Pharmacokinetics of Intermittent Intravenous Cefazolin and Tobramycin in Patients Treated with Automated Peritoneal Dialysis

Peritonitis remains a cause of significant morbidity and mortality in peritoneal dialysis (PD) patients (1,2,3). In 1996, the Ad Hoc Committee on the treatment of peritonitis in PD patients recommended a number of changes in the antibiotic regimens used to treat infections (4). There has been a general move toward the use of intermittent, as opposed to continuous, dosing of antibiotics (5,6,7). Intermittent antibiotic dosing initiatives have been promulgated because it is thought that this regimen provides specific advantages in PD, including convenience, reduced toxicity, and a decreased risk of accidental contamination of the system by the patient. Reversion to continuous therapy might be appropriate under certain circumstances, such as in patients who maintain significant residual renal function.

First-line agents recommended by the Ad Hoc Committee for the treatment of peritonitis are a first generation cephalosporin (e.g., cefazolin or cephalothin) and an aminoglycoside (e.g., gentamicin or tobramycin) by intraperitoneal administration (4). Two recent studies in continuous ambulatory PD (CAPD) patients demonstrated the effectiveness of these first-line agents (5,6). The pharmacokinetics of intraperitoneal cephalosporins and aminoglycosides given intermittently in CAPD patients demonstrate adequate serum and dialysate concentrations, and thereby help clarify the outcomes observed (7,8,9,10).

One further complication is the increasing use of different variants of PD. In 1997, there were about 222,000 end-stage renal disease patients in the United States treated with dialysis (11). Of these, 7.5% (16,630) were treated with CAPD and about 4.4% (9,756) with some type of automated system. Automated PD (APD) patients account for approximately 37% of all PD patients in 1997. In APD, three to four exchanges are carried out automatically at night using a cycler while the patient sleeps. Patients may then have either no daytime dwell (“dry day”), or one or more daytime ambulatory dwells.

These systems involve very different exchange characteristics since there are varying dialysate volumes and dwell durations. It might be expected, then, that the disposition of drugs would differ considerably between CAPD and APD. Although the intermittent regimen has been well studied in CAPD, there are few data for APD systems.

It was hypothesized that the serum and dialysate concentrations of cefazolin and tobramycin, administered using a once daily, intermittent intravenous regimen to cycler APD patients, will be maintained over a 24-h period at levels adequate to eradicate a bacterial peritonitis.

The two primary objectives were to quantify the pharmacokinetic parameters of cefazolin and tobramycin and to provide cefazolin and tobramycin dosing recommendations based on the pharmacokinetic parameters characterized. Secondary objectives were to characterize and compare the serum, dialysate, and urine concentrations of cefazolin and tobramycin at various times over a 24-h period attained in anuric and nonanuric APD patients and to correlate PD clearance with indices of dialysis adequacy.

Materials and Methods

Results

Ten patients were enrolled in the study. The mean duration on PD was 20.2 ± 25.5 mo. All 10 patients received tobramycin and eight received cefazolin (two patients had a cephalosporin allergy). The patient demographics are shown in Table 1. The mean GFR was 2.57 ± 1.46 ml/min per 1.73 m². The mean cefazolin and tobramycin serum peak concentrations (beginning of dwell 1) were 164.7 ± 36 and 4.1 ± 0.7 mcg/ml, respectively.

Summaries of pharmacokinetic parameters for cefazolin and tobramycin are shown in Table 2. The mean dwell times for dwells 1 to 3 (on cycler) were 2.4 ± 0.2, 2.6 ± 0.3, and 2.5 ± 0.2 h, respectively. The mean dwell times for dwells 4 to 5 (off cycler) were 7 ± 0.3 and 8.4 ± 0.6 h, respectively. The elimination half-life on the cycler was significantly less than off the cycler for both study drugs (cefazolin P value = 0.001 ; tobramycin P value < 0.001). The mean k_sd of dwells 1 to 3 for tobramycin were significantly different between anuric and nonanuric patients : dwell 1, 0.54 ± 0.27 h^-1 anuric, 0.39 ± 0.09 h^-1 nonanuric (P = 0.03) ; dwell 2, 0.57 ± 0.02 h^-1 anuric, 0.54 ± 0.06 h^-1 nonanuric (P = 0.05) ; dwell 3, 0.68 ± 0.08 h^-1 anuric, 0.55 ± 0.12 h^-1 nonanuric (P = 0.05). The mean k_sd of dwells 1 to 3 for cefazolin were not significantly different between anuric and nonanuric patients.

The mean cefazolin Cl_t was 4.82 ± 0.83 ml/min per 1.73 m². There was no significant difference observed in cefazolin Cl_t between anuric and nonanuric patients : 4.59 ± 1.5 and 4.9 ± 0.7 ml/min per 1.73 m², respectively (P = 0.34). The mean tobramycin Cl_t was 4.25 ± 0.65 ml/min per 1.73 m². There was no significant difference in tobramycin Cl_t between anuric and nonanuric patients : 4.13 ± 0.46 and 4.3 ± 0.75 ml/min per 1.73 m², respectively (P = 0.37). Cefazolin and tobramycin Cl_pd was 2.22 ± 0.6 and 4.45 ± 1.61 ml/min per 1.73 m², respectively. Cefazolin and tobramycin Cl_r was 1.33 ± 0.91 and 1.74 ± 1.37 ml/min per 1.73 m², respectively.

The mean cefazolin and tobramycin serum and dialysate concentrations at the end of each dwell (1,2,3,4,5) for all patients are shown in Figure 1. For cefazolin, the mean serum and dialysate concentrations remained in excess of minimum inhibitory concentrations (MIC) for sensitive organisms (approximately 8 mcg/ml) (14) throughout the 24-h period. For tobramycin, the mean serum and dialysate concentrations remained above the MIC for sensitive organisms (approximately 1 to 2 mcg/ml) (15) throughout the 24-h period. Statistical difference was not observed between anuric and nonanuric patients' serum and dialysate drug concentrations at the end of any dwell.

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Figure 1.

Mean cefazolin and tobramycin serum and dialysate concentrations at end of dwell. •, dialysate concentration ; ▴, serum concentration.

The correlation (r²) between GFR and cefazolin and tobramycin Cl_r was 36% (P = 0.05) and 52% (P < 0.005), respectively. The correlation between cefazolin and tobramycin Cl_pd and urea Kt/V_pd was 31% (P = 0.08) and 63% (P < 0.002), respectively.

The patients were divided into two groups depending on their duration on PD. The mean duration on PD for group 1 (patients A through D) and group 2 (patients E through J) was 44.3 ± 25.7 and 4.2 ± 1.3 mo, respectively (P = 0.05). The urea Kt/V_pd values for both groups were as follows : urea Kt/V_pd (group 1 = 0.19 ± 0.03 ; group 2 = 0.26 ± 0.08 ; P = 0.05). The Cl_pd values for both study drugs were as follows : cefazolin Cl_pd (group 1 = 2.2 ± 0.5 ml/min per 1.73 m², group 2 = 2.2 ± 0.9 ml/min per 1.73 m² ; P = 0.49) ; tobramycin Cl_pd (group 1 = 3 ± 0.6 ml/min per 1.73m² ; group 2 = 5.4 ± 1.3 ml/min per 1.73 m² ; P < 0.001).

Model-predicted serum and dialysate cefazolin and tobramycin end of dwell concentrations for a 70-kg individual post-intermittent intraperitoneal administration are shown in Table 3. The cefazolin and tobramycin intraperitoneal doses used in the model were 1000 and 40 mg, respectively. Intraperitoneal administration would yield an initial serum cefazolin concentration of 71.4 mcg/ml and tobramycin serum concentrations of 1.5 mcg/ml. Initial dialysate concentrations, in a 2-L exchange, would be 500 mcg/ml cefazolin and 20 mcg/ml tobramycin. Intermittent intraperitoneal cefazolin administration during the second ambulatory dwell (dwell 5) yielded adequate end of dwell serum concentrations throughout the 24-h period for sensitive organisms (MIC approximately 8 mcg/ml) (14). Cefazolin administered during the first ambulatory dwell would provide adequate serum, but not dialysate, coverage throughout the 24-h period. Intermittent intraperitoneal tobramycin administration yielded adequate dialysate concentrations (MIC approximately 1 to 2 mcg/ml) (15) for the antibiotic-containing exchange only. The remaining dwells, regardless of first or second ambulatory dwell administration, provided inadequate tobramycin end of dwell dialysate concentrations. Model-predicted tobramycin serum concentrations were within an acceptable MIC range during each dwell, regardless of first or second ambulatory dwell administration.

Discussion

The purpose of this study was to characterize the pharmacokinetics of a single intravenous dose of cefazolin and tobramycin in APD patients using three cycler exchanges over 8 h and two ambulatory exchanges occurring over 16 h. The mean serum and dialysate cefazolin concentrations, at the end of the study period after a 15 mg/kg intravenous dose, were about 57.7 and 18.9 mcg/ml, respectively. This would provide adequate coverage for even moderately resistant organisms (14). We have also demonstrated that tobramycin 0.6 mg/kg intravenously yielded adequate serum and dialysate concentrations for susceptible organisms throughout the study period (15).

Although the intermittent regimen of cephalosporins and aminoglycosides has been well studied in CAPD, there are few data for APD systems (8,9,10, 16,17,18,19). Extrapolation of our findings observed after intravenous administration to intraperitoneal administration would yield similar pharmacokinetic parameters. However, two significant differences occurred in patients after intraperitoneal administration of cefazolin or tobramycin compared with intravenous administration. First, the initial dialysate concentration in a 70-kg individual would be approximately 500 mcg/ml and 20 mcg/ml for cefazolin and tobramycin in a 2-L exchange, respectively. These concentrations are well above the MIC of even resistant organisms (14,15). This would also enable concentration-dependant killing (tobramycin). Second, intraperitoneal administration would produce lower initial cefazolin and tobramycin serum concentrations. With intraperitoneal administration, approximately 70% of cefazolin dose and approximately 56% tobramycin dose would be absorbed from the antibiotic-containing dwell (8,9,10). Resulting initial serum concentrations would be approximately 30% (cefazolin) and 44% (tobramycin) less than we observed in our study. The remaining pharmacokinetic parameters (elimination rate constants, half-lives, volumes of distribution, and clearances) should not change.

The Ad Hoc Committee recommends that intraperitoneal antibiotics be allowed to dwell for at least 4 h (4), which would necessitate administration to one of the daytime ambulatory exchanges in an APD patient. As shown in Table 3, model-predicted intraperitoneal cefazolin and tobramycin serum and dialysate concentrations in a 70-kg individual would vary depending on which ambulatory exchange the antibiotics were administered. For example, intraperitoneal cefazolin administration during the second ambulatory exchange would provide adequate serum and dialysate concentrations (8 mcg/ml) for all dwells, whereas intraperitoneal cefazolin administered during the first ambulatory exchange would not. According to our model, it would require 20 mg/kg cefazolin intraperitoneally during the first ambulatory exchange to provide adequate serum and dialysate concentrations throughout.

Model-predicted intraperitoneal tobramycin dosing provided adequate serum concentrations throughout the 24-h period and adequate dialysate concentrations for the antibiotic-containing dwell only. All remaining dwells, on and off the cycler, had inadequate tobramycin end of dwell dialysate concentrations regardless of timing of initial antibiotic-containing dwell. To provide sufficient tobramycin dialysate concentrations (> 1.0 mcg/ml), the initial intermittent intraperitoneal dose would have to be at least 1.43 mg/kg, if administered during the first ambulatory exchange, or 1.35 mg/kg if administered during the second ambulatory exchange. The overall elimination half-life of tobramycin was about 41 h. It would take approximately 1 wk (41/2 half-lives) before tobramycin steady state is achieved, resulting in accumulation. Subsequent daily intraperitoneal tobramycin (0.5 mg/kg), in either the first or second ambulatory exchange, would provide sufficient serum concentrations and dialysate concentrations (> 1.0 mcg/ml) throughout a 24-h period.

Aminoglycoside-associated otovestibular toxicity becomes a concern in renal failure patients when elevated levels are sustained (20). One study investigated cochlear function in 40 CAPD peritonitis patients who received 1.7 mg/kg tobramycin for the first exchange then 8 mg/L in each exchange thereafter (21). Their results did not demonstrate that tobramycin led to ototoxicity despite obtaining serum concentrations of 4.4 to 4.9 mcg/ml over a mean of 9.5 d. Our tobramycin dosing recommendations would maintain serum concentrations between 2.4 and 3.5 mcg/ml. However, caution is still warranted with prolonged or repeated courses of tobramycin treatment or concurrent use with other potentially ototoxic agents.

The Ad Hoc Committee recommends a 25% increase in antibiotic dose in nonanuric patients (4). Although statistical significance was not found between anuric and nonanuric patients in our study, the correlations between GFR and cefazolin and tobramycin clearance demonstrate the importance of residual renal function on drug elimination. Additionally, our nonstatistical results may be reflective of the low sample size comparisons (7 nonanuric patients versus 3 anuric patients) and relatively low residual renal function (GFR = 2 to 3 ml/min per 1.73 m²). However, patients may begin dialysis at much higher GFR (10 to 15 ml/min per 1.73 m²) once Dialysis Outcome Quality Initiative guidelines are implemented (13). Cefazolin and tobramycin clearances would be significantly higher in those “early-start” patients. Antibiotic doses will need to be increased appropriately to reflect the higher residual renal function.

During a peritonitis episode, drug pharmacokinetic parameters may be expected to change. With an inflamed peritoneum, more drug would be absorbed from intraperitoneal administration, resulting in higher serum concentrations and providing adequate coverage for more resistant organisms. Conversely, drug elimination from the serum to the dialysate would also increase during drug-free dialysate dwells. This may result in lower than acceptable serum and dialysate concentrations between dosing intervals. Until further investigation of drug pharmacokinetic parameters during peritonitis episodes has been undertaken, caution is warranted when applying our results to peritonitis patients.

We are aware of no other report correlating the effects of peritoneal function (urea Kt/V_pd) to cefazolin and tobramycin Cl_pd. We found that duration of PD has a significant effect on urea Kt/V_pd and drug removal. One might expect that over time the peritoneum becomes less able to transport solutes due to fibrosis and scarring, possibly due to prior episodes of peritonitis. For this reason, the Dialysis Outcome Quality Initiative recommends peritoneal equilibration testing (PET) and creatinine clearance after peritonitis and quarterly to assure that adequate dialysis is being delivered to the patient (13). Our results illustrate that drug removal through the peritoneum may be dependent on individual peritoneal function. The cefazolin and tobramycin absorptive characteristics (i.e., bioavailability) with varying degrees of peritoneal function using PET results would need to be investigated.

In summary, the current cefazolin recommendations (15 mg/kg intraperitoneally) would provide adequate coverage if administered during the second ambulatory exchange in an APD patient with three cycler exchanges occurring over 8 h. Cefazolin (20 mg/kg, intraperitoneally) would be necessary if administered during the first ambulatory exchange. Tobramycin dosing recommendations (0.6 mg/kg intraperitoneally need to be amended for APD patients with three cycler exchanges occurring over 8 h to 1.5 mg/kg intraperitoneally on day 1, then 0.5 mg/kg intraperitoneally thereafter during either ambulatory exchange. The pharmacokinetics of cefazolin and tobramycin in APD patients prescribed more than three cycler exchanges need further investigation.