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Objectives: Nitrofurantoin's use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin's efficacy and toxicity in the treatment of lower UTI., Methods: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials., Results: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin's clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare., Conclusions: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Quality of life (QoL) is a well-established outcome within clinical practice. Despite the adverse effects of substance use disorders on a wide range of patients' functionality and the multidimensional composition of QoL, the treatment field does not yet systematically assess QoL among patients. Exercise has established positive effects on the QoL of healthy and numerous clinical populations. The potential to integrate exercise within treatment, in order to improve QoL has not been satisfactorily explored., Aims: To measure changes in QoL after group exercise among residential substance use disorder patients and to explore the feasibility of the program within a treatment setting., Methods: We enrolled 35 patients in four long-term residential substance use disorder treatment facilities in Oslo, into a 10-week group exercise program. We analyzed the 24 participants who exercised as completers, while the 11 participants who did not were analyzed as non-completers. We measured QoL, mental distress, somatic health burden and addiction severity at the beginning and end of the program., Results: The program was feasible for participants and the completion rate was 69%. Completers' physical health domain and psychological health domain of QoL improved significantly. The program engaged the most physically and mentally vulnerable participants, and flexibility and motivational factors were important elements., Conclusions: This study provided promising evidence that low doses of group exercise can yield appreciable benefits, even to patients with more severe health problems., (© 2014 the Nordic Societies of Public Health.)

Objectives: The growing incidence of infections caused by Enterobacteriaceae producing ESBLs has led to increased use of carbapenems. Temocillin, which resists most β-lactamases, may be a useful alternative. The aim of this study was to assess the pharmacokinetics and target attainment rates of 6 g of temocillin daily divided into three administrations every 8 h (three times daily) or administered by continuous infusion in critically ill patients., Patients and Methods: This was a prospective, two-centre, randomized, controlled study in patients with intra-abdominal or lower respiratory tract infections caused by Enterobacteriaceae., Results: Thirty-two patients were included and analysed for clinical efficacy, and pharmacokinetics were measured in 29 of them. Four patients undergoing continuous veno-venous haemofiltration (CVVH) were analysed separately. Mean, median and range of percentages of the dosing interval during which the free drug concentration remained >16 mg/L were 76.4, 98 and 18.7-98.9 in patients treated three times daily and 98.9, 89.7 and 36.4-99.9 in patients with continuous infusion, respectively. Clinical cure rates were 79% and 93% in each of these groups, respectively (not significant). Patients with CVVH received a daily dose of 750 mg given by continuous infusion and had a mean free drug concentration of only 13.8 ± 1.9 mg/L. No adverse event attributable to temocillin was observed., Conclusions: Temocillin (6 g daily) given by continuous infusion allows a larger proportion of critically ill patients to have free drug serum concentrations covering infections caused by Enterobacteriaceae with an MIC of 16 mg/L compared with administration three times daily. Clinical efficacy compared with carbapenems in documented severe infections needs to be further studied., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The percentage of the dosing interval that the non-protein-bound plasma concentration is above the MIC (%fT>MIC) for cephalosporins has been shown to correlate with microbiological outcomes in preclinical studies. However, clinical data are scarce. Using data from a randomized double-blind phase 3 clinical trial, we explored the relationship of ceftobiprole exposure with microbiological and clinical outcomes in patients with nosocomial pneumonia. The individual ceftobiprole exposure was determined for different pharmacokinetic (PK)/pharmacodynamic (PD) indices using individual pharmacokinetic data and a previously published population model. The MICs used in the analysis were the highest MICs for any bacterium cultured at baseline or the end of treatment (EOT). Outcomes were microbiological cure at EOT and clinical cure at test of cure (TOC). Multiple logistic regression (MLR) and classification and regression tree (CART) analyses were applied to determine the relationships among exposure, patient characteristics, and outcomes. MLR indicated that the %fT>MIC of ceftobiprole was the best predictor for both microbiological eradication and clinical cure. CART analysis showed a breakpoint value of 51.1% (n = 159; P = 0.0024) for clinical cure, whereas it was 62.2% (n = 251; P < 0.0001) for microbiological eradication. Other factors also contributed, particularly to clinical outcome. These included the difference between VAP and non-VAP patients, systemic inflammatory response syndrome (SIRS), creatinine clearance, the use of anti-Pseudomonas combination therapy, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. There is a strong correlation between microbiological eradication and clinical cure with exposure to ceftobiprole. The %fT>MIC required to result in a favorable clinical outcome is >51% of the dosing interval, which is in line with the values found for microbiological eradication, the comparator ceftazidime, and preclinical models.

Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713-1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percent fT > MIC]) for a range of MIC values. For the ranges of percent fT > MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50% fT > MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percent fT > MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.

Objectives: The %fT>MIC of ceftazidime has been shown to correlate with microbiological outcome of Gram-negative bacteria (GNB) in preclinical studies. However, clinical data are still lacking. We explored the relationship of ceftazidime exposure and outcome in patients with nosocomial pneumonia using data from a recent randomized, double-blind Phase 3 clinical trial., Patients and Methods: Pharmacokinetic (PK) and demographic data from three clinical trials were used to construct a population PK model using non-linear mixed-effects modelling. Individual concentration-time curves and PK/pharmacodynamic indices were determined for individual patients. The MICs used in the analyses were the highest MICs for any GNB cultured at baseline or end of therapy., Results: A two-compartment model best fit the data, with creatinine clearance as covariate on clearance and age on the central compartment. Classification and regression tree analysis showed a breakpoint value of 44.9% (P<0.0001) for GNB in 154 patients. The Emax model showed a good fit (R(2) =0.93). The benefit of adequate treatment increased from an eradication rate of 0.4848 at %fT>MIC of 0% to 0.9971 at 100%. The EC50 was 46.8% and the EC90 was 95.5% for %fT>MIC. Exposure correlated significantly with both microbiological and clinical outcome at test-of-cure., Conclusions: We conclude that exposures to ceftazidime predict microbiological as well as clinical outcome, and the %fT>MIC required to result in a likely favourable outcome is >45% of the dosing interval. This value is similar to that observed in animal models and underscores the principle that adequate dosing can be predicted and is beneficial to patient care.

A broth for the screening of group B streptococcal (GBS) carriage during pregnancy is about to be introduced. Simulating conditions in everyday practice, we have compared the sensitivity of this Granada tube broth (GT) with that of classical Amies transport medium (AT) in vitro. A total of 1,485 GT and 1,485 AT were tested with 33 well-characterized GBS strains in three different concentrations, five different incubation times, and three different temperatures. After initial incubation at room temperature (RT) or 4°C, GT were placed at 37°C. GT were scored for the presence of orange pigment. GT and AT were subcultured on blood agar (BA). Pigment was observed in 98% of GT incubated at 37°C. GBS could be cultured in 91%, 73%, and 55% of GT incubated at 37°C, RT, or 4°C, respectively. For AT, these percentages were only 20% at 37°C, 52% at RT, and 59% at 4°C. When GT initially incubated at RT or 4°C were subsequently incubated at 37°C, the sensitivity improved significantly. We conclude that GT is a more sensitive GBS transport and culture medium than the conventional method, especially for low inocula and prolonged transport/incubation times. GT does not exclude the presence of GBS, and should always be incubated at 37°C and subcultured on solid agar for optimal sensitivity.

Nosocomial infections are a frequent concern in healthcare. Despite the available knowledge on nosocomial infections and preventive measures, outbreaks of infections continue to occur. An outbreak of severe sepsis in patients who underwent minor procedures in an operating theatre during two consecutive days is described and analysed in this study. We performed a retrospective cohort study using epidemiological data in order to investigate the source of infection together with microbiological and on-site investigations and interviews. Seven patients met the case definition of postoperative systemic inflammatory response syndrome (SIRS). All other patients operated on over the same period served as controls. Of the risk factors investigated, general anaesthesia and propofol were statistically significant (P=0.003). Klebsiella pneumoniae and Serratia marcescens were cultured from opened vials of propofol, propofol-related devices and from blood cultures from two of the patients. These strains were genotypically indistinguishable. Lapses in aseptic preparation, handling and storage of the propofol were observed, and were the most probable cause of the extrinsic contamination. The daily procedure of handling propofol was not performed according to the manufacturer's recommendations, the main departure being the use of a single-use vial for multiple patients. This study documents the risk of infection due to contaminated propofol and the importance of having written guidelines for its handling., (Copyright © 2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.)

The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 x 10(3) liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC(0-24)/MIC). At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease.

The pharmacokinetics of amoxicillin were studied in umbilical cord and neonatal sera relative to maternal concentrations in prevention of neonatal group B streptococcus infection. The subjects were 44 pregnant women receiving amoxicillin as 1 or 2 g as an intravenous infusion. To measure the concentrations, blood samples were obtained from the mother, the arterial and venous umbilical cord, and the neonate. The pharmacokinetics were characterized by a five-compartment model by using nonlinear mixed-effects (population) modeling. The population estimates for the clearance, central volume of distribution, and the two peripheral maternal volumes of distribution were 19.7 +/- 0.99 liters/h, 6.40 +/- 0.61 liters, and 5.88 +/- 0.83 liters (mean +/- standard error), respectively. The volume of distribution of the venous umbilical cord and the neonatal volume of distribution were 3.40 liters and 11.9 liters, respectively. The pharmacokinetic parameter estimates were used to simulate the concentration-time profiles in maternal, venous umbilical cord, and neonatal sera. The peak concentration in the venous umbilical cord serum was 18% of the maternal peak concentration. It was reached 3.3 min after the maternal peak concentration. The concentration-time profile in neonatal serum was determined by the profile in venous umbilical cord serum, which in turn depended on the profile in maternal serum. Furthermore, the simulated concentrations in maternal, venous umbilical cord, and neonatal sera exceeded the MIC for group B streptococcus for more than 90% of the 4-h dosing interval. In a first approximation, the 2-g infusion to the mother appears to be adequate for the prevention of group B streptococcal disease. However, to investigate the efficacy of the prophylaxis, further studies of the interindividual variability in pharmacokinetics are indicated.

Aims: Many physiological changes take place during pregnancy and labour. These might change the pharmacokinetics of amoxicillin, necessitating adjustment of the dose for prevention of neonatal infections. We investigated the influence of labour on the pharmacokinetics of amoxicillin., Methods: Pregnant women before and during labour were recruited and treated with amoxicillin intravenously. A postpartum dose was offered. Blood samples were obtained and amoxicillin concentrations were determined using high-pressure liquid chromatography. The pharmacokinetics were characterized by nonlinear mixed-effects modelling using NONMEM., Results: The pharmacokinetics of amoxicillin in 34 patients was best described by a three-compartment model. Moderate interindividual variability was identified in CL, central and peripheral volumes of distribution. The volume of distribution (V) increased with an increasing amount of oedema. Labour influenced the parameter estimate of peripheral volume of distribution (V(2)). V(2) was decreased during labour, and even more in the immediate postpartum period. For all patients the population estimates (mean +/- SE) for CL and V were 21.1 +/- 4.1 l h(-1) (CL), 8.7 +/- 6.6 l (V(1)), 11.8 +/- 7.7 l (V(2)) and 20.5 +/- 15.4 l (V(3)) respectively., Conclusions: The peripheral distribution volume of amoxicillin in pregnant women during labour and immediately postpartum is decreased. However, these changes are not clinically relevant and do not warrant deviations from the recommended dosing regimen for amoxicillin during labour in healthy pregnant patients.

The prevalence of group B streptococcus (GBS) carriage varies strongly with geographical region. A study was done to determine the prevalence of GBS in women in Maputo, Mozambique. The method used was a rectovaginal swab which was taken from women between 35 and 37 weeks of pregnancy who visited the clinic for antenatal consultation. GBS was cultured from 2 out of 113 samples, yielding a prevalence of 1.8% (95% Cl: 0.0-4.0). In conclusion, the prevalence of GBS carriage among pregnant women in Maputo, Mozambique was low.

Objectives: To describe prevalence of phenotypic and genotypic macrolide-resistance among GBS isolates in pregnant women and explore the possibility of clonal spread of resistant GBS isolates in a multicultural population., Study Design: Antimicrobial resistance patterns of 107 GBS isolates obtained from asymptomatic pregnant women were determined using E-tests. Macrolide resistance genes mef(A), erm(TR) and erm(B) were determined with PCR and a subset of 39 isolates, including the 8 isolates harbouring macrolide resistance genes, was subjected to RAPD analysis to detect clonal spreading., Results: Resistance to erythromycin and clindamycin was found in 8% and 7%, respectively. Macrolide resistance genes mef(A), erm(TR) and erm(B) were found in 1, 2 and 5 isolates, respectively; only five of these eight isolates exhibited both genotypic as well as phenotypic resistance. One genotype occured in 36% of the subset., Conclusions: Earlier reports on prevalence of phenotypic resistance were confirmed. Among the susceptible isolates one clonal type of GBS was clearly predominant; one of the resistant isolates shared its genotype. When such clonal types acquire resistance traits in the future, GBS disease may become harder to control.

Objective: This study was undertaken to study the pharmacokinetics of intravenously administered amoxicillin in pregnant women with preterm premature rupture of the membranes (PPROM)., Study Design: Healthy women with PPROM were recruited and treated with amoxicillin (2 g initially and 1 g subsequently). Blood samples were obtained from the opposite arm and concentrations determined with the use of high-pressure liquid chromatography. Nonlinear mixed-effects modeling was performed in nonlinear mixed effect (population) modeling., Results: The pharmacokinetics of 17 patients was described by a 3-compartment model. Clearance and volume of distribution at steady state were 22.8 L/h and 21.4 L/h, respectively, similar to values in nonpregnant individuals. There was little variability between patients. No relationship was observed between values of individual pharmacokinetic parameters and various covariates., Conclusion: The pharmacokinetics of amoxicillin in pregnant patients with PPROM similar to nonpregnant individuals. Given the small interindividual variability in pharmacokinetics, no dose adjustments are required to account for differences between subjects under normal circumstances.

The pharmacokinetics of penicillin G were studied in 20 preterm neonates with a gestational age of less than 32 weeks on day 3 of life by using a population approach performed with the nonlinear mixed effects modeling program NONMEM. The derived population estimates and the correlation matrix of these estimates were used to perform Monte Carlo simulations and obtain the probability of target attainment (PTA). The pharmacokinetics of penicillin G were best described by a two-compartment pharmacokinetic model. The population estimates of the central volume of distribution, the peripheral volume of distribution, the intercompartmental clearance, and the total body clearance were 0.359 +/- 0.06 liter, 0.152 +/- 0.03 liter, 0.774 +/- 0.28 liter/h, and 0.103 +/- 0.01 liter/h (mean +/- standard error), respectively. The terminal half-life was 3.9 h. Clearance increased significantly with increasing birth weight. Assuming the percentage of time that the concentration of unbound drug remained above the MIC of 50% for preterm neonates, the susceptibility breakpoint based on a 100% PTA was < or =4 mg/liter, simulating the current dosing regimen of 50,000 U/kg every 12 h. This regimen is therefore adequate for the treatment of common infections in neonates on the third day of life.

Group B streptococcus is known to be a leading cause of neonatal infection, but less appreciated is the fact that it causes maternal infection also. Maternal group B streptococcal infections during pregnancy and delivery threaten not only the mother, but the child as well. Postpartum infection, such as mastitis, bacteremia, sepsis, meningitis, endometritis, and wound infections are hazards to the mother. We describe the various maternal group B streptococcal infections, their characteristics, associated neonatal morbidity, and prevention and treatment strategies during pregnancy, delivery, and in the postpartum period.