Population pharmacokinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus.

OBJECTIVES: Cefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetic (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children in order to optimize individual dosing regimens. METHODS: We included all children (age < 18 years, body weight (BW) > 2.5 kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. A data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT > 4 ×MIC. RESULTS: Thirty-nine patients with a median (range) age of 7 (0.1-17) years and a BW of 21 (2.8-79) kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and estimated glomerular filtration rate (eGFR) on clearance were the two influential covariates. Continuous infusion with a dosing of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW < 10 kg or eGFR >200 mL/min/1.73m2 were the best schemes to reach the PK target of 100% fT> 4 ×MIC. CONCLUSIONS: In critically ill children infected with MSSA, continuous infusion seems to be the most appropriate scheme to reach the PK target of 100 % fT > 4 ×MIC in children with normal and augmented renal function.

Potentially clinically relevant concentrations of Cefazolin, Midazolam, Propofol, and Sufentanil in auto-transfused blood in congenital cardiac surgery.

BACKGROUND: Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient. METHODS: The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at - 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient. RESULTS: Blood samples were taken from 18 cellsaver runs in 18 patients, age 0-13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27-50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4-10), for cefazolin 5% (median, IQR 2-6) and for propofol 0% (median, IQR 0-0) respectively. CONCLUSION: Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase. TRIAL REGISTRATION: Registration at the Dutch Trial Registry ( NTR3579 ) at August 14 2012.

Comparative prophylactic efficacies of ciprofloxacin, ofloxacin, cefazolin, and vancomycin in experimental model of staphylococcal wound infection.

Recent shifts in the species and antibiotic resistance patterns of bacteria causing nosocomial infections present new challenges for providing effective prophylaxis in surgery. Traditional regimens lack activity against methicillin-resistant staphylococci and many gram-negative species causing nosocomial infections. The new fluoroquinolones exhibit in vitro activity against many emerging surgical wound pathogens. To determine the potential of this class of antimicrobial agents for use in surgery, we compared the prophylactic efficacies of ciprofloxacin and ofloxacin with those of cefazolin and vancomycin in a guinea pig model of abscess formation. Four Staphylococcus aureus strains, one Staphylococcus epidermidis strain, and one Staphylococcus haemolyticus strain were evaluated. Vancomycin was the most effective prophylactic agent, exhibiting in vivo activity against all strains which was superior or equivalent to those of all other agents tested. Cefazolin was the least effective agent and surpassed the two quinolones in prophylactic efficacy against only one organism, a quinolone- and methicillin-resistant strain of S. aureus. The two quinolones provided excellent protection against infection with all but the quinolone-resistant isolate. The in vivo emergence of quinolone resistance among quinolone-susceptible isolates was not detected. The methicillin-resistant, quinolone-susceptible S. epidermidis and S. haemolyticus isolates were extremely susceptible to prophylaxis, exhibiting 50% infective doses above 4 x 10(6) CFU for seven of the eight antibiotic-strain combinations. We conclude that ciprofloxacin and ofloxacin may be effective antistaphylococcal agents in surgery. The role of these agents remains to be defined, and the definition should include consideration of an adverse effect upon antibiotic resistance patterns of organisms causing nosocomial infections.

A comparative trial between cefotetan and cephazolin for wound sepsis prophylaxis during elective upper gastrointestinal surgery with an investigation of cefotetan penetration into the obstructed biliary tree.

Cefotetan is a cephamycin antibiotic theoretically suited to prophylaxis of wound infection during upper elective gastrointestinal surgery. In a prophylaxis trial 100 patients undergoing this type of surgery were randomly allocated to receive 1g cefotetan or cephazolin iv at induction of anaesthesia. Cefotetan-treated patients had significantly fewer postoperative infections overall (P less than 0.05) and there were no wound infections recorded in this group. In a separate pharmacokinetic study the penetration of cefotetan into common bile duct bile and gallbladder wall was measured in a further six patients, all of whom had been jaundiced preoperatively. At the time of maximum risk concentrations of cefotetan in bile and biliary tissue as well as blood and wound fat were in excess of the minimum inhibitory concentration for the majority of relevant pathogens. Cefotetan appears to be equally or more effective than cephazolin and is a suitable alternative prophylactic agent in elective upper gastrointestinal surgery.

Relevance of serum protein binding of cefoxitin and cefazolin to their activities against Klebsiella pneumoniae pneumonia in rats.

An experimental Klebsiella pneumoniae pneumonia in rats was used to study the effect of protein binding of cefoxitin and cefazolin on their therapeutic activity. Both cephalosporins were similar with respect to their antimicrobial activity against the K. pneumoniae in vitro, but they differed in their degree of protein binding, being 34% for cefoxitin and 89 to 93% for cefazolin in uninfected rats and 24 and 71 to 83%, respectively, in infected rats. Various doses of these agents were administered by continuous infusion, which started 5 h after bacterial inoculation and continued for 65 h. Antimicrobial response was evaluated with respect to the numbers of bacteria recovered from lung and blood at the end of treatment. An inhibitory effect of protein binding on the in vivo antimicrobial activity was demonstrated. Cefoxitin was therapeutically effective at a constant plasma level that reached the MIC. To obtain a similar effect with cefazolin the plasma level of that drug had to be increased to a concentration more than three times the MIC.

Importance of beta-lactamase inactivation in treatment of experimental endocarditis caused by Staphylococcus aureus.

To test the hypothesis that cephalosporins resistant to beta-lactamase are preferred in the treatment of serious staphyloccal infections, the ability of four cephalosporins to eradicate bacteria from the cardiac vegetations of rabbits with experimental endocarditis was examined. Two strains of Staphylococcus aureus were chosen as pathogens: one that rapidly and completely inactivated 50 micrograms of cefazolin in vitro (beta-lactamase-positive) and another that did not inactivate any cephalosporin (beta-lactamase-negative). Rabbits with a polyethylene catheter in the left ventricle were reliably infected witih 10(5) bacteria. Similar numbers of S. aureus were recovered from the cardiac vegetations of rabbits inoculated with the beta-lactamase-positive strain after 24 hr of treatment with each of four cephalosporins. However, when the animals were treated at intervals of 6 hr for four days, significantly fewer rabbits survived after treatment with cefazolin than with cephalothin. No difference in survival was observed in the treatment of rabbits with endocarditis due to the beta-lactamase-negative strain. The failure of cefazolin in the treatment of staphylococcal endocarditis in rabbits may be due to inactivation of the drug by beta-lactamase in vivo.

Cephazolin treatment of pneumococcal pneumonia and urinary tract infections.

Ten cases of pneumococcal pneumonia were treated with cephazolin 500 mg. q8h for at least 5 days. In every case therapy was accompanied by clinical improvement and eradication of the organism. Ten patients with E. coli bacteriuria (5 symptomatic) were treated with cephazolin 500 mg. q12h for 7 to 10 days. In every case the pathogen was eliminated during therapy but in one case bacteriologic relapse occurred following cessation of therapy. In 10 cases of bacteriuria caused by P. mirabilis, Klebsiella sp, Enterobacter, and Enterococcus, the urine became sterile during treatment, but relapse was common. Initial and final creatinine clearances obtained in 29 patients who received an average of 12.9 g. of cephazolin showed no tendency toward loss of renal function. Serial serum levels of cephazolin were determined following the first 500 mg. dose in 18 patients. The peak serum level occurred at one hour with a serum half life of approximately 2.2 hours. For 13 of these 18 patients serial serum levels were also obtained following the last dose of cephazolin. At this time the mean peak level occurred at 2 hours but again the serum half life was approximately 1.9 hours.

Cephazolin: clinical studies in obstetrics.

A clinical evaluation of a new cephalosporin, cephazolin, in obstetric patients is presented. Sixteen cardiac patients received the drug prophylactically as antibiotic cover during labour. Eighteen patients with miscellaneous antenatal and puerperal infections received the drug as primary treatment. The data obtained indicate adequate serum and tissue levels with the dose used, and corresponding clinical response. The impression is of a safe and efficaceous drug in the described obstetric situations requiring antibiotic therapy. It may be given prophylactically and with confidence to the cardiac patient in labour.