Anouk E. Muller

Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia

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.

Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials

OBJECTIVES Nitrofurantoins 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 nitrofurantoins 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, nitrofurantoins 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.

Morbidity related to maternal group B streptococcal infections

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.

Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration

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.

Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

ABSTRACT 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 × 103 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 (fAUC0-24/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.

Exposure to ceftobiprole is associated with microbiological eradication and clinical cure in patients with nosocomial pneumonia.

ABSTRACT 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.

Pharmacokinetics of Penicillin G in Infants with a Gestational Age of Less than 32 Weeks

ABSTRACT 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 ≤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.

Low carriage rate of group B streptococcus in pregnant women in Maputo, Mozambique

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.

MIC-based dose adjustment: facts and fables

Over recent decades, several publications have described optimization procedures for antibiotic therapy in the individual patient based on antimicrobial MIC values. Most methods include therapeutic drug monitoring and use a single MIC determination plus the relevant pharmacokinetics/pharmacodynamics to adjust the dose to optimize antimicrobial drug exposure and antibacterial effects. However, the use of an MIC obtained by a single MIC determination is inappropriate. First, routine clinical laboratories cannot determine MICs with sufficient accuracy to guide dosage owing to the inherent assay variation in the MIC test. Second, the variation in any MIC determination, whatever method is used, must be accounted for. If dose adjustments are made based on therapeutic drug monitoring and include MIC determinations, MIC variation must be considered to prevent potential underdosing of patients. We present the problems and some approaches that could be used in clinical practice.

The influence of labour on the pharmacokinetics of intravenously administered amoxicillin in pregnant women

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.