Improving antibiotic therapy in critically ill patients through pharmacokinetic dose optimization

Each year, thousands of critically ill patients admitted to Dutch intensive care units suffer from severe bacterial infections. Early and adequate antibiotic treatment significantly lowers the mortality of these infections. The efficacy and safety of antibiotics like gentamicin, vancomycin and ceftazidime depends on the concentrations that are achieved in serum and in infected body tissues. However, it is particularly difficult to achieve adequate antibiotic concentrations in critically ill patients because the pharmacokinetic processes may vary widely, both between these patients and within an individual patient during different stages of the infection. To increase the probability that effective antibiotic concentrations are reached timely in these patients, the use of optimized dosing strategies is recommended. This thesis investigates several of these strategies, ranging from the effect of a higher starting dose for all critically ill patients or for some individuals with specific patient characteristics to the use of continuous infusion or the use of therapeutic drug monitoring

Improving antibiotic therapy in critically ill patients through pharmacokinetic dose optimization

Each year, thousands of critically ill patients admitted to Dutch intensive care units suffer from severe bacterial infections. Early and adequate antibiotic treatment significantly lowers the mortality of these infections. The efficacy and safety of antibiotics like gentamicin, vancomycin and ceftazidime depends on the concentrations that are achieved in serum and in infected body tissues. However, it is particularly difficult to achieve adequate antibiotic concentrations in critically ill patients because the pharmacokinetic processes may vary widely, both between these patients and within an individual patient during different stages of the infection. To increase the probability that effective antibiotic concentrations are reached timely in these patients, the use of optimized dosing strategies is recommended. This thesis investigates several of these strategies, ranging from the effect of a higher starting dose for all critically ill patients or for some individuals with specific patient characteristics to the use of continuous infusion or the use of therapeutic drug monitoring

Multiple-azole-resistant Aspergillus fumigatus osteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery.

We describe a patient with chronic granulomatous disease and proven Aspergillus fumigatus osteomyelitis of the midfoot, while receiving itraconazole-prophylaxis. The isolate proved resistant to itraconazole as well as voriconazole, and showed reduced susceptibility to posaconazole. Although molecular analysis demonstrated the presence of a 53 base pair tandem repeat in the promoter region for cyp51A, i.e., the gene coding for the target enzyme of the azole antifungals, there were no mutations in the cyp51A gene. Since transformation of the promoter region into wild-type strains did not result in an azole resistant phenotype, a yet unknown mutation was suspected. The patient was treated with extensive surgery and two weeks of caspofungin therapy, followed by one year of posaconazole therapy. He made a complete recovery and did not experience any side effects. Long-term posaconazole proved to be a safe and effective treatment for multi-azole resistant A. fumigatus osteomyelitis in this immunocompromised patient

Optimization of therapy against Pseudomonas aeruginosa with ceftazidime and meropenem using chemostats as model for infections

Pseudomonas aeruginosa is an opportunistic pathogen that can cause life-threatening infections in patients admitted to intensive care units. Resistance rapidly develops against two drugs of choice: ceftazidime and meropenem. Several therapeutic protocols were compared for reduction in viable cells and limiting development of resistance. Chemostat cultures were exposed to antibiotic concentrations measured in the blood of patients at low (5th percentile), medium (50th percentile) or high (95th percentile) levels in several therapy protocols to simulate therapy. Cultures exposed to ceftazidime recovered after 1 day at low, 2 days at medium and 3 days at high concentrations and developed corresponding levels of resistance. Patterns were very similar for meropenem except that recovery was delayed. Fluctuating levels and intermittent treatment achieved similar reduction of cell numbers at lower resistance costs. Treatment alternating ceftazidime and meropenem reduced cell numbers more than monotherapy, while strongly limiting resistance. Combination therapy was even more effective in both respects. Therapeutic goals are best reached with least risk of resistance when ceftazidime and meropenem are used in combination or alternating, at the highest concentrations the patient can endure. Monotherapy should also apply the highest concentration that is safe for the shortest time that achieves treatment objectives

Development of Antibiotic Resistance during Simulated Treatment of Pseudomonas aeruginosa in Chemostats

During treatment of infections with antibiotics in critically ill patients in the intensive care resistance often develops. This study aims to establish whether under those conditions this resistance can develop de novo or that genetic exchange between bacteria is by necessity involved. Chemostat cultures of Pseudomonas aeruginosa were exposed to treatment regimes with ceftazidime and meropenem that simulated conditions expected in patient plasma. Development of antibiotic resistance was monitored and mutations in resistance genes were searched for by sequencing PCR products. Even at the highest concentrations that can be expected in patients, sufficient bacteria survived in clumps of filamentous cells to recover and grow out after 3 to 5 days. At the end of a 7 days simulated treatment, the minimal inhibitory concentration (MIC) had increased by a factor between 10 and 10,000 depending on the antibiotic and the treatment protocol. The fitness costs of resistance were minimal. In the resistant strains, only three mutations were observed in genes associated with beta-lactam resistance. The development of resistance often observed during patient treatment can be explained by de novo acquisition of resistance and genetic exchange of resistance genes is not by necessity involved. As far as conclusions based on an in vitro study using P. aeruginosa and only two antibiotics can be generalized, it seems that development of resistance can be minimized by treating with antibiotics in the highest concentration the patient can endure for the shortest time needed to eliminate the infection

Comparison of the PRNT and an immune fluorescence assay in yellow fever vaccinees receiving immunosuppressive medication

Conclusions: All immune-compromised patients mounted an adequate response with protective levels of virus neutralizing antibodies to the 17-D YF vaccine. No adverse effects were reported. Compared to the plaque reduction neutralization test, the sensitivity of the Immune Fluorescence Assay test was low. Further research is needed to ascertain that 17D vaccination in immune-compromised patients is safe. (C) 2016 Elsevier Ltd. All rights reserved.Immunogenetics and cellular immunology of bacterial infectious disease

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T(>MIC)) (for efficacy purposes and 100% T(>4×MIC) and 100% T(>5×MIC) to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T(>MIC) during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T(>MIC) during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T(>4×MIC) and 100% T(>5×MIC) are desired

Diagnosis and management of aspergillosis in the Netherlands: a national survey

A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B.Medical Microbiolog