Nov 7, 1984 - MICHAEL D. REED,1'2 ROBERT C. STERN,"2 CHERYL A. O'BRIEN,"2 ..... Ferber, J. L. Huber, K. H. Jones, F. M. Kahan, J. S. Kahan, H. Kropp ...
Vol. 27, No. 4
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1985, p. 583-588 0066-4804/85/040583-06$02.00/0 Copyright © 1985, American Society for Microbiology
Pharmacokinetics of Imipenem and Cilastatin in Patients with Cystic Fibrosis MICHAEL D. REED,1'2 ROBERT C. STERN,"2 CHERYL A. O'BRIEN,"2 TOYOKO S. YAMASHITA,"3 CAROLYN M. MYERS,"2 AND JEFFREY L. BLUMERI24* Divisions of Pediatric Pharmacology and Critical Care and Pulmonary Medicine, Rainbow Babies and Childrens Hospital,' and Departments of Pediatrics,2 Pharmacology,4 and Biometry, Case Western Reserve University Schlool of Medicine, Cleveland, Ohio 44106 Received 7 November 1984/Accepted 24 January 1985
The pharmacokinetics of imipenem, a new carbapenem antibiotic, and cilastatin, a metabolic inhibitor, were evaluated in 17 patients with cystic fibrosis. Imipenem and cilastatin were combined in a ratio of 1:1 in the infusion solution, and patients intravenously received 30, 60, or 90 mg of imipenem per kg of body weight per day, divided into four equal doses. Pharmacokinetic evaluation after the first dose and again under steady-state conditions revealed biodisposition characteristics which were similar and independent of the daily dose administered. Cilastatin concentrations in serum paralleled those of imipenem. A linear relationship between dose and area under the serum concentration-time curve for both compounds was observed, suggesting a first-order pharmacokinetic process. A total of 50 and 78% of the doses of imipenem and cilastatin, respectively, were recovered unchanged in the urine. The renal clearances of imipenem and cilastatin averaged 54 and 88%, respectively, of the serum clearance. These data suggest that an extrarenal mechanism may be involved in the overall elimination of imipenem. No patient experienced any clinical or biochemical abnormalities during drug therapy.
tional Review Board for Human Subject Investigation of the University Hospitals of Cleveland. Written, informed consent was obtained from each patient or family or both. Before drug administration, each patient underwent a complete physical examination and had a laboratory evaluation which included serum electrolytes, tests of renal and liver function, urinalysis, complete blood count with differential, and prothrombin and partial thromboplastin times. Drug administration. Imipenem was supplied as a sterile crystalline powder equivalent to 500 mg, and cilastatin was supplied as a sterile solution equivalent to 500 mg/10 ml (Merck Sharp & Dohme Research Laboratories, Rahway, N.J.). Imipenem powder was reconstituted with 10 ml of cilastatin solution and further added to 90 ml of 0.22% sodium chloride for a final infusate concentration of 5 mg of imipenem and 5 mg of cilastatin per ml. Doses were infused intravenously over 30 min through a peripheral vein. Immediately after drug administration, the intravenous infusion tubing was flushed with 20 to 30 ml of 0.22% sodium chloride solution to ensure administration of the total dose. Venous blood samples (minimum, 1 ml) for the determination of imipenem and cilastatin in serum were obtained at 0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 h after the beginning of the infusion and were repeated after the patients had received the same dose administered every 6 h for a minimum of 3 days. Blood was collected in sterile glass tubes, allowed to clot, and immediately centrifuged. Serum was removed and stabilized with 1 volume of 1 M morpholineethanesulfonic acid buffer (pH 6.0) and stored at -70°C until analyzed. Before administration of the first dose, a urine sample was obtained; thereafter, urine was obtained in 2-h aliquots during the 6-h study period. Determination of imipenem and cilastatin by high-pressure liquid chromatography. The concentrations of imipenem and cilastatin in both serum and urine were determined by high-pressure liquid chromatography. Concentrations in serum were determined as described previously (16). For
Imipenem, the N-formimidoyl derivative of thienamycin, is the first of a new class of 1-lactam antibiotics. In vitro studies of imipenem have demonstrated a broad spectrum of antibacterial activity (25, 28) which includes both ,-lactamand aminoglycoside-resistant pathogens (10, 14, 22, 26). In addition, the drug has been shown to be resistant to multiple 3-lactamases (3, 21) and to possess marked in vitro activity against methicillin-resistant staphylococci (14, 26, 29). Preliminary biodisposition studies of imipenem in animals and humans have demonstrated stable systemic profiles accompanied by variable amounts of renal degradation of the compound (13, 18). This finding is a result of the rapid renal hydrolysis of the imipenem ,B-lactam ring by the brush border enzyme dehydropeptidase I (13, 17, 18). To circumvent the renal inactivation of imipenem, cilastatin, a competitive inhibitor of renal dehydropeptidase I, is currently being evaluated for concomitant administration (17). The purpose of the present investigation was to assess the first-dose and steady-state pharmacokinetics of imipenem and cilastatin in patients with cystic fibrosis after the administration of these drugs in three different dosage regimens. (Portions of this work were presented at the 85th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Atlanta, Ga., March 1984 [Clin. Pharmacol. Ther. 35:268] and at the 5th Annual Meeting of the American College of Clinical Pharmacy, San Diego, Calif., June 1984 [Drug Intell. Clin. Pharm. 18:512].) MATERIALS AND METHODS Subjects. Patients with cystic fibrosis who were .12 years of age were eligible for enrollment in this study. No patient was in overt respiratory failure or demonstrated evidence of impaired renal or hepatic function. No patient received any additional antimicrobial therapy during the imipenem-cilastatin study period. This study was approved by the Institu*
Corresponding author.
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584
TABLE 1. Patient characteristics"
Dosage (mg/kg (mg/kg day) perper 30 (n = 7)
Aeyr
Age (yr)
creatinine Shwachman score' (m2) ara(l(mg/dl)
3/4
19.2 ± 6.1
34.8 ± 6.5
(25.4-42.7)
(14.5-31.6) 60 (n = 5) 90 (n
=
5)
SrmPO (mg' (mmHg)"
surface NoofBody Wt (kg) area
males/ ~~females
21.6 ± 8.4 (14-36)
3/2
15.7 ± 3 (12.3-19.6)
1/4
1.24 ± 0.16
(0.99-1.4)
45.5 ± 5.9 (39.8-53.1)
1.47 ± 0.1
31.9 ± 8.5 (22.5-44.0)
1.1 ± 0.2 (0.91-1.49)
(1.31-1.61)
GT (Ultr (ISU/IiPT)
42.9 ± 12.8 (24-57)
0.6 ± 0.2 (0.3-1.0)
33.4 ± 3.1 (29-37)
20.3 ± 7
46.5 ± 18.4 (33-72)
0.9 ± 0.2 (0.6-1.1)
44.6 ± 14 (30-60)
23 ± 15 (7-44)
39.8 ± 7.1 (30-45)
0.7 ± 0.3 (0.3-1.1)
34.5 ± 2.5 (32-38)
16.2 ± 8.6 (5-27)
(8-27)
a Values are means - standard deviations. Ranges are shown in parentheses. See reference 20. c PCO2, Partial pressure of carbon dioxide. d SGPT, Serum glutamic pyruvic transaminase. b
determination of concentrations in urine, after stabilization, particulate matter was removed by centrifugation and a 6- to 144-fold dilution was made of the supernatant. Urinary cilastatin analysis was performed by the method used for determination of concentrations in serum. Similar methodology was used for urinary imipenem concentrations, with the following modifications: a 25-,ul injection was employed, and the mobile phase consisted of 0.02 M sodium phosphate buffer, (pH 6.5) containing 5% methanol. A flow gradient from 0.5 to 1.0 ml/min was programmed over the first 12 min of each chromatographic run. To wash later interfering urinary components off the column, we often used a higher flow rate and methanol concentration after the imipenem peak emerged. Pharmacokinetic analysis. Imipenem and cilastatin concentrations in the serum of each patient were plotted against time on a semilogarithmic scale. Model independent pharmacokinetic techniques were used to describe the biodisposition of both agents (5). The area under the serum concentration-time curve (AUC) was obtained by using the linear trapezoidal rule up to the final measured concentration in serum and extrapolated to infinity after the first dose, and to the end of the dosing interval, T, during steady-state conditions. The elimination half-life was determined using the post-distributive terminal portion of the serum concentration-time curve. Serum clearance (CLs) was determined with the formula dose/AUC. after the first dose and dose/AUC,D_, during steady state. The apparent steady-state volume of distribution (Vss) after the first dose was determined using the equation Vss [(dose AUMC)/(AUC2)] [(dose * T)/(AUC * 2)], where AUMC is the area under the first moment of the concentration-time curve and T is the infusion duration. The determination of Vss after multiple dosing was calculated by the superposition method (2). The renal clearance (CLR) of imipenem and cilastatin for each patient was calculated as CLR = AGT/AUCo.,, where A is the cumulative amount of drug excreted (27). Statistical evaluations were performed with the paired and unpaired Student t test (24), analysis of variance (12), and regression analysis (11). =
-
RESULTS Seventeen patients were enrolled in the study. Combined first-dose and steady-state pharmacokinetic evaluations were possible in 15 patients. A single first-dose evaluation was performed in one patient (30 mg/kg per day) and a steadystate evaluation in one patient (90 mg/kg per day). Patient
characteristics, subdivided by imipenem-cilastatin dosage, are shown in Table 1. Overall, the groups were comparable, although children who received 90 mg of imipenem-cilastatin per kg per day were younger. Females predominated in two of the three groups. Cystic fibrosis scores were comparable for the three groups (23). Figures 1 and 2 depict the overall imipenem and cilastatin serum concentration-time curves after the first dose. Peak concentrations of both agents in serum were observed at the completion of the 30-min infusion and correlated directly with the dose administered (r = 0.86). Minimal differences were observed in the character of these curves after multiple dosing. Five of seven patients who received 30 mg/kg per day and one of five patients who received 90 mg/kg per day had no detectable imipenem in serum at the 360-min sampling period. In contrast, five of seven patients who received 30 mg/kg per day, three of five patients who received 60 mg/kg per day, and two of five patients who received 90 mg/kg per day had no detectable cilastatin at the 300-min sampling time. Overall, however, the biodisposition of cilastatin paralleled that of imipenem. Little or no drug accumulation was observed with either component after multidrug dosing. Tables 2 and 3 show the pharmacokinetic parameters for imipenem and cilastatin determined after the first dose and during steady-state conditions. Overall, the pharmacokinetic profile of cilastatin closely resembled that of imipenem. Differences observed for either agent between first-dose and steady-state pharmacokinetic parameters were statistically insignificant at any dose studied. Analysis of variance for these parameters revealed no differences for elimination half-life, Vs5, or CLs. Although statistically insignificant, the V5, for both imipenem and cilastatin were somewhat larger after the 30-mg/kg-per-day dosage regimen than at the other dosage levels. As expected, the AUC for both compounds increased with increasing dose. Evaluation of the relationship between dose (30, 60, or 90 mg/kg per day) and AUC is shown in Table 4. These data reveal a positive linear relationship between dose and AUC. When considered in context with the observed relationship between dose and peak imipenem (Fig. 1) or cilastatin (Fig. 2) concentration, a first-order elimination process is suggested for both components over the dosage range studied. First-dose urinary recovery data for both imipenem and cilastatin was available in 10 of the 17 children (Fig. 3). The largest amount of the dose was excreted in the first 2-h collection period for both agents. Overall, 49.8 and 78.4% of
IMIPENEM AND CILASTATIN IN CYSTIC FIBROSIS
VOL. 27, 1985
the administered doses of imipenem and cilastatin, respectively, were recovered in the urine during the 6-h study period. The CLR for both components is shown in Table 5. The CLR accounted for 54 and 88% of the imipenem and cilastatin CLs, respectively. During the 10-day study period, no hepatic, renal, or bone marrow toxicity was associated with imipenem or cilastatin administration in any patient. Two patients complained of mild nausea and vomiting (one each at the 30- and 90-mg/kgper-day regimens) which was associated with drug administration and lasted 2 and 3 days, respectively. In addition, intermittent phlebitis lasting between 2 and 3 days was observed in three patients (two at the 30- and one at the 60-mg/kg-per-day regimens). The intensity of these side effects was mild and did not necessitate alteration or discontinuation of drug therapy in any patient.
DISCUSSION Cystic fibrosis is a heritable disorder characterized by an elevated sweat chloride, pancreatic exocrine insufficiency,
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TIME (minutes) FIG. 2. Cilastatin serum concentration-time curves. Serum samples for determination of cilastatin concentrations were obtained at the times indicated after administration of 7.5 (0), 15 (A) and 22.5 (0) mg/kg over 30 min. Concentrations in serum were determined by high-pressure liquid chromatography as described in the text and were plotted semilogarithmically for pharmacokinetic analysis. The horizontal dotted line depicts the limit of detection for the high-pressure liquid chromatographic technique.
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TIME (minutes) FIG. 1. Imipenem serum concentration-time curves. Serum samples for determination of imipenem concentrations were obtained at the times indicated after administration of 7.5 (0), 15 (A), and 22.5 (0) mg/kg over 30 min. Concentrations in serum were determined by high-pressure liquid chromatography as described in the text and were plotted semilogarithmically for pharmacokinetic analysis. The horizontal dotted line depicts the limit of detection for the high-pressure liquid chromatographic technique.
and chronic obstructive pulmonary disease (6, 31). Advances in diagnosis, pancreatic enzyme replacement, dietary considerations, and chest physiotherapy have all assisted greatly in prolonging the survival of children afflicted with this disease. It is apparent, however, that the majority of the morbidity and mortality associated with this multisystem disorder is related primarily to the associated chronic obstructive pulmonary component. Chronic pulmonary infections, which are the hallmark of cystic fibrosis, increase in severity as patients age. Intensive chest physiotherapy and repeated courses of potent broadspectrum antibiotics are currently recommended (15, 30). This approach is confounded in that several studies have demonstrated that the biodisposition profiles of a number of drugs, including antibiotics, are altered in patients with cystic fibrosis (7-9, 19, 32). These data underscore the need for rigorous pharmacokinetic evaluations of therapeutic agents in these patients before assessment of their potential clinical efficacy. The current study was designed to describe the pharmacokinetics and tolerance of the imipenem-cilastatin combination in patients with cystic fibrosis under conditions proposed for its clinical use.
586
ANTIMICROB. AGENTS CHEMOTHER.
REED ET AL.
TABLE 2. First-dose and steady-state pharmacokinetics of imipenem in patients with cystic fibrosisa Dose (mi/min hcV,(iesk)CLs s (liters/kg) per 1.73 m2) (mg/kg per day)")b42 t1/23 (h)C
AUC
(jig h/ml)
30 262.4 ± 104.5
25.4 ± 9.4
0.8 ± 0.1 (0.6-1.0)
0.34 ± 0.15
(0.21-0.64)
(158.9-425.8)
(12.5-36.7)
SS (n = 6)
0.9 ± 0.2 (0.8-1.2)
0.32 ± 0.09 (0.23-0.47)
239.5 ± 55.2 (156.3-297.1)
25.5 ± 8.2 (19.5-37.3)
FD (n = 5)
1.0 ± 0.2 (0.9-1.3)
0.25 ± 0.06 (0.16-0.32)
181.0 ± 38.1 (152.2-237.6)
76.1 ± 15.1 (53.2-90.8)
SS (n = 5)
1.0 ± 0.2 (0.8-1.2)
0.29 ± 0.05 (0.21-0.35)
221.0 ± 56.5 (130.6-280.1)
64.5 ± 19.6 (50.0-98.4)
FD (n = 4)
0.8 + 0.1 (0.7-1.0)
0.27 ± 0.04 (0.23-0.32)
220.0 + 52.7 (172.3-291.1)
81.5 + 21.2 (57.7-104.3)
SS (n = 5)
1.0 ± 0.1 (0.9-1.1)
0.30 ± 0.17 (0.11-0.56)
218.4 ± 93.4 (113.0-359.4)
91.8 ± 35.3 (46.7-141.9)
FD (n = 7)
60
90
a Values are means + standard deviations. Ranges are shown in parentheses. FD, First dose; SS, steady state. c t 1a, Elimination half-life. b
The pharmacokinetic data generated in the present study are similar to imipenem profiles observed in unaffected adult volunteers (18). Norrby et al. (17, 18) have shown that the coadministration of either probenecid or dehydropeptidase inhibitors only mildly affect the systemic biodisposition of imipenem. From these data and data generated in chimpanzees, it appears that renal tubular secretion of imipenem accounts for a small fraction of the overall renal elimination (13). We have found previously that P-lactam compounds that undergo minimal renal tubular secretion show no alteration in overall biodisposition in cystic fibrosis patients (20). These data suggest that the more rapid elimination of certain antibiotics in these patients may be related to altered renal
excretory mechanisms. Arvidsson and colleagues (1), in assessing the urinary clearance of cefsulodin in cystic fibrosis patients and unaffected individuals, found comparable results, although the actual renal elimination pathway(s) was different in patients with cystic fibrosis. The overall serum concentration-time curves for imipenem and cilastatin are shown in Fig. 1 and 2, respectively. The cilastatin profiles closely resembled those of imipenem, supporting the coadministration of this dehydropeptidase inhibitor with imipenem. However, the concentration of cilastatin within the kidney is of greater importance than in serum, since the in vivo degradation of imipenem occurs primarily within the renal tubules. Measurable urinary con-
TABLE 3. First-dose and steady-state pharmacokinetics of cilastatin in patients with cystic fibrosis' Dose
t1/2 (h)c
v,, (liters/kg)
per 1.73m2)
AUC (,ug * h/ml)
FD (n = 7)
0.9 ± 0.3
0.3 ± 0.07
(0.2-0.4)
252.9 + 64.9 (198.8-374.2)
24.4 ± 5.7
(0.5-1.5) 1.1 ± 0.5
0.31 ± 0.09
30
SS (n = 6)
(0.6-2.0)
(0.21-0.45)
233.8 ± 33.9 (204.9-294.2)
24.9 + 5.0 (17.4-31.1)
0.7 + 0.3
(0.4-1.1)
0.23 ± 0.12 (0.13-0.43)
221.2 + 72.3 (136.8-332.9)
65.5 + 20.6 (38.0-94.0)
+ 0.2 (0.7-1.2)
0.26 ± 0.05 (0.21-0.33)
246.4 ± 68.5 (130.6-301.7)
59.2 ± 22.3 (45.8-98.4)
267.0 ± 149.1 (152.1-473.7)
79.7 + 39.6 (35.4-118.1)
243.0 + 138.8 (124.9-472.5)
88.5 + 37.7 (35.5-128.5)
60 FD (n = 5)
SS (n = 5)
0.9
FD (n = 4)
0.7
90
SS (n = 5)
(13.3-28.3)
0.2
0.25 ± 0.09
(0.5-0.9)
(0.17-0.37)
0.8 ± 0.2
0.25 ± 0.16
(0.6-1.1)
(0.09-051)
+
a Values are means + standard deviations. b FD, First dose; SS, steady state. c t1/2, Elimination half-life.
VOL. 27, 1985
IMIPENEM AND CILASTATIN IN CYSTIC FIBROSIS
TABLE 4. Linear regression of AUC or dose Correlation
Drug'
coefficient
Imipenem FD SS
0.82 0.77
y = 0.74 + 1.002x y = -6.12 + 1.11x
Cilastatin FD SS
0.73 0.77
y = -0.498 + 0.952x y= -6.25 + 1.063x
a FD, First dose, SS, steady state. b p < 0.001 for all r values. c y, AUC; x, dose.
centrations of cilastatin were observed throughout the 6-h study period. Concentrations of both imipenem and cilastatin in serum were proportional to the dose administered, supporting a first-order linear relationship between dose and concentration in serum. In addition, over the three dosage schedules studied, a linear relationship was observed between drug dose and AUC (Table 4). Both of these findings have been reported previously in unaffected adults (17, 18). A total of 50 and 78% of the administered doses of imipenem and cilastatin, respectively, were recovered in the urine over the 6-h study period (Fig. 3). The CLR for both imipenem and cilastatin averaged 54 and 88%, respectively, of the CLs of each compound (Table 5). Previous data in healthy volunteers demonstrated an imipenem CLR accounting for approximately 70% of the CLs (17). The reason for this potential discrepancy between the CLR/CLs ratio of imipenem in our study and the data reported by Norrby et al. is unclear. Possible explanations would include competitive inhibition of the renal elimination of imipenem by the coadministration of cilastatin, decreased affinity of dehydropeptidase I for cilastatin, and differences in the renal metabolism of imipenem in cystic fibrosis patients. The overall difference between imipenem CLR and CLs has been reported previously, suggesting extrarenal elimination or metabolism of imipenem (17).
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TABLE 5. Renal pharmacology of imipenem and cilastatin in 10 cystic fibrosis patientsa
Rgeso qain Regression equationc
(r)b
kL1T]
T
T
c_
j
2-4 4-6 0-6 TIME AFTER DOSE (hours) FIG. 3. Cumulative urinary excretion of imipenem ¢) and cilastatin (O). Each bar represents the mean standard deviation of the percent administered dose excreted unchanged in the urine during the indicated time period. ±
587
Drug
% of dose excreted 0-6
CLR
hml/min
Imipenem 49.8 ± 14.8 92.5 ± 40.1 Cilastatin 78.4 ± 20.4 150.4 ± 59.3
ml/mm per 1.73 m2
CLR/CLs
122.7 ± 59.7 0.54 ± 0.13 195.2 ± 75.6 0.88 ± 0.35
a Values are means ± standard deviations.
Drug dosing should be based, to a large extent, on the overall biodisposition characteristics of the agent in question in the target patient population. Since it is difficult to measure the amount of active drug at the site of action, the amount of drug in the plasma measured under chronic dosing conditions is thought to reflect the biologically active concentration (4). It would appear that imipenem administered at a dose of 90 to 100 mg/kg per day, divided every 6 h, should maintain concentrations in serum above the MIC for most Pseudomonas aeruginosa isolates throughout the dosing interval. Thus, we would recommend the use of this dose in a trial of clinical efficacy in patients with cystic fibrosis. ACKNOWLEDGMENT This work was supported in part by a grant from Merck Sharpe & Dohme Research Laboratories. LITERATURE CITED 1. Arvidsson, A. G., G. Alvan, and B. Stradvik. 1983. Difference in renal handling of cefsulodin between patients with cystic fibrosis and normal controls. Acta Paediatr. Scand. 72:293-294. 2. Bauer, L., and M. Gibaldi. 1983. Computation of model-independent pharmacokinetic parameters during multiple dosing. J. Pharm. Sci. 72:978-979. 3. Brown, J. E., V. E. Del Bene, and C. D. Collins. 1981. In vitro activity of N-formimidoyl thienamycin, moxalactam, and other new beta-lactam agents against Bacteroides fragilis: contribution of beta-lactamase to resistance. Antimicrob. Agents Chemother. 19:248-252. 4. Ferguson, J. 1939. The use of chemical potentials as indices of toxicity. Proc. R. Soc. London Ser. B 127:387-404. 5. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed., p. 409-417. Marcel Dekker, Inc., New York. 6. Holsclaw, D. S. 1980. Cystic fibrosis: overview and pulmonary aspects in young adults. Clin. Chest Med. 1:407-421. 7. Jusko, W. J., L. L. Mosovich, M. S. Gerbracht, M. E. Mattar, and S. J. Yaffe. 1975. Enhanced renal excretion of dicloxicillin in patients with cystic fibrosis. Pediatrics 56:1038-1044. 8. Kearns, G. L., B. C. Hilman, and J. T. Wilson. 1982. Dosing implications of altered gentamicin disposition in paients with cystic fibrosis. J. Pediatr. 100:312-318. 9. Kercsmar, C. M., R. C. Stern, M. D. Reed, C. M. Myers, D. Murdell, and J. L. Blumer. 1983. Ceftazidime in cystic fibrosis: pharmacokinetic and therapeutic response. J. Antimicrob. Chemother. 12(Suppl. A):289-295. 10. Kesado, T., T. Hashizume, and Y. Asahi. 1980. Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics. Antimicrob. Agents Chemother. 17:912-917. 11. Kleinbaum, D. G., and L. L. Kupper. 1978. Applied regression analysis and other multivariable methods, p. 37-70. PWS Publishers, Boston, Mass. 12. Kleinbaum, D. G., and L. L. Kupper. 1978. Applied regression analysis and other multivariable methods, p. 244-287. PWS Publishers, Boston, Mass. 13. Kropp, H., J. G. Sundelof, R. Hajdu, and F. M. Kahan. 1982. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase-I. Antimicrob. Agents Chemother. 22:62-70.
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14. Livingston, W. K., A. M. Elliott, and C. G. Cobbs. 1981. In vitro activity of N-formimidoyl thienamycin (MK0787) against resistant strains of Pseudomonas aeruginosa, Staphylococcus epidermidis, Serratia marcescens, and Enterococcus spp. Antimicrob. Agents Chemother. 19:114-116. 15. Marks, M. I. 1981. The pathogenesis and treatment of pulmonary infections in patients with cystic fibrosis. J. Pediatr. 98:173-179. 16. Myers, C. M., and J. L. Blumer. 1984. Determination of imipenem and cilastatin in serum by high-pressure liquid chromatography. Antimicrob. Agents Chemother. 26:78-81. 17. Norrby, S. R., K. Alestig, B. Bjorneg&rd, L. A. Burman, F. Ferber, J. L. Huber, K. H. Jones, F. M. Kahan, J. S. Kahan, H. Kropp, M. A. P. Meisinger, and J. G. Sundelof. 1983. Urinary recovery of N-formimidoyl thienamycin (MK0787) as affected by coadministration of N-formimidoyl thienamycin dehydropeptidase inhibitors. Antimicrob. Agents Chemother. 23:300-307. 18. Norrby, S. R., K. Alestig, F. Ferber, J. L. Huber, K. H. Jones, F. M. Kahan, M. A. P. Meisinger, and J. D. Rogers. 1983. Pharmacokinetics and tolerance of N-formimidoyl thienamycin (MK0787) in humans. Antimicrob. Agents Chemother. 23: 293-299. 19. Reed, M. D., R. C. Stern, J. S. Bertino, I. Ackers, C. M. Myers, T. S. Yamashita, and J. L. Blumer. 1984. Dosing implications of rapid elimination of trimethoprim-sulfamethoxazole in patients with cystic fibrosis. J. Pediatr. 104:303-307. 20. Reed, M. D., R. C. Stern, T. S. Yamashita, I. Ackers, C. M. Myers, and J. L. Blumer. 1984. Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis. Antimicrob. Agents Chemother. 25:579-581. 21. Richmond, R. H. 1981. The semi-synthetic derivative MK0787 and its properties with respect to a range of beta-lactamases from clinically relevant bacterial species. J. Antimicrob. Chemo-
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