Ciprofloxacin use and susceptibility of Gram-negative organisms to quinolone and non-quinolone antibiotics

A Trust strategy to reduce ciprofloxacin use was implemented at a University hospital. This study aimed to investigate whether the susceptibility of Gram-negative organisms (GNO) to alternative antimicrobials (co-amoxiclav, doxycycline, aztreonam, piperacillin/tazobactam, meropenem and gentamicin) changed, and whether there was any relationship between GNO susceptibility to these antimicrobials and ciprofloxacin usage.

Depletion of four nitrofuran antibiotics and their tissue-bound metabolites in porcine tissues and determination using LC-MS/MS and HPLC-UV

Depletion of the nitrofuran antibiotics furazolidone, furaltadone, nitrofurantoin and nitrofurazone and their tissue-bound metabolites AOZ, AMOZ, AHD and SEM from pig muscle, liver and kidney tissues is described. Groups of pigs were given feed medicated with one of the nitrofuran drugs at a therapeutic concentration (400 mg kg(-1)) for ten days. Animals were slaughtered at intervals and tissue samples collected for analysis for six weeks following withdrawal of medicated feed. These samples were analysed both for parent nitrofurans (using LC-MS/MS and HPLC-UV), and for tissue-bound metabolites (using LC-MS/MS). The parent drugs were detectable only sporadically and only in pigs subjected to no withdrawal period whatsoever. This confirms the instability of the four major nitrofuran antibiotics in edible tissues. In contrast, the metabolites accumulated to high concentrations in tissues (ppm levels) and had depletion half lives of between 5.5 and 15.5 days. The metabolites of all four drugs were still readily detectable in tissues six weeks after cessation of treatment. This emphasizes the benefits of monitoring for the stable metabolites of the nitrofurans.

Stability studies of the metabolites of nitrofuran antibiotics during storage and cooking

Nitrofuran antibiotics cannot be used in food production within the European Union because of their potential health risks to consumers. The recent discovery of their widespread use in global food industries and the finding of semicarbazide in baby food as a result of packaging contamination have focused attention on the toxicity and stability of these drugs and their metabolites. The stability of the nitrofuran marker residues 3-amino-2-oxazolidinone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidone (AMOZ), 1-aminohydantoin (AHD) and semicarbazide (SEM) were tested. Muscle and liver of nitrofuran treated pigs were cooked by frying, grilling, roasting and microwaving. Between 67 and 100% of the residues remained after cooking, demonstrating that these metabolites are largely resistant to conventional cooking techniques and will continue to pose a health risk. The concentration of metabolites in pig muscle and liver did not drop significantly during 8 months of storage at -20 degrees C. Metabolite stock and working standard solutions in methanol were also stable for 10 months at 4 degrees C. Only a 10 ng ml(-1) solution of SEM showed a small drop in concentration over this extended storage period.

Optimizing antibiotics in residents of nursing homes:protocol of a randomized trial.

BACKGROUND: Antibiotics are frequently prescribed for older adults who reside in long-term care facilities. A substantial proportion of antibiotic use in this setting is inappropriate. Antibiotics are often prescribed for asymptomatic bacteriuria, a condition for which randomized trials of antibiotic therapy indicate no benefit and in fact harm. This proposal describes a randomized trial of diagnostic and therapeutic algorithms to reduce the use of antibiotics in residents of long-term care facilities. METHODS: In this on-going study, 22 nursing homes have been randomized to either use of algorithms (11 nursing homes) or to usual practise (11 nursing homes). The algorithms describe signs and symptoms for which it would be appropriate to send urine cultures or to prescribe antibiotics. The algorithms are introduced by inservicing nursing staff and by conducting one-on-one sessions for physicians using case-scenarios. The primary outcome of the study is courses of antibiotics per 1000 resident days. Secondary outcomes include urine cultures sent and antibiotic courses for urinary indications. Focus groups and semi-structured interviews with key informants will be used to assess the process of implementation and to identify key factors for sustainability.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Background: There is no method routinely used to predict response to anthracycline and cyclophosphamide–based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.

Methods: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.

Results: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.

Conclusions: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide–based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

The In Vitro Susceptibility of Biofilm Forming Medical Device Related Pathogens to Conventional Antibiotics

Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum biofilm eradication concentration (MBEC) and kill kinetics were established for vancomycin, rifampicin, trimethoprim, gentamicin, and ciprofloxacin against the biofilm forming bacteria Staphylococcus epidermidis (ATCC 35984), Staphylococcus aureus (ATCC 29213), Methicillin Resistant Staphylococcus aureus (MRSA) (ATCC 43300), Pseudomonas aeruginosa (PAO1), and Escherichia coli (NCTC 8196). MICs and MBCs were determined via broth microdilution in 96-well plates. MBECs were studied using the Calgary Biofilm Device. Values obtained were used to investigate the kill kinetics of conventional antimicrobials against a range of planktonic and biofilm microorganisms over a period of 24 hours. Planktonic kill kinetics were determined at 4xMIC and biofilm kill kinetics at relative MBECs. Susceptibility of microorganisms varied depending on antibiotic selected and phenotypic form of bacteria. Gram-positive planktonic isolates were extremely susceptible to vancomycin (highest MBC: 7.81 mg L−1: methicillin sensitive and resistant S. aureus) but no MBEC value was obtained against all biofilm pathogens tested (up to 1000 mg L−1). Both gentamicin and ciprofloxacin displayed the broadest spectrum of activity with MIC and MBCs in the mg L−1 range against all planktonic isolates tested and MBEC values obtained against all but S. epidermidis (ATCC 35984) and MRSA (ATCC 43300).

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.

METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.

RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.

CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.