (1 mg/L) for selection of third-generation cephalosporin-resistant isolates, which were subjected to antimicrobial susceptibility testing by disc diffusion, characterization of resistance genes by PCR and ERIC-PCR analysis for strain clonality.ResultsAmong the 275 students, 55 (20%) carried a total of 56 E. coli (n = 35) and Klebsiella spp. (n = 21) isolates resistant to ceftriaxone and phenotypically positive for ESBL- and/or pAmpC-production. Forty-three percent of the isolates (24/56) contained only ESBL genes, 11% (6/56) only pAmpC genes, and 36% (20/56) both ESBL and pAmpC genes. The remaining six isolates were negative for the CTX-M/pAmpC genes included in the test panel. E. coli and Klebsiella spp. combined demonstrated 70% resistance to tetracycline and co-trimoxazole, 63% to ceftazidime and 34% to ciprofloxacin. In total, 89% of ESBL/pAmpC-positive isolates were defined as multi-resistant by being resistant to three or more antibiotic classes. ERIC-PCR fingerprinting demonstrated low similarity among isolates. None of the participants reported recent hospitalization and just 12.5% had taken antibiotics 3 months prior to the study.ConclusionThis study demonstrated 20% colonization with multi-resistant E. coli and Klebsiella spp. among Mozambican students with a diversity of ESBL and pAmpC genes. Colonization was not related to prior hospitalization or antimicrobial consumption.

Clinically Relevant ESBL-Producing K. pneumoniae ST307 and E. coli ST38 in an Urban West African Rat Population.

High-risk ESBL-producing Enterobacteriaceae (ESBL-E) have been described in wild birds and rodents worldwide. Rats are of special interest not only due to their indicator role for environmental pollution with multi-resistant bacteria but also as possible infection source. Data on the presence of high-risk ESBL-E in urban wildlife from Africa remain scarce, however. Twenty-nine animals from three different rat (Rattus) species were captured in the city of Conakry (Guinea, West Africa) in 2015. Rectal swabs were analyzed for ESBL-E using selective media. Species typing and phenotypic antimicrobial resistance analysis to broad-spectrum beta-lactams and other classes of antimicrobials was performed for Enterobacteriaceae-like isolates using the VITEK®2 system (BioMérieux, Germany). Confirmed ESBL-producing E. coli and K. pneumoniae were whole-genome sequenced and resistance genes, phylogenetic background and genes related to bacterial fitness and virulence were analyzed. In total, six of twenty-nine rats (20%) carried ESBL-E (K. pneumoniae and E. coli). All ESBL-producers were multi-drug resistant with blaCTX−M−15 as the dominating ESBL-type. Interestingly, ESBL-associated clonal lineages E. coli ST38 and K. pneumoniae ST307 were found. The ESBL-plasmid in K. pneumoniae ST307 revealed high sequence similarities to pKPN3-307_TypeC, a >200 kbp IncFII plasmid originating from a human clinical ST307 isolate. This was in contrast to the core genome: the rat isolate was distantly related to the human clinical ST307 isolate (27 SNPs/Mbp). In addition, we identified π-fimbrial, capsule 2, and glycogen synthesis clusters in the rodent ST307 isolate, whose involvement in the adaptation to survival outside the host and in human urinary tracts has been suggested. Our results demonstrate the presence of clinically relevant, ESBL-producing K. pneumoniae ST307 and E. coli ST38 clonal lineages in an urban West African rat population. The human community is likely the initial source of ESBL-E however, rats might function as infection source and transmission hub, accelerated by frequent interactions at a human-wildlife interface.

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean ± standard deviation parameter estimates were 8.38 ± 9.91 L/h for drug clearance and 25.54 ± 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC ≤16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.

Ultrahigh antibacterial efficacy of meropenem-loaded chitosan nanoparticles in a septic animal model

Antimicrobial resistance is one of the most significant health challenges worldwide. Meropenem is a broad spectrum beta-lactam antibiotic that possesses high activity against Gram-positive and Gram-negative bacteria. However, it has a short plasma half-life, and thus requiring frequent administration of high doses. For the first time, meropenem-loaded chitosan nanoparticles were prepared and evaluated as a potential tool to overcome antimicrobial resistance and to improve pharmacokinetics of the drug. Spherical nanosized particles were prepared and demonstrated ultrahigh encapsulation efficiency of meropenem (i.e. 76.3%). The nanoparticles could be stored in a freeze-dried powdered form while maintaining their physicochemical characteristics. In vitro, higher antibacterial activities of the drug-loaded nanoparticles were observed against methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, as compared to the free drug. The nanoparticles were then tested in a septic rat model of Klebsiella pneumoniae and showed exceptional improvement of survival and bacterial clearance, as compared to the animals treated with the free drug. Hence, meropenem-loaded chitosan nanoparticles might have great potential for overcoming antimicrobial resistance.

Clinical benefits of antimicrobial de-escalation in adults with community-onset monomicrobial Escherichia coli, Klebsiella species and Proteus mirabilis bacteremia

The clinical benefits of an antimicrobial de-escalation strategy were compared with those of a no-switch strategy in bacteremic patients. Adults with community-onset monomicrobial Escherichia coli, Klebsiella species and Proteus mirabilis bacteremia treated empirically using broad-spectrum beta-lactams, including third-generation cephalosporins (GCs), fourth-GC or carbapenems, were treated definitively with first- or second-GCs (de-escalation group), the same regimens as empirical antibiotics (no-switch group), or antibiotics with a broader-spectrum than empirical antibiotics (escalation group). The eligible 454 adults were categorized as the de-escalation (231 patients, 50.9%), no-switch (177, 39.0%), and escalation (46, 10.1%) groups. Patients with de-escalation therapy were more often female, had less critical illness and fatal comorbidity, and had a higher survival rate than patients in the other two groups. After propensity score matching in the de-escalation and no-switch groups, critical illness at onset (Pitt bacteremia score ≥ 4; 16.5% vs. 12.7%; P = 0.34) or day 3 (2.5% vs. 2.5%; P = 1.00), fatal comorbidity (16.5% vs. 21.5%; P = 0.25), time to defervescence (4.6 vs. 4.7 days; P = 0.89), hospital stays (11.5 vs. 10.3 days; P = 0.13) and 4-week crude mortality rate (4.4% vs. 4.4%; P = 1.00) were similar. However, lower antibiotic cost (mean: 212.1 vs. 395.6 US$, P < 0.001) and fewer complications of bloodstream infections due to resistant pathogens (0% vs. 5.1%, P = 0.004) were observed in the de-escalation group. De-escalation to narrower-spectrum cephalosporins is safe and cost-effective for adults with community-onset EKP bacteremia stabilized by empirical broad-spectrum beta-lactams.

Evaluation of early antimicrobial therapy adaptation guided by the BetaLACTA\xae test: a case-control study

BackgroundRapid diagnostic tests detecting microbial resistance are needed for limiting the duration of inappropriateness of empirical antimicrobial therapy (EAT) in intensive care unit patients, besides reducing the use of broad-spectrum antibiotics. We hypothesized that the betaLACTA® test (BLT) could lead to early increase in the adequacy of antimicrobial therapy.MethodsThis was a case-control study. Sixty-one patients with BLT-guided adaptation of EAT were prospectively included, and then matched with 61 “controls” having similar infection characteristics (community or hospital-acquired, and source of infection), in whom EAT was conventionally adapted to antibiogram results. Endpoints were to compare the proportion of appropriate (primary endpoint) and optimal (secondary endpoint) antimicrobial therapies with each of the two strategies, once microbiological sample culture results were available.ResultsCharacteristics of patients, infections and EAT at inclusion were similar between groups. Nine early escalations of EAT occurred in the BLT-guided adaptation group, reaching 98% appropriateness vs. 77% in the conventional adaptation group (p < 0.01). The BLT reduced the time until escalation of an inappropriate EAT from 50.5 (48–73) to 27 (24–28) hours (p < 0.01). Seventeen early de-escalations occurred in the BLT-guided adaptation group, compared to one in the conventional adaptation group, reducing patients’ exposure to broad-spectrum beta-lactam such as carbapenems. In multivariate analysis, use of the BLT was strongly associated with early appropriate (OR = 18 (3.4–333.8), p = 0.006) and optimal (OR = 35.5 (9.6–231.9), p < 0.001) antimicrobial therapies. Safety parameters were similar between groups.ConclusionsOur study suggests that a BLT-guided adaptation strategy may allow early beta-lactam adaptation from the first 24 hours following the beginning of sepsis management.

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

IntroductionWithin the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of...

Structure-based virtual screening to identify the beta-lactamase CTX-M-9 inhibitors: An in silico effort to overcome antibiotic resistance in E. coli

Recently, the quick spreads of broad-spectrum beta-lactams antibiotic resistance in pathogenic strains of bacteria have become a major global health problem. These new emerging resistances cause ineffectiveness of antibiotics and increasing the severity of diseases and treatment costs. Among different and diverse resistance targets, we chose a class A beta lactamase, CTX-M-9, with the aim of identifying new chemical entities to be used for further rational drug design. Based on this purpose, a set of 5000 molecules from the Zinc database have been screened by docking experiments using AutoDock Vina software. The best ranked compound, with respect of the previously proved inhibitor compound 19, was further tested by molecular dynamics (MD) simulation. Our molecular modeling analysis demonstrates that ZINC33264777 has ideal characteristics a potent beta lactamase CTX-M-9 inhibitor. In the free form of beta lactamase, NMR relaxation studies showed the extensive motions near the active site and in the Ω-loop. However, our molecular dynamics studies revealed that in the compound 1: beta lactamase complex, the flexibility of Ω-loop was restricted.

Restrictive antibiotic stewardship associated with reduced hospital mortality in gram-negative infection.

: Antimicrobial stewardship has an important role in the control of Clostridium difficile infection (CDI) and antibiotic resistance. An important component of UK stewardship interventions is the restriction of broad-spectrum beta-lactam antibiotics and promotion of agents associated with a lower risk of CDI such as gentamicin. While the introduction of restrictive antibiotic guidance has been associated with improvements in CDI and antimicrobial resistance, evidence of the effect on outcome following severe infection is lacking. : In 2008, Glasgow hospitals introduced a restrictive antibiotic guideline. A retrospective before/after study assessed outcome following Gram-negative bacteraemia in the 2-year period around implementation. : Introduction of restrictive antibiotic guidelines was associated with a reduction in utilization of ceftriaxone and co-amoxiclav and an increase in amoxicillin and gentamicin. Approximately 1593 episodes of bacteremia were included in the study. The mortality over 1-year following Gram-negative bacteraemia was lower in the period following guideline implementation (RR 0.852, P = 0.045). There was no evidence of a difference in secondary outcomes including ITU admission, length of stay, readmission, recurrence of bacteraemia and need for renal replacement therapy. There was a fall in CDI (RR 0.571, P = 0.014) and a reduction in bacterial resistance to ceftriaxone and co-amoxiclav but no evidence of an increase in gentamicin resistance after guideline implementation. : Restrictive antibiotic guidelines were associated with a reduction in CDI and bacterial resistance but no evidence of adverse outcomes following Gram-negative bacteraemia. There was a small reduction in one year mortality.

Detection of various beta lactamases in gram negative bacteria and their resistance pattern in northern India

Background: Resistance to broad spectrum beta lactam antibiotics due to ESBL/AmpC/MBL enzymes is an increasing problem worldwide. Estimation of their prevalence in the area is essential to formulate an effective antimicrobial policy for a particular hospital/area. Aim: The present study was done to know the prevalence of ESBL/AmpC/MBL in gram negative organisms isolated from clinical samples and their susceptibility pattern in a tertiary care hospital in northern India. Methods: Total of 160 isolates of gram negative organisms from clinical specimens were screened for the presence of various beta lactamases by standard phenotypic methods and their antibiotic susceptibility pattern to conventionally used antibiotics was determined by disc diffusion method as per CLSI guidelines. Results: 118 gram negative isolates showing reduced susceptibility to third generation cephalosporin’s were screened for ESBL/ AmpC/ MBL production. Beta lactamase production was seen in 74 out of the 160 gram negative isolates obtained from different samples. ESBL production alone or in combination with AmpC/MBL is seen in 60 isolates. ESBL/ AmpC and ESBL/ MBL coproduction was seen in 9(5.6%) and 3(1.9%) of the isolates respectively. Multi drug resistance was significantly higher in beta lactamase producers than non lactamase producers. Conclusions: There is need for continuous surveillance in the hospitals for the detection of various beta lactamases or resistant strains. Strict guidelines should be followed for antibiotic therapy so as to reduce burden of antibiotic resistance. Further phenotypic and genotypic studies should be undertaken to know the resistance pattern in bacteria.

Stability of amoxicillin and amoxicillin/clavulanic acid reconstituted in isotonic saline

An increasing proportion of intensive care units use extended or continuous infusion when administering broad spectrum beta-lactam antibiotics. Extended or continuous infusions increase pharmacokinetic/pharmacodynamic target attainment and are associated with improved outcomes for critically ill patients. 1,2 After identification of the causative microorganism, antimicrobial therapy may be adapted to the susceptibility profile of the microorganism. Use of focussed, narrower-spectrum agents reduces selection pressure for resistant pathogens. This process, known as antibiotic de-escalation, is an important element in antibiotic stewardship programmes. 3,4 Among other antibiotics, amoxicillin/clavulanic acid is frequently used in de-escalation from broader spectrum betalactam antibiotics. Currently extended and continuous infusions of amoxicillin/clavulanic acid are not used. However, a recent population pharmacokinetic study of amoxicillin/clavulanic acid in critically ill patients shows that higher dosages and alternative dosing strategies such as prolonged infusion may

Previous Antibiotic Exposure Increases Risk of Infection with Extended-Spectrum-β-Lactamase- and AmpC-Producing Escherichia coli and Klebsiella pneumoniae in Pediatric Patients.

The objective of this study was to determine whether antibiotic exposure is associated with extended-spectrum-beta-lactamase- or AmpC-producing Escherichia coli or Klebsiella pneumoniae infections in children. We collected extended-spectrum-beta-lactamase- or AmpC-producing E. coli or K. pneumoniae isolates and same-species susceptible controls from normally sterile sites of patients aged ≤21 years, along with associated clinical data, at four free-standing pediatric centers. After controlling for potential confounders, the relative risk of having an extended-spectrum-beta-lactamase-producing isolate rather than a susceptible isolate was 2.2 times higher (95% confidence interval [CI], 1.49 to 3.35) among those with antibiotic exposure in the 30 days prior to infection than in those with no antibiotic exposure. The results were similar when analyses were limited to exposure to third-generation cephalosporins, other broad-spectrum beta-lactams, or trimethoprim-sulfamethoxazole. Conversely, the relative risk of having an AmpC-producing versus a susceptible isolate was not significantly elevated with any antibiotic exposure in the 30 days prior to infection (adjusted relative risk ratio, 1.12; 95% CI, 0.65 to 1.91). However, when examining subgroups of antibiotics, the relative risk of having an AmpC-producing isolate was higher for patients with exposure to third-generation cephalosporins (adjusted relative risk ratio, 4.48; 95% CI, 1.75 to 11.43). Dose-response relationships between antibiotic exposure and extended-spectrum-beta-lactamase-producing or AmpC-producing isolates were not demonstrated. These results reinforce the need to study and implement pediatric antimicrobial stewardship strategies, and they indicate that epidemiological studies of third-generation cephalosporin-resistant E. coli and K. pneumoniae isolates should include resistance mechanisms when possible.

Impact of microbiology cascade reporting on antibiotic de-escalation in cefazolin-susceptible Gram-negative bacteremia

Cascade reporting (CR) involves reporting the susceptibilities of broad-spectrum agents only when the organism is resistant to more narrow-spectrum agents. The purpose of this study is to evaluate the impact of CR on antibiotic de-escalation practices and to characterize the impact of CR on clinical outcomes. CR rules were implemented in the microbiology laboratory at Atlantic Health System (AHS)in June 2013. A retrospective chart review was conducted at two community teaching hospitals in adult patients who had a blood culture positive for a Gram-negative organism susceptible to cefazolin and who were empirically treated with broad-spectrum beta-lactam (BSBL) antibiotics. De-escalation practices were compared in the pre-CR (July 2012-December 2012) and post-CR (July 2013-December 2013) periods. The primary endpoint was the percentage of patients whose BSBL agent was de-escalated to agents listed on the post-CR antibiotic susceptibility report within 48h of the final report. Secondary endpoints include the difference in pre-CR and post-CR periods in terms of hospital length of stay, in-hospital mortality, 30-day readmission, Clostridium difficile infections, and re-initiation of a BSBL agent within 7days. A total of 73 patients were included; 31 in the pre-CR and 42 in the post-CR period. Patients had similar baseline characteristics. Therapy was de-escalated in 48% of pre-CR vs 71% of post-CR patients (p = 0.043). No significant differences were observed in secondary endpoints between patients in the pre-CR and post-CR periods. CR resulted in significant improvements in de-escalation practices without affecting safety outcomes.