Effects of Impaired Renal Function, Hemodialysis, and Peritoneal

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1980, p. 81-87 Vol. 18, No. 1 0066-4804/80/07-0081/07$02.00/0

Effects of Impaired Renal Function, Hemodialysis, and Peritoneal Dialysis on the Pharmacokinetics of Mezlocillin DIETER KAMPF,' RANDOLF SCHURIG,' KLAUS WEIHERMULLER,' AND DIETER FORSTER2 Department of Nephrology, Klinikum Charlottenburg, Free University ofBerlin, Berlin,' and Institute of Chemotherapy, Bayer AG, Wuppertal,2 Federal Republic of Gernany

The pharmacokinetics of mezlocillin were examined in 8 patients with normal renal function (inulin clearance, >80 ml/min per 1.73 m2), 32 patients with moderately reduced renal function (inulin clearance, 80 to 5 ml/min per 1.73 m2), and 12 patients maintained by hemodialysis or peritoneal dialysis because of severely impaired renal function. A single dose of 60 mg of mezlocillin per kg of body weight was infused intravenously over 30 min. Antibiotic concentrations in plasma, urine, and dialysate were determined by the agar diffusion technique. The half-life of mezlocillin increased with decreasing renal function from an average of 53 min in subjects with normal function to 165 min in oligoanuric patients. The urinary recovery of this drug in 24 h decreased from 65% at a glomerular fitration rate of 92 ml/min to 7.6% at a glomerular filtration rate of 6.7 ml/min. Volume of distribution was not changed by the renal insufficiency, amounting on the average to 22.5% of body weight. Intermittent hemodialysis or peritoneal dialysis contributed to only a minor degree to the 24-h mezlocillin kinetics. The pharmacokinetic properties of mezlocillin permit a normal dosage over wide ranges of renal insufficiency; however, when the glomerular filtration rate is below 10 ml/min, the dosage interval should be increased from 8 to 12 h.

Mezlocillin, an acylureido penicillin with Drug administration. Mezlocillin was infused in- broad-spectrum antibacterial activity, is indi- travenously as a single dose of 60 mg per kg of body cated for use in severe bacterial infections which weight over exactly 30 min by means of a constant- are often complicated by temporary renal im- infusion pump (Injektomat, E. Fresenius KG). In pa- pairment. For this reason, the pharmacokinetic tients without dialysis, blood samples were collected properties of this in in heparinized syringes at 0.5, 1, 1.5, 2, 3, 4, 5, 6.5, and drug patients with various 8 h; in addition, in group VI blood samples were drawn degrees of renal insufficiency, from moderate to at 9 and 12 h after termination ofinfusion. Plasma was very severe (requiring dialysis), are of particular separated immediately by centrifugation and stored at interest; results of studies ofthese properties are -18°C before processing. Urine was collected at 0 to presented here. 4, 4 to 8, 8 to 12, and 12 to 24 h after mezlocillin administration. At the end of each collection period, MATERIALS AND METHODS a sample was stored at -18°C before processing. Subjects. The pharmacokinetics of mezlocillin Hemodialysis and peritoneal dialysis. Hemo- were examined in a total of 52 patients (29 males and dialysis was started 1 h after termination of infusion 23 females; 18 to 77 years old; mean 44 years old) and continued for 5 to 6 h, using the model Lundia referred to our department for treatment of arterial Optima (Gambro Medizintechnitz GmbH & Co KG; 1- hypertension or kidney disease. All had apparently m2 surface area, 13.5-,um cuprophan membrane) as the normal hepatic and cardiac function. In patients not dialyzer. The blood flow in the extracorporal circula- requiring dialysis, the glomerular filtration rate (GFR) tion measured electromagnetically with a Statham was determined by inulin clearance (Ci., anthrone flowmeter SP 2201 amounted to 200 ml/min with one method). The spectrum of normal to extremely re- exception (150 ml/min). The dialysate flow regularly duced function was divided into six categories: group amounted to 600 ml/min (single-pass system; Gambro I, GFR of >80; II, GFR of 80 to 40; III, GFR of 40 to AK 5). To determine total body clearance and dialyzer 20; IV, GFR of 20 to 10; V, GFR of 10 to 5; and VI, clearance, samples were taken at hourly intervals from GFR of 5 to 0 ml/min per 1.73 m2. With the exception blood entering and leaving the dialyzer. By simulta- of 12 patients in group VI, 8 patients were examined neous hematocrit determination, the plasma flow was in each group. The influence of hemodialysis or peri- calculated from the blood flow and used for compu- toneal dialysis treatment on the pharmacokinetics of tation of clearance. mezlocillin was studied in group VI. A total of 8 of Peritoneal dialysis via a Tenckhoffin-dwelling cath- these 12 patients (4 hemodialysis, 4 peritoneal dialysis) eter was also started 1 h after termination of the could be examined both under dialysis and in the infusion and continued for at least 8 h. The dialysate dialysis-free interval. Informed consent was obtained volume amounted to 2 liters in each case and was from all patients. changed three times per hour. Blood samples were 81 82 KAMPF ET AL. ANTImiCROB. AGENTs CHEMOTHER.

obtained at hourly intervals after dialysis was begun. The mean plasma concentrations (c) were calculated The dialysate was collected in 2-h portions, and sam- after fitting the concentration-time curves to an ex- ples from the middle of the collecting period were ponential function and determining cDo (concentration stored at -18°C. at the start of dialysis) and ke according to: Antibiotic assay. Mezlocillin concentrations were measured by the cup-plate agar diffusion method using C- =-1e* antibiotic medium no. 3 and 2% agar (Difco Labora- Te) was tories). The test strain used Bacillus subtilis where r is the duration of dialysis. The peritoneal (Bacto subtilis spore suspension; Difco catalog no. clearance (CPD) was determined by the clearance for- 0981-52). The procedure was sensitive to less than 1 mula: jig/ml. Standards for comparison were prepared in pooled human plasma, dialysate solution, or urine. CPD = Pharmacokinetic analysis. At first, a semiloga- C-T rithmic plot of the mezlocillin plasma concentrations versus time was generated and examined for each where D is the mean dialysate concentration, Vis the patient. Since in the time interval chosen for blood total dialysate volume, c is the mean plasma concen- sampling no distribution phase was apparent, we as- tration, and r is the duration of dialysis. sumed the data to be well described by a linear one- compartment open model. Curve fitting to an expo- RESULTS nential function was done by the method of least squares, allowing calculation of the total elimination rate constant (ke) and the concentration at the end of Examinations without dialysis. Table 1 infusion (ct). The correlation coefficients of the indi- shows the average time-dependent mezlocillin vidual curves were all above 0.987 (mean, 0.995 ± concentrations for the patients with normal and 0.004). Thereafter, the apparent volume ofdistribution various degrees of impaired renal function. The (lVd) was determined according to: results of the pharmacokinetic analysis are sum- marized in Table 2, which shows the data for Vd = (1 - e ke-t) ke- ct four patients of group VI with oligoanuria separately. Figure 1 shows individual representative where v is to the infusion speed (dose/time) and t is the duration of the previous infusion. The elimination curves of mezlocillin concentrations versus time half-life (t1/2) and total body clearance (CM.) were for various degrees of impaired renal function. calculated according to standard equations: In subjects with normal renal function, the elimination rate constant was 0.791 h-1, which t4/2 =- and Ctot = ke Vd progressively decreased to 0.271 h-' in patients ke with oligoanuria. Correspondingly, the elimina- a Under the assumption that no significant amount of tion half-life showed threefold increase, from drug was removed from erythrocytes, the dialyzer 53.4 to 165 min. Figure 2 shows the linear regres- clearance (CHD) was determined from the plasma flow sion for the total elimination rate constant (ke) (Q), and the mean substance concentration in the on the GFR (Cin). The least-squares linear blood entering (E,) and leaving (to) the dialyzer ac- regression of ke on Cin is ke = 0.366 + 4.99* 10-3 cording to: Cin. With the exception of group I, the distribu- ( -cO) * Q tion volume was constant and amounted on the CHD = - Ci average to 22.5% of body weight. There was no TABLE 1. Meziocillin plasma concentrations at various times after drug infusion in 48patients (8per group) with normal and impaired renal functiona Mezlocllhin concn (gml) Group 0.5" 1 1.5 2 3 4 5 6.5 8 9 12 I 143.5 90.0 58.5 37.2 13.5 6.7 2.9 1.4 0.6 *40.6 ±29.9 ±21.8 ±14.3 ±4.7 ±2.9 ±1.5 ±0.9 ±0.4 II 185.8 127.4 93.4 66.6 29.4 14.7 8.2 3.4 2.0 ±48.2 ±33.8 ±28.8 ±22.9 ±16.2 ±9.8 ±5.9 ±3.2 ±2.0 III 184.6 143.8 118.2 88.7 52.5 30.9 19.9 10.4 5.1 ±41.7 ±38.4 ±33.2 ±28.0 +21.2 ±16.4 ±13.0 ±8.0 ±4.0 IV 238.3 200.3 156.9 140.4 85.1 54.8 36.3 18.6 9.6 ±76.5 ±51.5 ±33.1 ±48.1 ±25.8 ±21.6 ±18.0 ±15.0 +11.0 V 209.1 181.0 150.8 140.6 96.0 63.7 47.5 27.9 16.2 ±55.5 ±51.4 ±47.7 ±45.3 ±39.8 ±27.7 ±26.5 ±19.1 ±12.1 VI 182.0 163.3 145.5 113.0 86.8 68.1 47.6 25.9 12.0 ±43.9 ±42.7 ±45.6 ±39.6 ±36.3 ±33.2 t29.0 ±19A ±11.6 a Values indicate mean ± standard deviation. b Time (hours) after the end of infusion. VOL. 18, 1980 PHARMACOKINETICS OF MEZLOCILLIN 83

dependence on the degree of renal insufficiency 3). The dialysis-related increase in ke as well as (Table 2). in Ctt amounted to 44%. In healthy subjects, recovery of mezlocillin in Peritoneal dialysis. In the six patients ex- urine averaged 65% of the administered dose amined, the 8-h peritoneal dialysis led to com- with 85% eliminated within the first 4 h (Fig. 3). paratively small changes in mezlocillin kinetics. Renal elimination of mezlocillin decreased with The mean values of ke (0.347 h-'), t1/2 (149 min), increasing renal insufficiency and amounted to and CtOt (79.2 ml/min) differed negligibly from 7.6% (=278 mg/24 h) at a GFR of 6.7 ml/min those of the nondialyzed patients (group VI in (Fig. 3). At the same GFR, 0.3% of the adminis- Table 2; Fig. 5). The peritoneal clearance (CPD) tered dose was recovered in the third collection amounted to 7 ml/min, and the substance re- period. Thus, with a single 4-g dose of mezlo- moved amounted to 179 mg (_5% of the admin- cillin, minimal urine levels of about 34 ,ug/ml istered dose). The dialysate concentrations mea- were still achieved 8 to 12 h after the end of sured during peritoneal dialysis decreased from infusion. 7.3 ,ug/ml at the end of the 1st hour to 1.2 ,ug/ml Figure 4 shows the total body clearance (Cwt), at the end ofthe 7th hour. In Table 3, the results the urinary recovery rate within 24 h (R.), and from four patients examined both with and with- the extrarenal clearance of mezlocillin ( C,,). Ex- out peritoneal dialysis are presented as an in- cept for a slightly divergent behavior in the traindividual comparison. higher functional range, the Ctt and the mezlo- Based on the pharmacokinetic analysis, Table cillin elimination rate showed an almost parallel 4 shows the calculated maximal, minimal, and decrease. The renal clearance (Cr), which was mean serum concentrations for the steady state, determined from Cr = Ctt.Ru (percentage of and the area under the curve for various degrees dose), and the Ctt were used to calculate the of renal insufficiency (3 x 4 g of mezlocillin per extrarenal clearance (GClr) according to the equa- 24 h). tion = - Cr. With G, Ctot increasing renal insuf- DISCUSSION ficiency, the C,,, showed a tendency to decrease from 88 to 60 ml/min (-32%) (Fig. 4). The elimination half-life of mezlocillin in sub- Hemodialysis. The six patients under 5- to jects with normal renal function is only slightly 6-h hemodialysis showed marked differences in shorter than that ofazlocillin (12), ampicillin (9), the mean values of ke (0.502 h-'), t1/2 (91.7 min), or carbenicillin (8). However, considerable dif- and Ctt (102 ml/min) compared with the non- ferences result from increasing renal insuffi- dialyzed patients (group VI in Table 2; Fig. 5). ciency. Whereas in oligoanuria the mezlocillin The dialyzer clearance amounted to 33 ml/min, half-life rises to only 2.8 h, that of azlocillin and the substance removed amounted to 797 mg increases to 5.0 h (16), that of carbenicillin in- (_24% of the administered dose). The pharma- creases to 12 to 16 h (5,8), and that of ampicillin cokinetic data of the four patients examined increases to 10 to 20 h (9,11). Our results for both with and without hemodialysis are pre- various degrees of renal insufficiency confirm sented as an intraindividual comparison (Table the findings of Bergan et al. (2), who found only

TABLE 2. Pharmacokinetic parameters ofmezlocillin in 48patients (8per group) with normal and impaired renal functiona GFR Dose Ctb k, t1/2 Vd Group (ml/min) (mg) (jig/ml) (h-') (mini) (% body wt) (ml/min)Cto, I 92 3,819 179 0.791 53.4 30.6 250 ±13 ±602 ±62 ±0.102 ±6.8 ±9.7 ±77 II 64 4,094 245 0.717 59.1 22.5 181 ±11 ±692 ±63 ±0.105 ±13.4 ±7.6 ±70 III 28 3,936 256 0.528 84.8 21.7 115 ±6.2 ±1,100 ±60 ±0.147 ±25.7 ±7.5 ±19 IV 14 3,988 329 0.477 94.7 17.6 91 ±2.9 +525 ±101 ±0.123 ±34.7 ±5.3 +35 V 6.7 3,784 286 0.410 118.0 20.7 80 ±1.3 ±951 ±80 ±0.180 ±44.7 ±7.2 +27 VI 1.5 3,801 254 0.300 155.5 22.5 71 ±1.3 ±712 ±48 ±0.119 ±53.2 ±4.0 ±34 Oligoanuriac 0.4 3,788 260 0.271 165.3 21.8 60 ±0.3 ±705 ±33 ±0.073 ±58.4 ±2.4 ±15 a Values indicate mean ± standard deviation. b Concentration after the end of infusion. 'Four patients are included in group VI. %-r,xAA KAMPF ET AL. ANTIMICROB. AGENTS CHEMOTHER.

= 300- E 200- CIN 20-40 ml/min

C ,o 100-

4 - C c -

10-

300- 200 - ,%*Zo ~CIN

...0~~~~~~~

%-<'o--,...o~ 101--

I I I 1 1 I I I I I I I 1 0 2 4 6 8 0 2 4 6 8 10 12 Time after termination of infusion (hours) FIG. 1. Mezlocillin plasma concentrations as a function of time for 19 patients with different degrees of renal impairmnent. a moderate increase in half-life up to a GFR of (10) differs from the results presented here. The 11 ml/min. In two of four patients with a GFR longest half-life in our cohort amounted to 4.2 h of 5 to 8 ml/min, Kosmidis et al. (10) observed in a patient with anuria (Fig. 1). a biphasic elimination phase with a steeper,8f- Disrupted sodium and water elimination with slope and flatter -y-slope. Such a course could enlargement of the extracellular space as well as not be observed in any of our 16 patients with a a decrease in protein binding are frequently GFR below 10 ml/min. In three of four cases observed in advanced renal insufficiency (4, 14). with oligoanuria, elimination of more than 97% Both changes result in an increase in the volume of the administered drug could be observed in of distribution. In the case ofmezlocillin, no such the chosen time interval. But even in these cases dependence could be demonstrated. In its order with the severest renal impairment, such a pro- of magnitude, the distribution volume largely longed elimination phase could not be demon- corresponded to that of other penicillins (azlo- strated (Fig. 1). Accordingly, the increase in half- cillin [16], ampicillin [9], carbenicillin [13]). life up to 14 h that was shown by Kosmidis et al. The urinary recovery rate of mezlocillin is VOL. 18, 1980 PHARMACOKINETICS OF MEZLOCILLIN 85 ke (h-1) function (3, 9). In spite of the lower mezlocillin elimination in urine and the considerable de- 1,0 - crease with increasing renal insufficiency, therapeutic urine levels are obtained over wide 0,8 - ranges of functional loss. Ctot or Cnr RU/24 h 0,6 - (ml/min) (% dose) r 100 0,4 - ke = 0,366 + 4,99 x 10-3 C IN 240 - n = 48 = 0,2 - r 0,80 -80 200 -

0- 160 - 0 10 20 30 40 50 60 70 80 90 100 110 120 130 -60 C IN (ml/min/1,73 m2) FIG. 2. Relationship between total elimination 120 - rate constant (ke) of mezlocillin and renal function 40 (CIN). The straight line represents the best fit calcu- Cnr lated by the method of least squares with a corre- 80- sponding correlation coefficient of 0.800 (P < 0.001). -20 40 - Ru (%dose) 701 LAv III I 0 10 20 30 40 50 60 70 80 90 100 110 60 C IN (ml/min/1,73m2) FIG. 4. Total body clearance (CLot 0), extrarenal clearance (C,r, 0), and urinary recovery/24 h (R,/24 50 h, ()) of mezlocillin in normal and impaired renal function (CIN). Bars represent mean ± standard error of groups I to VI. Mean ± standard error of four 40- patients with oligoanuria is depicted separately.

=300 30 E, 200-

o 100- 20 - C 8-

10 - E

X 10 no dialysis 0 - < 3 ml/min I I CIN n = 6 0 4 8 12 16 20 24 time (h) FIG. 3. Cumulative urinary recovery ofmezlocillin as percentage of dose administered) for various (R. 1 - degrees of renal insufficiency (GFR = CIN). Bars 0 2 4 6 8 10 12 represent mean standard error, n = 40. Time (hours) after termination of infusion or start of dialysis (PD + HD-group) FIG. 5. Mezlocillin plasma concentrations in ad- quite similar to that of azlocillin (6, 12). The vanced renal insufficiency (CN < 3 ml/min) during 8 significantly higher renal excretion rate of am- h ofperitoneal dialysis and 5 to 6 h of hemodialysis. picillin and carbenicillin in healthy subjects (up Bars represent mean standard error ofsixpatients, to 90%) corresponds to their markedly prolonged and the curve is the best least-squares fit to the elimination half-life in cases of reduced renal means. 86 K"PF ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 3. Pharmacokinetic parameters ofmezlocilin in eightpatients with and without 5 to 6 h ofhemodi- alysis (HD) or 8 h ofperitoneal dialysis (PD)0 Amt of GFR 4/2 Patients (ml/min) Dose(mg) (h-')ke (mini) (mi/mun)CtO (mi/min)CD. ) -C-CD dialyzeddrug (mg) Without HD 1 3,587 0.322 153 71 ±0.3 ±915 ±0.156 ±72 ±34 With HD 3,548 0.462 100 102 33 69 825 ±947 ±0.172 ±40 ±36 ±5.4 ±36 ±279 Without PD 2.2 3,738 0.358 129 90 ±0.9 ±848 ±0.141 ±44 ±38 With PD 3,628 0.371 127 96 7.4 89 179 ±544 ±0.176 ±41 ±51 ±3.9 ±48 ±52 aValues indicate mean ± standard deviation; four patients in each dialysis group. TABLE 4. Pharmacokinetic parameters ofmezlocilin in patients with various degrees ofrenal insufficiency: effects ofdosage adjustments and hemodialysisa Dosage (ml/min)GFR (h')ke (pg/ml)c1a (pg/mi)c (g/mil)cm_ (ug/mlAUCx h) 3 x 4.0 g/24-h 100 0.791 274 43 0.5 346 steady state, 60 0.583 276 59 2.6 469 65 kg body wt 40 0.479 280 71 6.1 571 30 0.427 283 80 9.3 641 20 0.375 288 91 14 729 10 0.323 296 106 22 847 5 0.297 302 115 28 921 0 0.271 309 126 35 1,009 Dosage adjustment 10 0.323 279 71 5.8 847 2 x 4.0 g/24 h 5 0.297 281 77 8.0 921 0 0.271 285 84 11 1,009 2 x 4.0 g/24h + 5-6 h 5 0.328 279 69 5.5 834 of hemodialysis 0 0.302 281 75 7.5 906 aCmax, Maximum concentration; cm,in, minimum concentration; AUC, area under the curve.

The extrarenal clearance (Cr) in anuria of 60 processing could explain the discrepancy. Fur- ml/min for mezlocillin is twice as high as that of ther studies are in progress to clarify this point. azlocillin (30 ml/min [16]). This explains their Mezlocillin can be dialyzed relatively well by different pharmacokinetics in cases of reduced hemodialysis (Fig. 5). The clearance ofthe dialy- renal function. But, in contrast to anuria in zer used corresponds to approximately half of healthy subjects, a Cnr of 88 ml/min can be the total body clearance ofthe patients requiring calculated for mezlocillin. In addition, Fig. 4 dialysis (Table 3). However, with intermittent shows that the Cr, remains nearly constant up hemodialysis treatment and taking into account to a GFR of 30 ml/min but decreases continu- the dialyzer clearance for the 24-h elimination, ously thereafter. According to Gundert-Remy et this is of no consequence. Even with daily di- al. (7), the bile recovery in subjects with healthy alysis (5 to 6 h), e.g., in cases of acute hyperca- liver and kidneys amounts to 14 to 26% of the tabolic renal failure, an increase of Ctt from, for administered mezlocillin dose. After this, the C,r example, only 86 to 97 liters/24 h (13%) must reaches values of 35 to 65 ml/min and, taking be expected. Compared with hemodialysis, peri- into consideration the incomplete bile drainage, toneal dialysis is completely ineffective (Fig. 5). corresponds to our findings in patients with oli- Even with daily peritoneal dialysis over 8 h, only goanuria. Therefore, the comparatively lower a 4% increase in Ctt can be expected. Basically C,r in oligoanuria seems not to result from re- similar fndings were reported for ampicillin (15) duced hepatic drug elimination capacity caused and carbenicillin (5). On the other hand, the low by uremia. On the other hand, in nonoliguric peritoneal clearance leads to minimal mezlocillin patients, C,, was calculated according to Cir = dialysate concentrations. Systemic therapy of Ct.t- C. Therefore, the renal elimination of diffuse peritonitis should take this into consid- about 10% of the administered mezlocillin dose eration. in the form of microbiologically ineffective me- The pharmacokinetic properties of mezlo- tabolites or a mezlocillin instability before urine cillin, particularly the relatively high extrarenal VOL. 18, 1980 PHARMACOKINETICS OF MEZLOCILLIN 87 clearance, considerably simplify the use of this 5. Eastwood, J. B., and J. R. Curtis. 1968. Carbenicillin drug in cases of chronic renal administration in patients with severe renal failure. Br. insufficiency. The Med. J. 1:486-487. therapeutic range of the penicillins and the fact 6. Fiegel, P., and K. Becker. 1978. Pharmacokinetics of that the dosage of mezlocillin is only half that of azlocillin in persons with normal and impaired renal carbenicillin permits a doubling of the mean function. Antimicrob. Agents Chemother. 14:288-291. serum concentration without in- 7. Gundert-Remy, J., D. Forster, and P. Schacht. 1978. significantly Pharmakokinetische Untersuchungen von Mezlocillin creasing the risk of toxicity. In this respect, as unter besonderer Berucksichtigung der Galleausschei- shown in Table 4, a change in dosage becomes dung, p. 137-143. In K. H. Spitzy, H. Weuta, and E. necessary only when the GFR decreases to 10 to Wiechert (ed.), Berichte uber das Internationale Sym- 15 ml/mmi; in this case, an increase in the dosage posium Acylureido-Penicilline, Stuttgart. Verlag fur angewandte Wissenschaften, Munich. interval from 8 to 12 h is sufficient. The dosage 8. Hoffman, Th. A., R. Cestero, and W. E. Bullock. 1970. adjustment is further simplified by the fact that Pharmacodynamics ofcarbenicillin in hepatic and renal any hemodialysis or peritoneal dialysis treat- failure. Ann. Intern. Med. 73:173-178. ment, as specified above, need not be taken into 9. Jusko, W. J., G. P. Lewis, and G. W. Schmitt. 1972. Ampicillin and hetacillin pharmacokinetics in normal consideration (Table 4). and anephric subjects. Clin. Pharmacol. Ther. 14:90- Two restrictions must, however, be empha- 99. sized. First, these dosage guidelines presuppose 10. Kosmidis, J., P. Doundoulaki, Ch. Stathakis, N. Zer- a normal liver function. The occurrence ofa liver efos, A. Bounia, and G. K. Daikos. 1978. Elimination kinetics of mezlocillin in normal and impaired renal lesion, such as, for example, in septicemia, ne- function including the effect of dialysis, p. 174-181. In cessitates a further dose reduction. Second, for K. H. Spitzy, H. Weuta, and E. Wiechert (ed.), Berichte mezlocillin, Bergan (1) has dopnonstrated dose- iiber das Internationale Symposium Acylureido-Peni- dependent pharmacokinetics in sub- cilline, Stuttgart. Verlag fur angewandte Wissenschaf- healthy ten, Munich. jects; i.e., Ctt decreases as the dose increases. 11. Kunin, C. M., and Z. Finkelberg. 1970. Oral cephalexin Since this problem has not been studied in renal and ampicillin: antimicrobial activity, recovery in urine, insufficiency, the dosage recommendations must and persistence in blood ofuremic patients. Ann. Intern. be restricted to the mezlocillin doses used in the Med. 72:349-356. 12. Lode, H., M. Niestrath, P. Koeppe, and H. Lang- present investigation (3 to 5 g). Further studies maack. 1977. Azlocillin und Mezlocillin: Zwei neue are needed in similar patients with renal insuf- semisynthetische Acylureidopenicilline. Infection 5: ficiency, using different dosage levels. 163-169. 13. Pancoast, St. J., and H. C. Neu. 1978. Kinetics of LITERATURE CIED mezlocillin and carbenicillin. Clin. Pharmacol. Ther. 24: 108-116. 1. Bergan, T. 1978. Pharmacokinetics of mezlocillin in 14. Reidenberg, M. M. 1977. The binding of drugs to plasma healthy volunteers. Antimicrob. Agents Chemother. 14: proteins and the interpretation of measurements of 801-806. plasma concentrations of drugs in patients with poor 2. Bergan, T., E. K. Brodwall, and E. Wiik-Larsen. 1979. renal function. Am. J. Med. 62:466-470. Mezlocillin pharmacokinetics in patients with normal 15. Ruedy, J. 1966. The effects of peritoneal dialysis on the and impaired renal functions. Antimicrob. Agents physiological disposition of oxacilhin, ampicillin and tet- Chemother. 16:651-654. racycline in patients with renal disease. Can. Med. 3. Bodey, G. P., V. Rodriguez, and D. Stewart. 1969. Assoc. J. 94:257-261. Clinical pharmacological studies of carbenicillin. Am. J. 16. Schurig, R., D. Kampf, H. Becker, and D. Forster. Med. Sci. 257:185-190. 1979. Pharmakokinetik von Azlocillin bei Niereninsuf- 4. Coles, G. A. 1972. Body composition in chronic renal fizienz und Hamodialyse. Arzneim. Forsch. 29:1944- failure. Q. J. Med. 41:25-47. 1948.