Cefazolin serum concentrations with fixed intravenous dosing in patients on chronic hemodialysis treatment

D. Kuypers, J. Vanwalleghem, B. Maes, T. Messiaen, Y. Vanrenterghem and W. E. Peetermans1

Department of Nephrology and Renal Transplantation 1 Department of Internal Medicine and Infectious Diseases, Universitaire Ziekenhuizen Leuven, Herestraat 49, Leuven, Belgium

Sir,

Staphylococcus aureus and coagulase-negative staphylococci are the most frequent causes of sepsis in chronic haemodialysis patients. Due to the emergence of vancomycin-resistant enterococci (VRE) and staphylococci, the use of vancomycin as empirical treatment for sepsis or because of dosing convenience in patients with renal failure has been discouraged. The spectrum of anti-bacterial activity of cefazolin, a first-generation cephalosporin, offers an attractive alternative for vancomycin (with or without aminoglycoside) as treatment for sepsis in patients on chronic haemodialysis, however data about cefazolin pharmacokinetics and efficacy in this population are sparse. Recently it was shown that a titrated dose of cefazolin 20 mg/kg given i.v. after dialysis was effective for achieving therapeutic serum concentrations with resolution of clinical infections [5].

We conducted a study with a fixed cefazolin dose of 2 g i.v. in our chronic haemodialysis patients to establish whether this more convenient dosing strategy would also be effective.

Methods. Fifteen stable chronic ambulatory haemodialysis patients from our low-care dialysis centre (14 male patients) gave informed consent to participate in the pharmacokinetic part of the study. They were free of infection for at least 4 weeks at the time of inclusion. Patients known to be allergic to penicillins or cephalosporins were excluded. Fourteen patients were on haemodialysis (4 h sessions) and one on haemodiafiltration (4 h sessions); 14 patients used high-flux membranes and the remaining one a medium-flux membrane. Patients age ranged from 41 to 77 years (mean 64.5 years); the mean body weight for this group was 72 kg (range 53–104 kg). Etiology of chronic renal insufficiency was diabetic nephropathy (two patients), chronic glomerulonephritis (four), adult dominant polycystic kidney disease (three), renal vascular disease (one) and unknown (five).

Residual renal function was calculated from measured 44-h urine collections and ranged from 0 to 1 ml/min; eight patients were completely anuric.

Two grams cefazolin was administrated i.v. to these 15 patients at the end of each dialysis treatment (over 15 min) for three consecutive dialysis sessions (on day 0, 2 and 4). Cefazolin trough serum levels were measured just before each next dialysis session, 44 or 68 h after the previous dose (on day 2, 4 and 7).

Blood samples were collected on heparin from the dialysis acces line. Cefazolin serum concentrations were randomly determined by high-performance liquid chromatography and blinded to the investigator. Data are expressed as mean±standard deviation unless otherwise stated.

Results. The dose of cefazolin expressed in milligram per kilogram of body weight for our patients ranged from 37.7 mg/kg to 19.2 mg/kg with a mean of 28.7±5.22 mg/kg. The mean cefazolin serum trough levels for these 15 patients measured on day 2, 4 and 7 were 84±24 µg/ml (range 47–130 µg/ml); 97±27 µg/ml (range 52–145 µg/ml) and 61±22 µg/ml (range 26–99 µg/ml) respectively. Minimum inhibitory concentration (MIC) for cefazolin susceptible bacteria is <=8 µg/ml, according to the 1998 NCCLS guidelines [1].

Clinical signs and symptoms occuring during the study period and interpreted as probably related to cefazolin administration were: urticaria (one patient) not reccuring on subsequent dosing, superficial mouth ulcers (one patient), clostridium difficile colitis requiring oral vancomycin therapy (one patient) and vomiting (one patient), although the latter patient was subsequently diagnosed with reflux oesophagitis grade IV.

Discussion. The emergence of VRE not only in intensive care units but also in haemodialysis and nephrology wards is responsible for large hospital VRE outbreaks [2]. The Hospital Infection Control Practices Advisory Committee (HICPAC) published recommendations for preventing the spread of VRE in the hospital setting [3].

Using vancomycin for the treatment of infections due to ß-lactam-sensitive Gram-positive bacteria in patients with renal failure should be discouraged and reserved only for ß-lactam-resistant Gram-positive isolates or patients with ß-lactam allergy. The International Society for Peritoneal Dialysis also recommended not to use vancomycin plus aminoglycosides as first choice therapy for initial empiric treatment of peritoneal dialysis-related peritonitis, but to treat with cefazolin and gentamicin [4].

Our results show that administration of a fixed dose of 2 g cefazolin i.v. to stable chronic haemodialysis patients at the end of each consecutive dialysis session produces pre-dialysis trough serum concentrations of cefazolin 3–18 times the MIC for susceptible microorganisms.

Despite the fact that almost all our patients used high flux dialysis membranes (4 h total dialysis time), our standard dose of 2 g cefazolin rendered trough serum concentrations higher than those of Marx et al. who used a titrated cefazolin dose of 20 mg/kg (mean dose 1.6 g). Marx achieved clinical resolution of a variety of infections and further showed that high-flux haemodialysis treatment for 3.4±0.2 h causes a 60% reduction in cefazolin blood concentration [5].

The higher serum levels of cefazolin in our study could be responsible for some of the side-effects we documented in three of our patients. However, the patient who contracted Clostridium difficile colitis was the only one with a substantially higher cefazolin dose per kg body weight (33.9 mg/kg) but with average serum concentrations of cefazolin.

These data confirm that the i.v. administration of a fixed dose of 2 g cefazolin to chronic haemodialysis patients on consecutive dialysis days (three times a week) is sufficient for reaching serum concentration levels well above the MIC of most blood culture isolates in dialysis units that do not have a MRSA problem. A fixed dose of 2 g cefazolin could therefore be used for empiric treatment of sepsis in chronic haemodialysis patients as an alternative for vancomycin.

References

  1. Anonymous. Performance Standards for Antimicrobial Susceptibility Testing; eight international supplement. NCCLS 1998; 18(1)
  2. Leclercq R, Courvalin P. Resistance to glycopeptides in Enterococci. Clin Infect Dis 1997; 24: 545–554[ISI][Medline]
  3. Hospital Infection Control Practices Advisory Committee. Recommendations for preventing the spread of vancomycin resistance. Infect Control Hosp Epidemiol 1995; 16: 109–113
  4. Keane WF, Alexander SR, Bailie GR et al. Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update. Peritoneal Dial Int 1996; 16: 557–573[ISI][Medline]
  5. Marx MA, Frye RF, Matzke GR, Golper TA. Cefazolin as empiric therapy in hemodialysis-related infections: efficacy and blood concentrations. Am J Kidney Dis 1998; 32: 410–414[ISI][Medline]




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