ANTIMICRoBIAL AGENTS AND CHEMOTHERAPY, June 1977, p. 933-935 Copyright © 1977 American Society for Microbiology
Vol. 11, No. 6
Printed in U.S.A.
Penetration of Cefamandole into Spinal Fluid EVAN A. STEINBERG,* GARY D. OVERTURF, LARRY J. BARAFF, AND JEANETTE WILKINS Department of Pediatrics, Los Angeles County-University of Southern California Medical Center; and Department of Pediatrics and Hastings Infectious Disease Laboratory, University of Southern California School of Medicine, Los Angeles, California 90033* Received for publication 7 December 1976
Twelve patients, aged 6 months to 62 years, with proven bacterial meningitis, were given a single intravenous dose of cefamandole (33 mg/kg) 75 to 140 min before a routine lumbar puncture. Infecting organisms included Haemophilus influenzae (eight cases), Streptococcus pneumoniae (two cases), and Neisseria meningitidis and (8-hemolytic streptococcus (one each). Cerebrospinal fluid (CSF) was analyzed by microbiological assay for cefamandole. The median concentration was 0.60 ,ug/ml, ranging from undetectable to 7.4 ,ug/ml. CSF cefamandole concentrations correlated with CSF protein: in six patients with CSF protein less than 100 ,ug/dl, the range of drug concentration was 0 to 0.62 ,ug/ml; and in six patients with CSF protein above 100 mg/dl, the range was 0.57 to 7.4 ,ug/ml. No significant correlation was noted between severity of illness, type of organism involved, or patient age and concentration of drug achieved.
Cefamandole nafate, 7-D-mandelamido-3 {[(1-
methyl-lH-tetrazole-5-yl)-thiolmethyl)-3 ce-
phem-4-carboxylic acid, formate (ester), sodium salt, is a semisynthetic cephalosporin antibiotic with broad antibacterial spectrum (4, 14, 15), and is 70 to 80% protein bound (7, 8). It is notably active against (8-lactamase-producing Haemophilus influenzae type b (9). Therefore, a pilot study was conducted to evaluate achievable antibiotic levels in cerebrospinal fluid (CSF) after the intravenous administration of a single dose of cefamandole to patients with bacterial meningitis. MATERIALS AND METHODS Patients. Twelve patients admitted to the Los Angeles County-University of Southern California Medical Center with bacterial meningitis were selected for study. The diagnosis was confirmed by a positive CSF culture on all patients. Informed written conserit was obtained from patients or from their parents or responsible guardians. The patients included two adults (62 and 46 years), one adolescent (13 years), and nine children (6 months to 3.5 years with a median age of 10 months). Patients 4 and 5 had Streptococcus pneumoniae isolated from CSF; patient 12 had a /-hemolytic streptococcus; patient 10 had Neisseria meningitidis. All other patients had H. influenzae type b isolated (Table 1). The severity of meningitis upon admission wasI graded according to the criteria of Mathies (13). All patients were treated with ampicillin intravenously, 200 mg/kg per day in six divided doses. One dose of cefamandole, 33 mg/kg, was substituted for ampicillin before a routine lumbar puncture within the first 72 h of treatment in all patients, except no.
12, whose dose was given on day 7 of treatment. Infusion times varied from 10 to 25 min. Two serum samples were obtained for cefamandole concentration (micrograms per milliliter): the first at 35 to 135 min, the second at 5 to 9 h. CSF was obtained for cefamandole assay at 75 to 140 min postinfusion, a time interval yielding the highest CSF concentrations of ampicillin and carbenicillin (16). Antibiotic assay. A modification of the standard microbiological assay of Bennett et al. (2) was used. Test plates were prepared with polystyrene petri dishes (Van-Lab) (150 by 15 mm). The assay agar used nutrient agar (pH 6.8, Difco), in 40-ml portions, seeded with 0.3 ml of a Bacillus subtilis spore suspension prepared by the addition of one vial of spores (Difco) to 50 ml of 0.1 M phosphate buffer (pH 7.4). Two thousand units of penicillinase (Difco) was added concomitantly with the spore inoculum. Standard curves, utilizing cefamandole lithium, with CSF or serum as diluent, were run simultaneously by the inclusion ofthree control wells (0.8, 6.25, and 50 .g/ml). Sera and CSF that were not analyzed immediately were stored at -20°C; no specimen was stored longer than 7 days before analysis. Susceptibility testing. Minimal inhibitory concentrations (MICs) were determined for cefamandole lithium by standard twofold serial dilution methods: Levinthal broth was used for H. influenzae; tryptic soy broth was used for streptococcus. An inoculum of approximately 105 organisms was prepared from overnight growth. Minimal bactericidal concentrations (MBCs) were determined by plating broth, with a 3-mm loop, from tubes without growth after 24 h of incubation. Chocolate agar plus supplement B was used for H. influenzae; sheep blood agar was used for streptococcus. MBC was defined as the lowest antibiotic concentration which allowed growth of no greater than 10 colonies after
933
934
STEINBERG ET AL. Az.mmicRoB. AGzNTs CHRMOTHZR. TAB.z 1. C.efamandole concentrations in serum and CSF ofpatients with bacterial meningitisa Serum
Patient
Ae Age
Day of therPoetinfuapyapy sion time
~
CSF
CnnCnnCnn PostinfuConcn ConcnPiision time sion time ml) 1) Il/ Bisml) ml) ~~~~M)
Po tein
(mt/
dml)
1 h, 20 min 0 1 60 min 0 19.20 9 h 9 mo 69 1 h, 50 min 0.24 3 1 h, 20 min 36.70 ND6 ND 9 mo 32 1 h, 35 min 0.30 2.60 5 h, 45 min 0 2 yr, I mo 3 1 h, 55min 93 3 65 min 40.00 6 h 0.33 2 h, 15 min 0.42 13 yr 37 1 h, 25 min 0.54 3 1 h, 10 min 18.00 5 h, 30 min 0.29 46 yr 118 1 40 min ND 1 h, 35 min 0.57 38.50 ND 77 6 mo 1 h, 15 min 0.62 2 yr, 3 mo 3 1 h, 20 min 6.25 6 h 0 87 2.60 2 h, 20 min 2.00 37.00 5 h 1 50 min 196 10 mo 1 h, 35 min 2.55 3 1 h, 20 min 27.50 6 h, 20 min 0.19 2 yr 159 0.93 2 h, 20 min 3.10 1 35 min 120 35.00 6 h 3 yr, 9 mo 1 h, 30 min 5.20 6.25 6 h, 20 min 0 3 1 h, 52 min 10 mo 1,000 62 yr 7 2 h, 15 min 35.00 6 h, 30 min 7.40 2 h, 20 min 7.40 160 a Concentrations were measured after single dose of cefamandole, 33 mg/kg, given intravenously. b ND, Not done.
1 2 3 4 5 6 7 8 9 10 11 12
18 h of incubation. All H. influenzae isolates were tested for (3-lactamase production by the method of Thornsberry (19).
RESULTS Serum concentrations of cefamandole ranged from 2.6 to 40 ,ug/ml, with a median of 31.25 ,ug/ ml in 12 patients, at 35 to 135 min after administration (Table 1), and from undetectable to 7.4 ,ug/ml, with a median of 1.17 ,ug/ml, in 10 patients, at 5 to 9 h after administration (Table 1). The wide range in serum cefamandole concentrations may be explained by the fact that the rate of antibiotic infusion and the time of serum collection postinfusion were not kept constant. All patients had normal renal function, as indicated by serum urea nitrogen, which was less than 18 mg/dl, or serum creatinine, which was less than 1.1 mg/dl. CSF concentrations of cefamandole ranged from undetectable in one patient to 7.4 ,ug/ml, with a median of 0.60 ,ug/ml, at 75 to 140 min after administration. No correlation was apparent between the concentration attained and type of organism or severity of disease upon admission. Greater CSF concentrations were observed in CSF with higher protein concentrations. In six patients with CSF protein less than 100 mg/dl, concentrations ranged from undetectable to 0.62 ,tg/ml, with a median of 0.36 ,ug/ml. In six patients with CSF protein above 100 mg/dl, concentrations ranged from 0.54 to 7.4 ,ug/ml, with a median of 2.83 pg/ml. (Table 1).
All H. influenzae type b isolates were nega-
tive for /3-lactamase production. Susceptibility studies to cefamandole on five of these yielded an MIC of 0.4 ,ug/ml and an MBC of 0.4 ,ug/ml
on each organism. The single (8-hemolytic streptococcus had an MIC of 0.1 ug/ml and an MBC of 0.8 pLg/ml. Two patients manifested unusual symptoms in association with administration of the drug. One adult developed agitation and a generalized urticarial rash within 15 min. All symptoms resolved within 3 h, after the administration of 50 mg of diphenhydramine intravenously. One child had an increase in temperature from 1004°F to 102"°F (ca. 37.8 to 38.9°C) at 1 h and 45 min after administration of the drug. This was associated with generalized shaking, but there was no change in other vital signs and no loss of consciousness.
DISCUSSION The spectrum of cefamandole includes the three organisms responsible for most bacterial meningitis in children and adults. S. pneumoniae is highly susceptible; reported MICs have ranged from 97% inhibited at less than or equal to 0.4 ,ug/ml (4, 14) to 100% inhibited at less
than or equal to 0.2 ug/ml (5, 15). N. meningiti-
dis has MICs less than or equal to 0.25 pLg/ml (12). Reported MICs for H. influenzae type b have ranged from 90% susceptible to less than or equal to 2.5 ,ug/ml (4, 14) to 100% susceptible to 2.0 ,ug/ml, including ampicillin-resistant strains producing (8-lactamase (9). Concentrations achieved in CSF during treatment of bacterial meningitis have been reported for several antibiotics (18). An antibiotic that fails to achieve measurable CSF concentrations in the presence of meningitis is generally ineffective in treating central nervous system infections. However, neither proof of CSF penetration nor actual concentrations
VOL. 11, 1977
PENETRATION OF CEFAPMANDOLE
measured, by themselves, assures the efficacy of an antibiotic (6). Penicillin and ampicillin generally attain CSF concentrations between 0.5 and 10 ,ug/ml during treatment of meningitis (1, 18, 20, 22), but single random samples may have no detectable concentrations despite clinical evidence of therapeutic efficacy (16, 22). On a daily dosage of 200 mg/kg given in six doses of 33 mg/kg, ampicillin achieved a median concentration of 0.45 a/ml, with a range of 0.1 to 2.3 ,ug/ml in 15 patients with CSF protein less than 75 mg/dl. At a similar dosage, in 14 patients with CSF protein greater than 75 mg/dl, ampicillin achieved a median concentration of 2.20 ,&g/ml, with a range of 0.37 to 30 ,ug/ml (16). Cephalosporins have also demonstrated penetration of CSF in the presence of meningeal inflammation. Cephalothin (3, 10, 17, 21) and cephaloridine (11) each have attained CSF median concentrations in the range of 0.1 to 6 ug/ml. Yet, despite adequate drug dosage and measured antibiotic concentrations exceeding the MIC of the infecting organism, these cephalosporins have, on occasion, been associated with persistence of bacteria in CSF and poor clinical response (3, 6). Chloramphenicol is, at present, the most reliable effective antibiotic for infections with H. influenzae type b. The documented occurrence of aplastic anemia after the administration of chloramphenicol, although rare, has caused concern about its use. The results of this pilot study show that cefamandole does penetrate inflamed meninges. It is possible that this agent may be useful in the therapy of meningitis, but further in vitro and careful in vivo research is required before cefamandole can be considered as a therapeutic agent for central nervous system infections. LITERATURE CITED 1. Barrett, F. F., W. A. Eardley, M. D. Yow, and H. A. Leverett. 1966. Ampicillin in the treatment of acute suppurative meningitis. J. Pediatr. 69:343-353. 2. Bennett, J. V., J. L. Brodie, E. J. Benner, and W. M. Kirby. 1966. Simplified accurate method for antibiotic assay for clinical specimens. Appl. Microbiol. 14:170177. 3. Brown, J. D., A. W. Mathies, Jr., D. Ivler, W. S. Warren, and J. M. Leedom. 1970. Variable results of cephalothin therapy for meningococcal meningitis, p. 432-440. Antimicrob. Agents Chemother. 1969. 4. Eykyn, S., C. Jenkins, A. King, and I. Phillips. 1973. Antibacterial activity of cefamandole, a new cephalosporin antibiotic, compared with that of cephalori-
935
dine, cephalothin, and cephalexin. Antimicrob. Agents Chemother. 3:657-661. 5. Finland, M., C. Garner, C. Wilcox, and L. D. Sabath. 1976. Susceptibility of pneumococci and Haemophilus
influenzae to anti-bacterial agents. Antimicrob. Agents Chemother. 9:274-287. 6. Fisher, L. S., A. W. Chow, T. T. Yoshikawa, and L. B. Guze. 1975. Cephalothin and cephaloridine therapy for bacterial meningitis. Ann. Intern. Med. 82:689693. 7. Fong, I. W., E. D. Ralph, E. R. Engelking, and W. M. M. Kirby. 1976. Clinical pharmacology of cefamandole as compared with cephalothin. Antimicrob. Agents Chemother. 9:65-69. 8. Griffith, R. S., H. R. Black, G. L. Brier, and J. D. Wolney. 1976. Cefamandole: in vitro and clinical pharmacokinetics. Antimicrob. Agents Chemother. 10:814-823. 9. Kammer, R. B., D. A. Preston, J. R. Turner, and L. C. Hawley. 1975. Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to sixteen antibiotics. Antimicrob. Agents Chemother. 8:91-94. 10. Lerner, P. I. 1969. Penetration of cephalothin plus lincomycin into the cerebrospinal fluid. Am. J. Med. Sci. 257:125-131. 11. Lerner, P. I. 1971. Penetration of cephaloridine into cerebrospinal fluid. Am. J. Med. Sci. 262:321-326. 12. Lilly Research Laboratories. 1976. Cefamandole nafate clinical investigation manual, p. 6. Lilly Research Laboratories, Indianapolis. 13. Mathies, A. W., Jr. 1972. Penicillin in the treatment of bacterial meningitis. J. R. Coll. Physicians London 6:139-146. 14. Meyers, B. R., B. Leng, and S. Z. Hirschman. 1975. Cefamandole: antimicrobial activity in vitro of a new cephalosporin. Antimicrob. Agents Chemother. 8:737-741. 15. Neu, H. C. 1974. Cefamandole, a cephalosporin antibiotic with an unusually wide spectrum of activity. Antimicrob. Agents Chemother. 6:177-182. 16. Overturf, G. D., E. A. Steinberg, A. E. Underman, J. Wilkins, J. M. Leedom, A. W. Mathies, Jr., and P. F. Wehrle. 1977. Comparative trial of carbenicillin and ampicillin therapy for purulent meningitis. Antimicrob. Agents Chemother. 11:420426. 17. Riley, H. D., Jr., E. C. Bracken, and M. Flux. 1963. Studies of cephalothin in infants and children, p. 716723. Antimicrob. Agents Chemother. 1962. 18. Taber, L. H., M. D. Yow, F. G. Nieberg. 1967. The penetration of broadspectrum antibiotics into the cerebrospinal fluid. Ann. N. Y. Acad. Sci. 145:473-481. 19. Thornsberry, C., and L. A. Klrven. 1974. Ampicillin
resistance in Haemophilus influenzae as determined by a rapid test for beta-lactamase production. Antimicrob. Agents Chemother. 6:653654. 20. Thrupp, L. D., J. M. Leedom, D. Ivler, P. F. Wehrle, B. Portnoy, and A. W. Mathies, Jr. 1966. Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis, p 206-213. Antimicrob. Agents Chemother. 1965. 21. Vianna, N. J., and D. Kaye. 1967. Penetration of cephalothin into the spinal fluid. Am. J. Med. Sci. 254:216220. 22. Wilson, H. D., and K. C. Haltalin. 1975. Ampicillin in
Haemophilus influenzae meningitis. Am. J. Dis. Child. 129:208-215.
Vol. 11, No. 6
Printed in U.S.A.
Penetration of Cefamandole into Spinal Fluid EVAN A. STEINBERG,* GARY D. OVERTURF, LARRY J. BARAFF, AND JEANETTE WILKINS Department of Pediatrics, Los Angeles County-University of Southern California Medical Center; and Department of Pediatrics and Hastings Infectious Disease Laboratory, University of Southern California School of Medicine, Los Angeles, California 90033* Received for publication 7 December 1976
Twelve patients, aged 6 months to 62 years, with proven bacterial meningitis, were given a single intravenous dose of cefamandole (33 mg/kg) 75 to 140 min before a routine lumbar puncture. Infecting organisms included Haemophilus influenzae (eight cases), Streptococcus pneumoniae (two cases), and Neisseria meningitidis and (8-hemolytic streptococcus (one each). Cerebrospinal fluid (CSF) was analyzed by microbiological assay for cefamandole. The median concentration was 0.60 ,ug/ml, ranging from undetectable to 7.4 ,ug/ml. CSF cefamandole concentrations correlated with CSF protein: in six patients with CSF protein less than 100 ,ug/dl, the range of drug concentration was 0 to 0.62 ,ug/ml; and in six patients with CSF protein above 100 mg/dl, the range was 0.57 to 7.4 ,ug/ml. No significant correlation was noted between severity of illness, type of organism involved, or patient age and concentration of drug achieved.
Cefamandole nafate, 7-D-mandelamido-3 {[(1-
methyl-lH-tetrazole-5-yl)-thiolmethyl)-3 ce-
phem-4-carboxylic acid, formate (ester), sodium salt, is a semisynthetic cephalosporin antibiotic with broad antibacterial spectrum (4, 14, 15), and is 70 to 80% protein bound (7, 8). It is notably active against (8-lactamase-producing Haemophilus influenzae type b (9). Therefore, a pilot study was conducted to evaluate achievable antibiotic levels in cerebrospinal fluid (CSF) after the intravenous administration of a single dose of cefamandole to patients with bacterial meningitis. MATERIALS AND METHODS Patients. Twelve patients admitted to the Los Angeles County-University of Southern California Medical Center with bacterial meningitis were selected for study. The diagnosis was confirmed by a positive CSF culture on all patients. Informed written conserit was obtained from patients or from their parents or responsible guardians. The patients included two adults (62 and 46 years), one adolescent (13 years), and nine children (6 months to 3.5 years with a median age of 10 months). Patients 4 and 5 had Streptococcus pneumoniae isolated from CSF; patient 12 had a /-hemolytic streptococcus; patient 10 had Neisseria meningitidis. All other patients had H. influenzae type b isolated (Table 1). The severity of meningitis upon admission wasI graded according to the criteria of Mathies (13). All patients were treated with ampicillin intravenously, 200 mg/kg per day in six divided doses. One dose of cefamandole, 33 mg/kg, was substituted for ampicillin before a routine lumbar puncture within the first 72 h of treatment in all patients, except no.
12, whose dose was given on day 7 of treatment. Infusion times varied from 10 to 25 min. Two serum samples were obtained for cefamandole concentration (micrograms per milliliter): the first at 35 to 135 min, the second at 5 to 9 h. CSF was obtained for cefamandole assay at 75 to 140 min postinfusion, a time interval yielding the highest CSF concentrations of ampicillin and carbenicillin (16). Antibiotic assay. A modification of the standard microbiological assay of Bennett et al. (2) was used. Test plates were prepared with polystyrene petri dishes (Van-Lab) (150 by 15 mm). The assay agar used nutrient agar (pH 6.8, Difco), in 40-ml portions, seeded with 0.3 ml of a Bacillus subtilis spore suspension prepared by the addition of one vial of spores (Difco) to 50 ml of 0.1 M phosphate buffer (pH 7.4). Two thousand units of penicillinase (Difco) was added concomitantly with the spore inoculum. Standard curves, utilizing cefamandole lithium, with CSF or serum as diluent, were run simultaneously by the inclusion ofthree control wells (0.8, 6.25, and 50 .g/ml). Sera and CSF that were not analyzed immediately were stored at -20°C; no specimen was stored longer than 7 days before analysis. Susceptibility testing. Minimal inhibitory concentrations (MICs) were determined for cefamandole lithium by standard twofold serial dilution methods: Levinthal broth was used for H. influenzae; tryptic soy broth was used for streptococcus. An inoculum of approximately 105 organisms was prepared from overnight growth. Minimal bactericidal concentrations (MBCs) were determined by plating broth, with a 3-mm loop, from tubes without growth after 24 h of incubation. Chocolate agar plus supplement B was used for H. influenzae; sheep blood agar was used for streptococcus. MBC was defined as the lowest antibiotic concentration which allowed growth of no greater than 10 colonies after
933
934
STEINBERG ET AL. Az.mmicRoB. AGzNTs CHRMOTHZR. TAB.z 1. C.efamandole concentrations in serum and CSF ofpatients with bacterial meningitisa Serum
Patient
Ae Age
Day of therPoetinfuapyapy sion time
~
CSF
CnnCnnCnn PostinfuConcn ConcnPiision time sion time ml) 1) Il/ Bisml) ml) ~~~~M)
Po tein
(mt/
dml)
1 h, 20 min 0 1 60 min 0 19.20 9 h 9 mo 69 1 h, 50 min 0.24 3 1 h, 20 min 36.70 ND6 ND 9 mo 32 1 h, 35 min 0.30 2.60 5 h, 45 min 0 2 yr, I mo 3 1 h, 55min 93 3 65 min 40.00 6 h 0.33 2 h, 15 min 0.42 13 yr 37 1 h, 25 min 0.54 3 1 h, 10 min 18.00 5 h, 30 min 0.29 46 yr 118 1 40 min ND 1 h, 35 min 0.57 38.50 ND 77 6 mo 1 h, 15 min 0.62 2 yr, 3 mo 3 1 h, 20 min 6.25 6 h 0 87 2.60 2 h, 20 min 2.00 37.00 5 h 1 50 min 196 10 mo 1 h, 35 min 2.55 3 1 h, 20 min 27.50 6 h, 20 min 0.19 2 yr 159 0.93 2 h, 20 min 3.10 1 35 min 120 35.00 6 h 3 yr, 9 mo 1 h, 30 min 5.20 6.25 6 h, 20 min 0 3 1 h, 52 min 10 mo 1,000 62 yr 7 2 h, 15 min 35.00 6 h, 30 min 7.40 2 h, 20 min 7.40 160 a Concentrations were measured after single dose of cefamandole, 33 mg/kg, given intravenously. b ND, Not done.
1 2 3 4 5 6 7 8 9 10 11 12
18 h of incubation. All H. influenzae isolates were tested for (3-lactamase production by the method of Thornsberry (19).
RESULTS Serum concentrations of cefamandole ranged from 2.6 to 40 ,ug/ml, with a median of 31.25 ,ug/ ml in 12 patients, at 35 to 135 min after administration (Table 1), and from undetectable to 7.4 ,ug/ml, with a median of 1.17 ,ug/ml, in 10 patients, at 5 to 9 h after administration (Table 1). The wide range in serum cefamandole concentrations may be explained by the fact that the rate of antibiotic infusion and the time of serum collection postinfusion were not kept constant. All patients had normal renal function, as indicated by serum urea nitrogen, which was less than 18 mg/dl, or serum creatinine, which was less than 1.1 mg/dl. CSF concentrations of cefamandole ranged from undetectable in one patient to 7.4 ,ug/ml, with a median of 0.60 ,ug/ml, at 75 to 140 min after administration. No correlation was apparent between the concentration attained and type of organism or severity of disease upon admission. Greater CSF concentrations were observed in CSF with higher protein concentrations. In six patients with CSF protein less than 100 mg/dl, concentrations ranged from undetectable to 0.62 ,tg/ml, with a median of 0.36 ,ug/ml. In six patients with CSF protein above 100 mg/dl, concentrations ranged from 0.54 to 7.4 ,ug/ml, with a median of 2.83 pg/ml. (Table 1).
All H. influenzae type b isolates were nega-
tive for /3-lactamase production. Susceptibility studies to cefamandole on five of these yielded an MIC of 0.4 ,ug/ml and an MBC of 0.4 ,ug/ml
on each organism. The single (8-hemolytic streptococcus had an MIC of 0.1 ug/ml and an MBC of 0.8 pLg/ml. Two patients manifested unusual symptoms in association with administration of the drug. One adult developed agitation and a generalized urticarial rash within 15 min. All symptoms resolved within 3 h, after the administration of 50 mg of diphenhydramine intravenously. One child had an increase in temperature from 1004°F to 102"°F (ca. 37.8 to 38.9°C) at 1 h and 45 min after administration of the drug. This was associated with generalized shaking, but there was no change in other vital signs and no loss of consciousness.
DISCUSSION The spectrum of cefamandole includes the three organisms responsible for most bacterial meningitis in children and adults. S. pneumoniae is highly susceptible; reported MICs have ranged from 97% inhibited at less than or equal to 0.4 ,ug/ml (4, 14) to 100% inhibited at less
than or equal to 0.2 ug/ml (5, 15). N. meningiti-
dis has MICs less than or equal to 0.25 pLg/ml (12). Reported MICs for H. influenzae type b have ranged from 90% susceptible to less than or equal to 2.5 ,ug/ml (4, 14) to 100% susceptible to 2.0 ,ug/ml, including ampicillin-resistant strains producing (8-lactamase (9). Concentrations achieved in CSF during treatment of bacterial meningitis have been reported for several antibiotics (18). An antibiotic that fails to achieve measurable CSF concentrations in the presence of meningitis is generally ineffective in treating central nervous system infections. However, neither proof of CSF penetration nor actual concentrations
VOL. 11, 1977
PENETRATION OF CEFAPMANDOLE
measured, by themselves, assures the efficacy of an antibiotic (6). Penicillin and ampicillin generally attain CSF concentrations between 0.5 and 10 ,ug/ml during treatment of meningitis (1, 18, 20, 22), but single random samples may have no detectable concentrations despite clinical evidence of therapeutic efficacy (16, 22). On a daily dosage of 200 mg/kg given in six doses of 33 mg/kg, ampicillin achieved a median concentration of 0.45 a/ml, with a range of 0.1 to 2.3 ,ug/ml in 15 patients with CSF protein less than 75 mg/dl. At a similar dosage, in 14 patients with CSF protein greater than 75 mg/dl, ampicillin achieved a median concentration of 2.20 ,&g/ml, with a range of 0.37 to 30 ,ug/ml (16). Cephalosporins have also demonstrated penetration of CSF in the presence of meningeal inflammation. Cephalothin (3, 10, 17, 21) and cephaloridine (11) each have attained CSF median concentrations in the range of 0.1 to 6 ug/ml. Yet, despite adequate drug dosage and measured antibiotic concentrations exceeding the MIC of the infecting organism, these cephalosporins have, on occasion, been associated with persistence of bacteria in CSF and poor clinical response (3, 6). Chloramphenicol is, at present, the most reliable effective antibiotic for infections with H. influenzae type b. The documented occurrence of aplastic anemia after the administration of chloramphenicol, although rare, has caused concern about its use. The results of this pilot study show that cefamandole does penetrate inflamed meninges. It is possible that this agent may be useful in the therapy of meningitis, but further in vitro and careful in vivo research is required before cefamandole can be considered as a therapeutic agent for central nervous system infections. LITERATURE CITED 1. Barrett, F. F., W. A. Eardley, M. D. Yow, and H. A. Leverett. 1966. Ampicillin in the treatment of acute suppurative meningitis. J. Pediatr. 69:343-353. 2. Bennett, J. V., J. L. Brodie, E. J. Benner, and W. M. Kirby. 1966. Simplified accurate method for antibiotic assay for clinical specimens. Appl. Microbiol. 14:170177. 3. Brown, J. D., A. W. Mathies, Jr., D. Ivler, W. S. Warren, and J. M. Leedom. 1970. Variable results of cephalothin therapy for meningococcal meningitis, p. 432-440. Antimicrob. Agents Chemother. 1969. 4. Eykyn, S., C. Jenkins, A. King, and I. Phillips. 1973. Antibacterial activity of cefamandole, a new cephalosporin antibiotic, compared with that of cephalori-
935
dine, cephalothin, and cephalexin. Antimicrob. Agents Chemother. 3:657-661. 5. Finland, M., C. Garner, C. Wilcox, and L. D. Sabath. 1976. Susceptibility of pneumococci and Haemophilus
influenzae to anti-bacterial agents. Antimicrob. Agents Chemother. 9:274-287. 6. Fisher, L. S., A. W. Chow, T. T. Yoshikawa, and L. B. Guze. 1975. Cephalothin and cephaloridine therapy for bacterial meningitis. Ann. Intern. Med. 82:689693. 7. Fong, I. W., E. D. Ralph, E. R. Engelking, and W. M. M. Kirby. 1976. Clinical pharmacology of cefamandole as compared with cephalothin. Antimicrob. Agents Chemother. 9:65-69. 8. Griffith, R. S., H. R. Black, G. L. Brier, and J. D. Wolney. 1976. Cefamandole: in vitro and clinical pharmacokinetics. Antimicrob. Agents Chemother. 10:814-823. 9. Kammer, R. B., D. A. Preston, J. R. Turner, and L. C. Hawley. 1975. Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to sixteen antibiotics. Antimicrob. Agents Chemother. 8:91-94. 10. Lerner, P. I. 1969. Penetration of cephalothin plus lincomycin into the cerebrospinal fluid. Am. J. Med. Sci. 257:125-131. 11. Lerner, P. I. 1971. Penetration of cephaloridine into cerebrospinal fluid. Am. J. Med. Sci. 262:321-326. 12. Lilly Research Laboratories. 1976. Cefamandole nafate clinical investigation manual, p. 6. Lilly Research Laboratories, Indianapolis. 13. Mathies, A. W., Jr. 1972. Penicillin in the treatment of bacterial meningitis. J. R. Coll. Physicians London 6:139-146. 14. Meyers, B. R., B. Leng, and S. Z. Hirschman. 1975. Cefamandole: antimicrobial activity in vitro of a new cephalosporin. Antimicrob. Agents Chemother. 8:737-741. 15. Neu, H. C. 1974. Cefamandole, a cephalosporin antibiotic with an unusually wide spectrum of activity. Antimicrob. Agents Chemother. 6:177-182. 16. Overturf, G. D., E. A. Steinberg, A. E. Underman, J. Wilkins, J. M. Leedom, A. W. Mathies, Jr., and P. F. Wehrle. 1977. Comparative trial of carbenicillin and ampicillin therapy for purulent meningitis. Antimicrob. Agents Chemother. 11:420426. 17. Riley, H. D., Jr., E. C. Bracken, and M. Flux. 1963. Studies of cephalothin in infants and children, p. 716723. Antimicrob. Agents Chemother. 1962. 18. Taber, L. H., M. D. Yow, F. G. Nieberg. 1967. The penetration of broadspectrum antibiotics into the cerebrospinal fluid. Ann. N. Y. Acad. Sci. 145:473-481. 19. Thornsberry, C., and L. A. Klrven. 1974. Ampicillin
resistance in Haemophilus influenzae as determined by a rapid test for beta-lactamase production. Antimicrob. Agents Chemother. 6:653654. 20. Thrupp, L. D., J. M. Leedom, D. Ivler, P. F. Wehrle, B. Portnoy, and A. W. Mathies, Jr. 1966. Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis, p 206-213. Antimicrob. Agents Chemother. 1965. 21. Vianna, N. J., and D. Kaye. 1967. Penetration of cephalothin into the spinal fluid. Am. J. Med. Sci. 254:216220. 22. Wilson, H. D., and K. C. Haltalin. 1975. Ampicillin in
Haemophilus influenzae meningitis. Am. J. Dis. Child. 129:208-215.
