Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial.

BACKGROUND: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding. METHODS: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors. RESULTS: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam. CONCLUSIONS: There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam. TRIAL REGISTRATION: clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

Treatment Options for Carbapenem- Resistant Gram-Negative Infections.

BACKGROUND: Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS: Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION: The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.

[Construction of the quantitative structure retention relationship of cefdinir related substances].

The molecular descriptors of impurities with known structure in cefdinir were calculated, selected and associated with the chromatographic retention behavior to establish a model. This quantitative structure retention relationships (QSRR) model for the related substances of cefdinir was established under specific chromatographic condition and verified by other impurities. 12 molecular descriptors were used to establish the QSRR model, F_AFRBWF, Blbn_J, SsCH3, SssCH2, SsNH2, SssNH, SssS, SHdCH2, EEM_AFc, EEM_AFpl, EEM_XFpl and Pi_MaxQ. The relativity between true values and predictions in QSRR of cefdinir is R2 = 0.9836 (n = 18), ΔRRT is no more than 0.154, as 10.17% in RRT. The results indicate that the QSRR model for the related substances of cefdinir can be used to evaluate the analysis methods for related substances and predict the chromatographic behavior of new impurities, which will provide a new way for the evaluation of the effectiveness for drug quality control.

Molecular characterization of extended-spectrum beta-lactamases and its correlation with clinical laboratory standards institute interpretive criteria for disk diffusion susceptibility testing in enterobacteriaceae isolates in Thaialnd.

We performed extended-spectrum beta-lactamase (ESBL) phenotypic testing and molecular characterization of three ESBL genes (TEM, SHV and CTX-M) and susceptibility testing by Clinical Laboratory Standards Institute (CLSI) disk diffusion method against three cephalosporins (ceftriaxone, ceftazidime, cefepime) and a cephamycin (cefoxitin) among 128 Thai Escherichia coli and 84 Thai Klebsiella pneumoniae clinical isolates. ESBL production was discovered in 62% of E. coli and 43% of K. pneumoniae isolates. All isolates susceptible to ceftriaxone were ESBL-negative. Nearly all isolates non-susceptible to ceftriaxone, ceftazidime and cefepime produced ESBL; the presence of CTX-M genes in the isolates correlated with a ceftriaxone non-susceptible phenotype. Thirty-nine of 83 isolates (47%) of ceftazidime-susceptible E. coli and 50 of 99 isolates (50.5%) of cefepime-susceptible E. coli were ESBL-producing. SHV-type beta-lactamase genes were more prevalent among K. pneumoniae than E. coli isolates. CTX-M was the major ESBL gene harbored by ESBL-producers in both E. coli and K. pneumoniae isolates. Non-CTX-M ESBL-producers were found only among K. pneumoniae isolates. This study reveals an increase in ESBL-producing Enterobacteriaceae among Thai isolates and demonstrates gaps in the current CLSI disk diffusion susceptibility guidelines; it indicates the results of ceftazidime and cefepime disk diffusion susceptibility testing using CLSI criteria should be interpreted with caution.

The comparative efficacy of two long-acting dry-cow cephalonium products in curing and preventing intramammary infections.

AIMS: To test equivalence between two different cephalonium dry-cow therapy (DCT) products with regard to the incidence of bacteriological cure of existing infections of quarters, the incidence of new intramammary infections (IMI) from 2-5 days postpartum and the incidence of clinical mastitis from drying-off to 21 days postpartum. METHODS: All cows (n=1,570) on four commercial dairy farms in Southland were eligible for inclusion. Power analysis using a variance inflation factor indicated a required minimum of 2,101 quarters per treatment group. Cows were blocked by herd, parity, previous history of mastitis and most recent somatic cell count (SCC), and then randomly allocated to either of two cephalonium treatments at the cow level, viz the treatment group (new formulation cephalonium) or the positive control group (existing reference formulation cephalonium). All quarters within a cow were assigned the same treatment. Samples collected from all quarters with a SCC ≥500,000 cells/mL at drying-off, and those with a positive culture postpartum were cultured, as well as samples from all quarters collected between 2-5 days postpartum. All cases of mastitis were recorded and sampled for culture. The risk of quarter-level incidence of bacteriological cure, IMI and clinical mastitis was modelled using a GLM and generalised estimating equation (GEE), including the effects of treatment group, age,farm, udder-health status at drying-off and length of dry period. RESULTS: For 829 infected quarters, the estimated incidence of bacteriological cure for all pathogens was 78.0 (95% CI=64.3-91.6)% for the treatment group and 75.7 (95% CI=61.6-89.8)% for the positive control group (p=0.71). Incidence of cure varied with the farm (p=0.001), type of pathogen pre-treatment (p=0.009) and log(10)SCC at drying-off (p<0.001). For 4,530 quarters, the estimated incidence of new IMI, with any pathogen, for treatment and positive control groups was 16.1 (95% CI=13.1-19.7)% and 16.0 (95% CI=13.0-19.5)% respectively (p=0.91). Incidence of IMI varied with farm (p<0.001), pathogen and SCC status before treatment (p<0.001), and length of the dry period (in days) (p<0.001). For 5,136 quarters, the estimated incidence of clinical mastitis was 1.0 (95% CI=0.5-1.7)% in the treatment group and 1.1 (95% CI=0.6-2.0)% in the positive control group (p=0.64). CONCLUSIONS: Use of the two different cephalonium products at drying-off in four dairy herds in Southland resulted in equivalence with respect to incidence of bacteriological cure of existing infections, incidence of new IMI postpartum, and incidence of clinical mastitis in early lactation.

Validation of the SL3 beta-Lactam Test for screening milk in compliance with U.S. pasteurized milk ordinance: performance tested method 040701.

The SL3 beta-Lactam Test is a 3 min, receptor-based lateral flow Rapid One Step Assay (ROSA) that detects 5 of 6 beta-lactam drugs approved for dairy cattle in the United States. The method was evaluated through the AOAC Research Institute Performance-Tested Method program following a U.S. Food and Drug Administration protocol. Three combined lots detected penicillin G 4.2 parts per billion (ppb), ampicillin 8.7 ppb, amoxicillin 7.8 ppb, cephapirin 16.0 ppb, and ceftiofur (total metabolites) 51 ppb at least 90% of the time, with 95% confidence as determined by dose response probit analysis. These detection levels are less than safe level/tolerances but not more than 50% less. Lot repeatability was within 20%. Incurred residues were detected comparably or more sensitively to fortified samples due to the cumulative effect of biologically active metabolites. There were no interferences from somatic cells at 1 M/mL, bacterial cells 500 000 colony-forming units/mL, or 30 other non-beta-lactam drugs. These performances met approval conditions of the National Conference on Interstate Milk Shipments. Ruggedness conditions were incorporated into public health procedures for annual laboratory proficiency and certification.

Isolation, structural elucidation and characterization of impurities in Cefdinir.

Three unknown impurities in Cefdinir bulk drug at levels below 0.2% (ranging from 0.05 to 0.2%) have been detected by high performance liquid chromatography (HPLC). These impurities were isolated from crude sample of Cefdinir using preparative HPLC. Based on the spectral data (NMR, IR and MS) the structures of these impurities were characterized as (6R, 7R)-7-[(z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-5-oxide (I). (6R, 7R)-7-[(z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-8-oxo-3-vinyl-5-thia-1-azabi-cyclo [4.2.0] oct-3-ene-2-carboxylic acid (II). (6R, 7R)-7-[(z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-8-oxo-3-methyl-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid (III), respectively. The origin and structural elucidation of all impurities have been discussed.

Development and in-house validation of a microbiological assay for determination of cefepime in injectable preparations.

Cefepime is a new parenteral cephalosporin that has been described as a fourth-generation, broad-spectrum antibiotic. This paper reports the development and in-house validation of an agar diffusion bioassay using a cylinder-plate method for the determination of cefepime in powder for injection. The validation performed yielded good results in terms of linearity, precision, accuracy, and robustness. The assay is based on the inhibitory effect of cefepime upon the strain of Micrococcus luteus ATCC 10240 used as the test microorganism. The results of assays were treated statistically by analysis of variance (ANOVA) and were found to be linear (r = 0.99993) in the selected range of 8.0-32.0 microg/mL; precise [repeatability: relative standard deviation (RSD) = 1.39%, intermediate precision: between-day RSD = 1.77%, and between-analyst RSD = 1.97%] and accurate. Comparison of bioassay and liquid chromatography by ANOVA showed no significant difference between methodologies. The results demonstrated the validity of the proposed bioassay, which is a simple and useful alternative methodology for cefepime determination in routine quality control.

1H and 13 C spectral assignments of 7beta-(cinnamoyl-substituted)amino-3-acetoxymethyl-cephalosporins.

The (1)H and (13)C spectroscopic data for 7beta-(cinnamoyl-substituted)amino-3-acetoxymethyl-cephalosporins were fully assigned by a combination of one- and two-dimensional experiments. Substitution on the aromatic ring and on the double-bond alpha-position of the cinnamoyl moiety has little influence on the spectroscopic properties of the 7beta-aminocephalosporanic acid parent moiety.

Single low-dose ceftriaxone for the treatment of gonococcal ophthalmia--implications for the national programme for the syndromic management of sexually transmitted diseases.

We prospectively analysed a total of 21 baby-mother pairs with culture-proven Neisseria gonorrhoeae treated with a single low dose of ceftriaxone, namely 62.5 mg for babies and 125 mg for mothers respectively. N. gonorrhoeae was eradicated from all babies' eyes with no residual damage, as well as from the mothers' cervixes. A single low dose of 62.5 mg ceftriaxone has emerged as the treatment of choice for gonococcal ophthalmia neonatorum because of its excellent activity against N. gonorrhocae, including penicillinase-producing strains.

Antimicrobial activity of U-76,252 (CS-807), a new orally administered cephalosporin ester, including recommendations for MIC quality control.

U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807), was tested against 4,742 fresh clinical isolates from four large medical centers. U-76,253A was very active against nearly all species of Enterobacteriaceae (87.7% inhibited at less than or equal to 4.0 micrograms/ml). Staphylococcus spp., and the streptococci. The U-76,253A spectrum was superior to the comparison orally administered cephalosporins (cephalexin, cephradine, cefaclor). Pseudomonas spp., Acinetobacter spp., and the enterococci were resistant to U-76,253A and the other tested drugs. Broth microdilution MIC quality control (QC) limits were established for U-76,253A in a multilaboratory investigation using a minimum of 125 MIC determinations per organism. The following MIC QC ranges were recommended; Escherichia coli (ATCC 25922) = 0.25-1.0 micrograms/ml, Staphylococcus aureus (ATCC 29213) = 2.0-4.0 micrograms/ml and Pseudomonas aeruginosa (ATCC 27853) = greater than 32 micrograms/ml.

Particulate-matter content of 11 cephalosporin injections: conformance with USP limits.

The particulate-matter content of 11 dry-powder cephalosporin injections was determined using a modified version of the official United States Pharmacopeial Convention (USP) method for particulate matter in small-volume injections (SVIs). Ten vials of each cephalosporin product were each constituted with 10 mL of Water for Injections BP that had been filtered through a 0.22-micron membrane. The pooled contents of the 10 vials for each product were allowed to stand under reduced pressure to ensure removal of gas bubbles. Particulate-matter content was determined using a HIAC/Royco particle counter on six 10-mL samples obtained from the pooled solutions for each product. All solution preparation and particle counting was performed in a horizontal-laminar-airflow hood. Modifications of the USP method used in this study included the use of six rather than two samples from each pooled solution, the addition of diluent to the injections through the rubber closure with a needle instead of into the open container, and changes in the degassing method. Particle counts for all products examined were lower than USP limits for SVIs. All but two products contained less than 15% of USP limits for particles greater than or equal to 10 microns in effective diameter and particles greater than or equal to 25 microns in effective diameter. The standard USP method for degassing (standing for two minutes) was inadequate. Application of reduced pressure for up to 10 minutes was necessary for thorough degassing of products.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefuroxime, cefamandole, cefoxitin, and cephalothin in vitro susceptibility tests: reassessment of the "class representative" concept, confirmation of disk interpretive criteria, and proposed quality control guidelines.

The relationship of cefuroxime in vitro susceptibility tests to similar cephalosporins (cefamandole, cefoxitin, and cephalothin) was evaluated using 396 recent clinical isolates. The previously published interpretive criteria of greater than or equal to 18 mm (less than or equal to 8.0 micrograms/mL) = susceptible and less than or equal to 14 mm (greater than or equal to 32 micrograms/mL) = resistant for each drug were considered appropriate. The results of all study methods demonstrated cefuroxime to be slightly less active than cefamandole against most species, yet both drugs possessed nearly identical antimicrobial spectra. Cephalothin and cefoxitin were confirmed to have spectra significantly different from cefamandole and from each other, thus requiring separate testing. The application of the "class representative" concept to cefuroxime and cefamandole seems justified. Use of a 30-micrograms cefuroxime disk yielded the best predictive results and minimized the number of false-susceptible (very major) interpretive errors. Quality control guidelines are presented in a tentative form for cefuroxime, and modifications in the cephalothin and cefamandole zone limits are suggested.