Clinical pharmacology of extended-spectrum penicillins in infants and children

Clinical pharmacology of extended-spectrum penicillins in infants and children Compared with previously available penicillins, piperacillin, azlocillin, and mezlocillin have increased activity in vitro against gram-negative bacilli. After intravenous administration o f conventional doses (50 to I00 mg/kg) in children, peak concentrations o f these drugs are ~ 7 0 to 350 t~g/ml. For piperacillin, azlocillin, and mezlocillin, the half-lives during the beta elimination phase (t89 are approximately 0.5 to 0.75, 0.8 to 1.7, and 0.8 to 1.0 hours, respectively. In patients receiving the higher dosage, particularly of azlocillin, the t 89 may be prolonged by ~ 20 %. A total daily dosage o f 300 mg/kg or 9 gm/m 2 given in four to six divided dosages should produce peak concentrations o f ~150 #g/ml, and concentrations >16 tzg/ml for at least 2 hours after each administration. Lower daily dosages are needed in neonates, but precise dosage recommendations cannot be made at this time. Only ~ 6 0 % of piperacillin and ~ 4 5 % of azlocillin are eliminated unchanged in the urine; thus only modest dosage reductions are needed in patients with decreased renal function. In children, adverse effects have been infrequent. (J PEDIATR 106:1049, 1985)

Christopher B. Wilson, M.D., and Jeffrey R. Koup, Pharm.D. Seattle, Washington

RECENTLY, three new penicillins with expanded gramnegative activity were introduced. The acylureidopenicillins, or acylanfinopenicillins, piperacillin, azlocillin, and mezlocillin, are chemical derivatives of ampicillin in which the c~-amino group has been converted to a ureido group. ~ Piperacillin and azlocillin inhibit P s e u d o m o n a s aeruginosa, and piperacillin and mezlocillin inhibit many of the enteric gram-negative bacilli at lower concentrations in vitro than do ticarcillin and carbenicillin? However, these apparent advantages are less evident when bacteria are tested at high densities (the inoculum effect) or when bactericidal concentrations are compared. These compounds have only recently been introduced into clinicaluse, and data regarding their safety and efficacy in children are limited. Accordingly, their ultimate role in the antibacterial armamentarium of physicians responsible for the care of children has not been

From the Children's Orthopedic Hospital and Medical Center, the Department o f Pediatrics, School o f Medicine, and the Department o f Pharmacy Practice, School oJ"Pharmacy, University o f Washington. Reprint requests: Christopher B. Wilson, M.D., Children's Orthopedic Hospital and Medical Center, 4800 Sand Point Way, NE, Seattle, WA 98105.

defined. In the interim, to assist the practitioner who chooses to use one of these newer agents, we review the more extensive data on their pharmacology. Safety data are also reviewed briefly.

PHARMACOLOGY Adults. The expanded-spectrum penicillins are poorly absorbed orally and are intended only for parenteral administration. In most studies drug concentration vs time curves have been best fit by a one-compartment model

tV2/3 V~

semconcentationvstim rvI

Half-life during beta elimination phase Volumeof distribution during beta elimination phase

after intravenous infusion or intramuscular administration, and by a two-compartment model after intravenous bolus administration.3'4 Bergan 5has studied the pharmacokinetics of these compounds in adults after a single intravenous bolus ( ~ 3 minutes) (Table I). His studies show significa~,dose-dependent pharmacokinetics over a fourfold to fivefold,dosage range. Clearance of each drug decreased ~ 25% with a twofold and ~ 50% with a fourfold to fivefold increase in dosage. The fraction of drug recovered in the urine increased as well, suggesting satura-

TheJournalofPED1ATRICS

1049

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Wilson and Koup

The Journal of Pediatrics June 1985

Table I. Dose-dependent pharmacokinetics in adults

Dose

Patients (n) Piperacillin 4 4 4 Azlocillin ~10 !0 10 Mezlocillin 10 10 10

~

(rnl/min/m 2)

Renal clearance (%)

(L/kg)

CL

v~

(rng/kg)

(mg/m 2)

C,,,~ (#g/ml)

15.0 30.0 60.0

606.0 t 212.0 2424.0

101.8 231.9 522.4

4.41 3.34 2.76

178.5 135.2 111.8

50.0 61.0 71.0

0.28 0.30 0.23

11.46 I2.11 9.37

14.6 29.3 73.0

546.0 1092.0 2730.0

173.3 352.8 771.4

2.91 2.23 1.57

119.8 90.2 63.7

59.4 72.5 74.7

0.23 0.19 0.21

8.45 7.18 7.72

13.6 27.2 68.0

52910 1058.0 2645.0

75.1 225.1 467.1

7.08 4.78 3.84

247.1 185.9 149.6

60.8 67.0 69.0

0.47 0.33 0.40

18.13 13.02 15.71

(rnl/rnin/kg)

Llrn2)

Drugs were given by intravenousbolus administrationover 4 to 5 minutes. Cm,~,peak concentration;CL, total body clearance; V~, volume of distribution during beta elimination phase; Vs, volume of distribution at steady state. Table II. Pharmacokinetics of expanded-spectrum penicillins in children and adolescents

Patients (n) Piperacillin 14 7

Age (yr) 8

to 16

CF

12

to 21

CF

15

3.3 to 14.3

37

712 to 11

Azlocillin 10 5

10 Mezlocillin 25

31

Patient population

11 5

to 28 to 13

CF and non-CF

Non-CF

CF CF

8%2 to 281~1z

CF

2

to 17

2

to 19

Malignancies; normal renal and hepatic function Malignancies; normal renal and hepatic function

Cm,~ (#g/ml)

Dose 75 mg/kg qid, 30-min infusion 58.3 to 83.3 mg/kg q4h i hr infusion 1500 mg/m2/day (4 to 6 equal doses) 30-min infusion 50 mg/kg q4h 30-min infusion 58.3 tO 87.5 mg/kg 100 mg/kg 200 mg/kg (single-dose study) 200 mg/kg q8h 20-rain infusion

102.5 30 rain after infusion ~230 at end of infusion 69 to 354 at end of infusion 166 _+_42 at end of infusion 364 161 593

!

~_ Total body clearance I (ml/rnin/me) (ml/min/kg)

89.5 80 to 280 (Clca 5 to 120 ml/min) --<6 mo 71.7 >6 mo 130 2.05 260 97.3

399 _+ 15 day 2-3 523 _+ 64 day 6-7

3.9 ~

50 mg/kg q4h 75 mg/kg q4h 30-min infusion

241 _+ 26 278 +_ 34

3.17 3.17

12.5 to 125 mg/kg q4h 30-rain infusion

245 __+90

3.5

C~,x, peak concentration;V~, volumeof distribution during beta eliminationphase; CLerk,creatinine clearance. *Calculated from investigatordata. tion of nonrenal elimination. However, renal elimination also decreased somewhat, reflecting a partial saturation of tubular secretion. Tubular secretion of these agents is indicated by the fact that renal clearance exceeds creatinine clearance by twofold to threefold and by the reduction 2

m renal clearance caused by concurrent administration of

probenecid (reviewed in BerganS). The 0/2/3 and area under the A U C of azlocillin are affected more by dose s than are those of piperacillin and mezlocillin. W h e n each of these drugs is given by intravenous infusion, tV2~ values are similar but peak serum concentrations are lower. 3,6,7 The elimination of these agents is delayed in patients

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Pharmacology of extended-spectrum penicillins

V~ f

(L/kg)

[

(L/m 2)

(hr)

Reference

0.22 0.22 0.20

9.02 9.11 7.94

0.83 1.04 0.92

44

0.19 0.18 0.18

7.09 6.53 6.91

0.89 0.98 1.53

45

0.31 0.22 0.27

12.03 8.55 10.46

0.96 0.79 1.21

46

k

(L/m2)

Renal clearance (%)

t89 (hr)

IRrence

--

0.75

24

0.617

47

4.78 7.3

56.6

0.617

20

5.16

66.6 (34 to 88)

~<6 mo 0.78 >6 mo 0.5

37

1.74 0.82 0.98

38 22

0.30 0.80 0.34 0.46*

47 82 45 - -

1.4

25

1.3

0.20 0.31 0.26

- -

0.80 0.97

23

0.97

48

with severe renal failure. This effect is most marked for azlocillin: its t89 increased from 1.1 hours in patients with normal renal function to 5.7 hours in patients with renal failure? Similar values for piperacillin are 1.0 and 4.0 hours 8 for mezlocillin, 0.9 and 2.8 hours6; for carbenicillin, 1.0 and 15.7 hoursg; and for ticarcillin, 1.2 and 14.8

105 1

hours.~~ removes from 10% to 48% of a given dose of azlocillin, piperacillin, and meziociilin.2 Patients with hepatic failure clear carbenicillin somewhat more slowly than norrnalg; however, this is probablY of no clinical significance. Similar data are not available for the newer agents. Protein binding is complex and reflects binding both to albumin and to globulin. At concentrations of 2 ~g/ml, 46% of azlocillin and 42% of mezlocillin are bound, whereas at 200 #g/ml, 30% and 27% are boufid, respectively. ~ Approximately 16% of piperacillin is protein bound? Carbenicillin (50%) and tiearcillin (65%) ai"e more highly bound. ~2 At high concentrations, certain penicillins and aminoglycosides react with each other chemica!ly and are thereby inactivated. In patients with normal renal function, concentrations of the penicillin appear not to be high enough for a sufficiently long time to cause significant inactivation.13 However, in patients with renal failure this does occur and leads to more rapid clearance and therefore lower mean concentrations of the aminoglycoside. Of the aminoglycosides, tobramycin is the most susceptible to inactivation, followed by gentamicin; arnikacin is inactivated at a much slower rate? 4 Carbenicillin and ticarcillin inactivate the aminoglycosides more rapidly in vitro and increase clearance more in patients with renal failure than do the newer extended-spectrum penicillins.~5Aminoglycoside levels should be monitored in patients treated with these combinations, and higher aminoglycoside dosages may be required than in patients not receiving Concomitant therapy with one of these penieillins. Children Piperacillin has been studied both in children with mixed infections and in patients with Cystic fibrosis (Table II). Clearance o f piperacillin was similar to that reported for adults, and 0/2/3 was somewhat less than that reported in adults. In contrast to results with certain other antibiotics, including the t3-1actams cloxacillin,J6 dicloxacillin,~7 methicillin,~8 and ceftazidime, ~9 pharmacokinetic parameters for patients with cystic fibrosis were similar to those of children without cystic fibrosis. In the study by Wilson et al., 2~clearance of piperaciliin correlated directly with creatinine clearance (r = 0.82); this Correlation was not examined in the other studies. The magnitude of V~ suggests distribution of the drug in the extravascular Compartment. The three studies with azlocillin were conducted in patients with cystic fibrosis; the youngest patient studied was 5 years of age, There was greater variability in results than in the piperacilfin studies, perhaps reflecting differences in dosage, duration of intravenot~ infusion, and multiple vs single-dose administration. A consistent finding in each of the studies was a longer t89 than that of piperacillin.

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Wilson and Koup

The Journal of Pediatrics June 1985

Table IlL P h a r m a c o k i n e t i c s of expanded-spectrum penicillins in neonates

Patients (n)

Patient population

Total body clearance

Cm~ (#g/m1)

Dose

(ml/min/kg)

(ml/min/m2) ...,,...

Piperacillin 20 Azlocillin 37

25

Mezlocillin 26

Premature ~1625 gm, 31.5 wk Premature ~1770 gm, 34 wk Term

50 mg/kg 50 mg/kg 100 mg/kg 100 mg/kg 50 mg/kg

<38 wk, -<7 day >~38 wk, _<7 day >--38 wk, >7 day

60

--<7 days > 7 days to <1 mo 72% <36 wk

~ 1 3 0 to 300

50 mg/kg iv

Term (n = 13) ~3140 gin, Premature (n = 12) ~2120 gm, 2 to 26 day

13 8

53

100 to 200 mg/kg ql2h

122.5+ 29.5 1 hr after infusion 105-+ 31 150.8 +-- 29.2 26t --- 53 260 +-- 87 333

iv IM ~v 1M 5-rnin bolus

75 mg/kg, 10-min infusion

75 to 100 mg/kg IV, 5-min infusion 75 mg/kg, 2- to 3-min infusion (n = 9) 75 mg/kg IM (n = 44)

1.63" 1,25

278

1.38

252 -+ 50

5.38

272 _+ 40 139 -+ 44 at end of infusion 140 30 min after infusion 231 _+ 63 IV

7.11 12.14

1.3t

133 _+ 23 IN 2 hr

Cm~x,peak concentration; V~, volume of distribution during beta elimination phase; V~,,volume of distribution at steady state. *Calculated from investigator data. tCL increased from 0.8 to 1.3 ml/min/kg as gestational age increased from 28 to 38 weeks in infants "<7 days of age. Table IV. Adverse effects of expanded-spectrum penicillins in children

Elevated liver transaminase Diarrhea activity Piperacillin Azlocillin Mezlocillin

166 205 84

0 2 0

0 0 5

0 14 6

Mezlocillin pharmacokinetics were studied only in children with hematologic malignancies. T h e tl/23 were intermediate between those reported for piperacillin and azlocillin. Values of the other parameters were similar to those of piperacillin and azlocillin. The t 89 (0.9 hours), clearance (102 m l / m i n / m 2 ) , and V3 (0.35 L / k g ) of ticarcillin in children 2E are also similar. In most of the studies, the dosage range was not wide enough to d e t e r m i n e whether pharmacokinetics are dose dependent. In studies by Bergan and Michaelsen 22 with azlocillin a n d by Picketing et al. 23 with mezlocillin, the t89 increased by ~ 2 0 % with, respectively, a twofold or a 50% increase in dosage. This is similar to the results in adults

Thrombocytopenia

Neutropenia

4 0 0

5 0 0

Reference 2 12 1

20, 24, 37, 47, 52 33, 38, 53, 54 23, 26

(see above). F u r t h e r studies are needed to d e t e r m i n e whether this occurs consistently with these drugs and with piperacillin in children. Similar to data in adults, a substantial fraction of piperacillin and of azlocillin was cleared by nonrena! mechanisms (Table II). Such studies have not been done with mezlocillin in children. Tissue penetration. Penetration of these drugs into the sputum of patients with cystic fibrosis was variable. Some of the a p p a r e n t variability m a y reflect patient population differences, i n a s m u c h as direct comparative studies have not been done. Piperacillin concentrations were 0.2 to 12.0 tzg/ml (1.1% of serum concentrations), 24 whereas azloci!lin

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Pharmacology of extended-spectrum penicillins

v~

V~s

(L/kg)

(Vkg)

t~

(hr)

Reference

6.5 (3.5 to 14)

49

0.34

4.41

50

0.29

0.35

2.65 2.65 2.65 2.65 2.6

33

0.33

2.5

0.34

--

4.5

0.37 0.42 --

---

3.0 1.8 4.33 2.55

0.38

3.71

1 053

neonates. Clearance9 was greater in term than in preterm neonates, with the exception of the study by Heimann with azlociltin33; however, all of the premature neonates in this study weighed >2 kg and their mean postnatal age was 12 days. Two studies with mezlocillin34,35 showed a shorter tlAfl in neonates >7 days of age. These results are similar to but less detailed than those of Nelson et al? 6 with ticarcillin. The tVz/3of ticarcillin was 3.7 and 2.5 hours, respectively, in premature (<35 weeks) and term neonates (<3 days postnatal age). In those >15 days postnatal age, the tlAB was 2.1 and 1.5 hours, respectively. The V~ was found to be greater at birth in premature than in term infants, but the opposite was true for those >15 days of age. DOSAGE RECOMMENDATIONS

34

34

51

concentrations varied from 1.5 to 38.0 gg/ml in the study by Malmborg et at? 5 Very high concentrations of mezlocillin (50.9 to 198.0 #g/ml) were found in the sputum in one study,26but not in another (1.5 to 12.8 #g/ml) (reviewed in BerganS). For comparison, ticarcillin concentrations in the sputum of patients with cystic fibrosis were 2.8 to 12.0 #g/ml. 27 Thus, sputum concentrations are generally much lower than serum concentrations, but nonetheless are at or near those needed to inhibit or kill relevant pathogens such as Pseudomonas aeruginosa. 28 Penetration into the cerebrospinal fluid is similar to that o f other penicillins. Mezlocillin concentrations averaged 3% of those in serum in neonates26 and 0% to 11% of those in serum in adults with aseptic meningitis?9 In adults with gram-negative meningitis, piperacillin concentrations were 8% to 53% of those in serum? ~ These drugs are concentrated in bile.3''32 Neonates. In general the pharmacology of these three agents in neonates is similar (Table III), although the data on piperacillin are limited. As expected, clearance is decreased and tV2/3 increased compared with that in older children and adults. Therapeutic concentrations were achieved with dosages of 50 to 100 mg/kg. The reported volumes of distribution were similar in premature and term

Published dosing recommendations for the expandedspectrum penicillins in children are reasonably uniform. A total daily dosage of 300 mg/kg or 9 gm/m 2 given in four to six equally divided dosages by 30-minute intravenous infusion should provide peak levels of ~150 #g/ml. Trough concentrations would be <10 izg/ml, but would generally be >16 #g/ml for at least 2 hours after each administration.2~ In certain patients in whom penetration to the site of infection may be low (e.g., sputum of patients with cystic fibrosis), daily dosages of 450 to 600 mg/kg have been used by some authors? 3,2s Diminished renal function necessitates only modest reductions in dosage. This may be approximated by the following formula: corrected daily dose = normal daily dose x (fraction nonrenal elimination + [fraction renal elimination X {Clca/ 0.06}]), where ClcR is the estimated creatinine clearance/ m2. 20

N0nrenal elimination is ~35% for piperacillin2~ and ~55% for azlocillin.22,38 Concurrent administration of probenecid decreases renal clearance and increases the AUC of piperacillin, azlocillin, and mezlocillin in adults? Similar data are not available in children. Thus, specific recommendations on concurrent use of probenecid in children cannot be made. Appropriate dosages for neonates are less certain. Pending additional data, individual doses of 50 to 75 mg/kg in premature neonates and 70 to 100 mg/kg in term neonates may be given every 12 hours during the first week of life. Thereafter, 75 to 100 mg/kg may be given every 8 hours. ADVERSE EFFECTS Side effects were uncommon in repoffed studies (Table IV). Elevations in liver .transaminase activities, neutropenia, and thrombocytopenia were transient. Allergic reac-

10 5 4

Wilson and K o u p

tions included eosinophilia, rash, a n d fever. T h r o m b o p h l e bitis has been noted in adults b u t was not a significant problem in children receiving the extended-spectrum penicillins. H y p o k a l e m i a was not noted in any patients given piperacillin, azlocillin, or mezlocillin, a l t h o u g h in one study, ~ 10% of children given carbenicillin or ticarcillin developed hypokalemia. 39 Carbenicillin a n d ticarcillin are disodium salts: 1 g m carbenicillin contains 4.7 m E q sodium; 1 g m ticarcillin contains 5.2 m E q sodium. The a m o u n t of sodium administered m a y be of concern in children with impaired renal or c a r d i a c function. In contrast, piperacillin, mezlocillin, and azlocillin are monosodium salts: 1 g m piperacillin or mezlocillin contains 1.85 m E q sodium; 1 grn azlocillin contains 2.17 m E q sodium. Side effects in adults have been similar. However, increased potassium requirements or hypokalemia were c o m m o n in adults with sepsis and chemotherapy-induced neutropenia. This occurred in 36% to 61% of patients receiving carbenicillin or ticarcillin, which are disodium salts, 4~ and in 12% to 63% of those receiving piperacillin or mezlocillin, which are monosodium salts. 4~+43 REFERENCES

1. Neu HC: Structure-activity relations of new fl-lactam compounds and in vitro activity against common bacteria. Rev Infect Dis 5:$319, 1983. 2. Eliopoulos GM, Moellering RC Jr: Azlocillin, mezlocillin, and piperacillin: New broad-spectrum penicillins. Ann Intern Med 97:755, 1982. 3. Leroy A, Humbert G, Godin M, Fillastre JP: Pharmacokinetics of azlocillin in subjects with normal and impaired renal function. Antimicrob Agents Chemother 17:344, 1980. 4. Tjandramaga TB, Mullie A, Berbesselt R, et al: Piperacillin: Human pharmacokinetics after intravenous and intramuscular administration. Antimicrob Agents Chemother 14:829, 1978. 5. Bergan T: Overview of acylureidopenicillin pharmacokinetics. Scand J Infect Dis 29(suppl):33, 1981. 6. Kampf D, Schurig R, Weihermuller K, Forster D: Effects of impaired renal function, hemodialysis, and peritoneal dialysis on the pharmacokinetics of mezlocillin. Antimicrob Agents Chemother 18:81, 1980. 7. Meyers BR, Hirschman SZ, Strougo L, Srulevitch E: Comparative study of piperacillin, ticarcillin, and carbenicillin pharmacokinetics. Antimicrob Agents Chemother 17:608, 1980. 8. Deschepper PJ, Tjandramaga TB, Mullie A, et al: Comparative pharmacokinetics of piperacillin in normals and in patients with renal failure. J Antimicrob Chemother 9(suppl B):49, 1982. 9. Hoffman TA, Cestero R, Bullock WE: Pharmacodynamies of carbenicillin in hepatic and renal failure. Ann Intern Med 73:173, 1970. 10. Parry MF, Neu HC: Pharmacokinetics of ticarcillin in

The Journal o f Pediatrics June 1985

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patients with abnormal renal function. J Infect Dis 133:46, 1976. Rosenkranz H, Forster D: Comparative study of the binding of acylureidopenicillins and carbenicillin to human serum proteins. Infe&ion 7:102, 1979. Libke RD, Clarke JT, Ralph ED, et al: Ticarcillin vs carbenicillin: Clinical pharmacokinetics. Clin Pharmaeol Ther 17:441, 1975. Lau A, Lee M, Flascha S, Pra,~d R, Sharifi R: Effect of piperacillin on tobramycin pharmacokinetics in patients with normal renal function. Antimicrob Agents Chemother 24:533, 1983. Jorgensen JH, Crawford SA: Selective inactivation of aminoglycosides by newer beta-lactam antibiotics. Curr Ther Res 32:25, 1982. Thompson MIB, Russo ME, Saxon BJ, Atkinthor E, Matsen J M: Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease. Antimicrob Agents Chemother 21:268, 1982. Spino M, Chai RP, Isles AF, Thiessen J J, et al: Cloxacillin absorption and disposition in cystic fibrosis. J PEDIATR 105:829, 1984. Jusko WJ, Mosovich LL, Gerbracht MS, et al: Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis. Pediatrics 56:1038, t975. Yafl'e S J, Gerbracht LM, Mosovich LL, et al: Pharmacokinetics of methicillin in patients with cystic fibrosis. J Infect Dis 135:828, 1977. Leeder JS, Spino M, Isles AF, et al: Ceftazidime disposition in acute and stable cystic fibrosis. Clin Pharmacol Ther 36:355, 1984. Wilson CB, Koup JR, Opheim KE, et al: Piperacillin pharmacokinetics in pediatric patients. Antimicrob Agents Chemother 22:442, 1982. Nelson JD, Kusmiesz H, Shelton S, et al: Clinical pharmacology and efficacy of ticarcillin in infants and children. Pediatrics 61:858, 1978. Bergan T, Michalsen H: Pharmacokinetics of azlocillin in children with cystic fibrosis. Arzneimittelforsch 29:1955, 1979. Pickering LK, Kramer WG, Armes DA, et al: Clinical pharmacology and efficacy of mezlocillin in paediatric patients with malignancy. J Antimicrob Chemother 9(suppl A):245, 1982. Hoogkamp-Korstanje JAA, van der Laag J: Piperacillin and tobramycin in the treatment of Pseudomonas lung infections in cystic fibrosis. J Antimicrob Chemother 12:175, 1983. Malmborg AS, Alfredsson H, Kusoffsky E, et aI: Azlocillin and gentamicin in respiratory tract infections with Pseudomonas aeruginosa in patients with cystic fibrosis. Scand J Infect Dis 29(suppl):64, 1981. Weingartner L: Clinical aspects of mezlocillin therapy in childhood. J Antimicrob Chemother 9(suppl A):257, 1982. Parry MF, Neu HC, Merlino M, et al: Treatment of pulmonary infections in patients with cystic fibrosis: A comparative study of ticarcillin and gentamicin. J PEDIATR 90:144, 1977. Fu KP, Neu HC: Piperacillin, a new penicillin active against many bacteria resistant to other penicillins. Antimicrob Agents Chemother 13:358, 1978. Modai J, Pierre J, Bergogne-Berezin E, et al: Cerebrospinal

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41.

fluid penetration of mezlocillin. Arzneimittelforschung 29:1, 1979. Dickinson GM, Droller DG, Greenman RL, et al: Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid. Antimicrob Ageiats Chemother 20:481, 1981. Giron JA, Meyers BR, Hirschman SZ: Biliary concentrations of piperacillin in patients undergoing cholecystectomy. Antimicrob Agents Chemother 19:309, 1981. Brogard JM, Kopferschmitt J, Arnaud JP, et al: Biliary elimination of mezlocillin: An experimental and clinical study. Antimicrob Agents Chemother 18:69, 1980. Heimann G: Pharmacokinetics and clinical aspects of azlocillin in paediatrics. J Antimicrob Chemother ll(suppl B):127, 1983. Odio C, Threlkeld N, Thomas ML, et al: Pharmacokinetic properties of mezlocillin in newborn infants. Antimicrob Agents Chemother 25:556, 1984. Rubio T, Wirth F, Karotkin E: Pharmacokinetic studies of mezlocillin in newborn infants. J Antimicrob Chemother 9(suppl A):241, 1982. Nelson JD, Shelton S, Kusmiesz H: Clinical pharmacology of ticarcillin in the newborn infant: Relation to age, gestational age, and weight. J PEDIATR 87:474, 1975. Thirumoorthi MC, Asmar BI, Buekley JA, et al: pharmacokinetics of intravenously administered piperacillin in preadolescent children. J PEDIATR 102:941, 1983. BOsso JA, Saxon BA, Herbst J J, et al: Azlocillin pharmacokinetics in patients with cystic fibrosis. Antimicrob Agents Chemother 25:630, 1984. Parry MF, Neu HC: A comparative study of ticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram-negative bacilli. Am J Med 64:961, 1978. Kohler RB, Foerster LA, Wheat J, et al: Piperacillin and gentamicin vs. carbenicillin and gentamicin for treatment of serious gram-negative infections. Arch Intern Med 142:1335, 1982. Hann I, Noone P, Prentice HG, et al: The results of a randomized trial of empirical antibiotic treatment in febrile

COMMENTS DR. NELSON: W h a t laboratory methods were used to determine drug concentrations in body fluids in the various studies? DR. WILSON: T h e data in our investigations, as well as those of T h i r u m o o r t h i and Janicke, are based on highpressure liquid c h r o m a t o g r a p h y ( H P L C ) . Almost all other data were derived from bioassays, which m a y account for some of the variability in published results. DR. KLEIN: Piperacillin has a very low degree of protein binding, only a b o u t 15%. A l t h o u g h the pertinence of protein binding to clinical efficacy in terms of antibiotic use is not clear, are there any assets t h a t m i g h t emerge from the low binding of piperacillin to proteins?

Pharmacology of extended-spectrum penicillins

42. 43.

44. 45.

46. 47.

48.

49. 50. 51.

52.

53.

54.

1 055

neutropenic patients with four/3-1actam/aminoglycoside combinations. J Antimicrob Chemother ll(suppl C):57, 1983. Wade JC, Schimpff SC, Newman KA, et al: Piperacillin or ticarcillin plus amikacin. Am J Med 71:983, 1981. Winston D J, Barnes RC, Ho WG, et al: Moxalactam plus piperacillin versus mnxalactam plus amikacin in febrile granulocytopenic patients. Am J Med 77:442, 1984. Bergan T, Williams JD: Dose dependence of piperacillin pharmacokinetics. Chemotherapy 28:153, 1982. Bergan T, Thorsteinsson SG, Steingrimsson O: Dose-dependent pharmacokinetics of azlocillin compared to mezlocillin. Chemotherapy 28:160, 1982. Bergan T: Pharmacokinetics of mezlocillin in healthy voluilteers. Antimicrob Agents Chemother 14:801, 1978. Prince AS, Neu HC: Use of piperacillin, a semisynthetic penicillin, in the therapy of acute exacerbations of pulmonary disease in patients with cystic fibrosis. J PEDIATR 97:148, 1980. Kramer WG, Pickering LK, Culbert S, et al: Mezlocillin pharmacokinetics in pediatric oncology patients. Antimierob Agents Chemother 25:62, 1984. Placzek M, Whitelaw A, Want S, et al: Piperacillin in early neonatal infection. Arch Dis Child 58:1006, 1983. Sitka U, Weingartner L, Patsch R, et al: Pharmacokinetics of azlocillin in neonates. Chemotherapy 26:171, 1980. Janicke DM, Rubio TT, Wirth FH, Jr: Developmental pharmacokinetics of mezlocillin in newborn infants. J PEDIATR 104:773, 1984. Bassetti D, Viscoli C, Giacchino R, et al: Study on the efficacy of piperacillin in the treatment of severe infections of the child and of the young adult. Curr Ther Res 33:874, 1983. Michalsen H, Bergan T: Azlocillin with and without an aminoglycoside against respiratory tract infections in children with cystic fibrosis. Scand J Infect Dis 29(suppl):92, 198l. Weingartner L, Sitka U, Patsch R, et al: Pharmacokinetic and clinical investigations of azlocillin in pediatric patients. In Nelson JD, Grassi C, editors: Current chemotherapy and infectious diseases. I1. Washington, D.C., 1980, American Society for Microbiology, p 1142.

DR. WILSON: i would say t h a t the low protein binding seen with piperacillin does not have a great deal of significance in terms of comparison with other extendedspectrum penicillins. N o n e of these agents is highly protein bound, on the order of >_90%, a level at which the effects of protein binding assume significance. DR. OGRA: W o u l d the degree of protein binding have an effect on the frequency of allergic reactions? DR. KLEIN: Protein binding has not been identified as an i m p o r t a n t factor in frequency of allergic reactions. T h e r e does not a p p e a r to. be any increased incidence of allergic reactions a m o n g the,penicillins t h a t are 90% or so bound, for example, nafcillin or oxacillin, compared with those t h a t exhibit less protein binding.

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DR. OGRA:Might not, however, the antigenicity of some of the penicillins be enhanced if they were bound to a protein? DR. KLEIN:That relationship has not emerged during the long experience with drugs of both high and low protein binding, although it might be an interesting feature to explore in the future. DR. NELSON:Has thrombocytosis been noted with piperaciUin use? This is seen very commonly with the newer cephalosporins that have been investigated in recent years, but it is usually passed off as a function of the illness--the fact that the patients are very ill and such findings are acute-phase reactions. DR. WILSON:Thrombocytosis (platelet count >450,000/ mm 3) was not reported in any of our patients, nor was it mentioned in any of the reports that were reviewed. However, that may have been because this finding was attributed by the investigators to the illnesses treated rather than the drug used. DR. NELSON: It is now being postulated in the neurology world that children with meningitis who are being given the new cephalosporins may have an enhanced likelihood of cerebral artery thromboses, specifically as a result of the thrombocytosis that is commonly seen with these drugs. For example, in our comparative study of ceftriaxone vs ampicillin and chloramphemicol in infants with meningitis, 16 of 39 patients given ceftriaxone had peak platelet counts > 1 million, with 1.8 million the highest. A similar phenomenon was seen in only six children given ampicillin and chloramphenicol. There have been isolated reports of children with meningitis who developed a marked thrombocytosis and severe thromboses after antibiotic treatment, but whether this was coincidental is not known. DR. OGRA: IS the mechanism for the development of thrombocytosis known? DR. NELSON:This is presently under investigation. At the University of Texas Health Science Center at Dallas, we are now determining the incidence of thrombocytosis in children receiving cefuroxime, ampicillin, chloramphenicol, or ceftriaxone. Then, with the aid of hematologists who specialize in coagulation, we will attempt to develop a prospective protocol to evaluate the cause and effects of this phenomenon. DR. BROWN:Does the neutropenia seen with piperacillin therapy occur with any greater frequency than that seen with the other penicillins? Is it dose related?

The Journal of Pediatrics June 1985

DR. WILSON: The incidence of neutropenia (absolute granulocyte count <1000/mm 3) in our study was 3%, which is in line with the 1% to 2% incidence seen with prolonged use of any of the penicillins. Incidentally, the patients who developed this complication did so late. Whether it was related to the duration of therapy or to the dosage is not known, but it did not develop before 10 to 14 days of therapy. Fortunately, it was reversible, within 5 days of cessation of therapy in each of our patients as well as in those in the literature. DR. STARR: Are there any specific antibiotic combinations that result in inactivation of the acylaminopenicillins? DR. WILSON: Some investigators have shown in vitro antagonism between aminoglycosides and extended-spectrum penicillins, which is not to say that the drugs involved are Clinically inactivated. This is due to chemical inactivation, the most significant of which is aminoglycoside inactivation by the penicillin. In general, carbenicillin or ticarcillin with gentamicin or tobramycin have been considered to be more affected than piperacillin and amikacin. DR. STARR:What about antagonism in combinations of cephalosporins and acylaminopenicillins? DR. WILSON: Because of variations in methods and because it is so hard to extrapolate in vitro data to in vivo experience, I do not believe any such determination can be made at the present time. DR. BROWN:Would the varying degrees of/3-1actamase induction seen with/3-1actam antibiotics have a bearing on potential antagonism in double/3-1actam combinations? DR. WILSON:A number of the newer cephalosporins are very potent inducers of/3-1actamases and thus potentially of widespread antimicrobial resistance to a number of antibiotics. However, I think that this has more bearing on the individual use of these drugs than on their use in combination. It is important to realize that the relatively penicillinase-stable or/3-1actamase-stable agents, such as cefamandole, appear to be very potent inducers of inactivating enzymes or of nonenzymatic mechanisms of resistance to a broad range of antimicrobial agents. This raises concern about using potent enzyme inducers, in general. DR. NELSON: The extended-spectrum penicillins have less tendency to induce /3-1actamases. Carbenicillin, for example, is considered an intermediate inducer, and piperacillin a low inducer.