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Development of Haemophilus influenzae meningitis in patients treated with cefamandole
Volume 98 Number 6
Brief clinical and laboratory observations
therapy could easily lead to s u b t h e r a p e u t i c peak c h l o r a m phenicol concentrations, which would be particularly dangerous in treating infections of the central nervous system, in which cerebrospinal fluid c h l o r a m p h e n i c o l concentrations m a y be only 30 to 50% of s e r u m values? This case illustrates the n e e d for close m o n i t o r i n g o f c h l o r a m p h e n i c o l s e r u m concentrations for the d u r a t i o n o f therapy, particularly w h e n concomitantly using drugs which m a y i n d u c e hepatic microsomal enzymes.
5. 6.
7.
8.
,REFERENCES 1. Meissner HC, and Smith AL: The current status of chloramphenicol, Pediatrics 64:348, 1979. 2. Conney AH: Pharmacological implications of microsomal enzyme induction, Pharmacol Rev 19:317, 1967. 3. Nahata MC, and Powell DA: Simultaneous determination of chloramphenicol and its succinate ester by high performance liquid chromatography, J Chromatogr 223:247, 1981. 4. Sack CM, Koup JR, and Smith AL: Chloramphenicol
9.
10.
1 0 03
pharmacokinetics in infants and young children, Pediatrics 66:579, 1980. Vincent FM, Mills L, and Sullivan JK: Choramphenicolinduced phenytoin intoxication, Ann Neurol 3:469, 1978. Bloxham RA, Durbin GM, Johnson T, et al: Chloramphenicol and phenobarbitone: A drug interaction, Arch Dis Child 54:76, 1979. Koup JR, Gibaldi M, McNamara P, et al: Interaction of chloramphenicol with phenytoin and phenobarbital: Case report, Clin Pharmacol Ther 24:571, 1978. Windorfer A, and Pringsheim W: Studies on the concentrations of chloramphenicol in the serum and cerebrospinal fluid of neonates, infants and small children. Reciprocal reactions between chl0ramphenicol , penicillin and phenobarbitone, Eur J Pediatr 124:129, 1977. Durbin GM, and Winterborn MH: Chloramphenicol and phenobarbitone: A drug interaction, Arch Dis Child 54:564, 1979. Buchanan NN, and Moodley GP: Interaction between chloramphenicol and paracetamol, Br Med J 2:307, 1979.
Development of Haemophilus influenzae meningitis in patients treated with cefamandole Stephen A. Chartrand, M.D., Melvin I. Marks, M.D.,* Rosemary Roberts, M.D., David P. Jubelirer, M.D., and Daniel C. Plunket, M.D., Oklahoma City, and Tulsa, Okla.
BECAUSE o f its in vitro activity against gram-positive cocci a n d Haemophilus influenzae, c e f a m a n d o l e is widely used to treat septic arthritis, cellulitis, a n d p n e u m o n i a in infants a n d children. O u r experience with two patients who developed Haemophilus meningitis while o n cefam a n d o l e t h e r a p y provides a w a r n i n g against this practice.
protein concentration of 17 mg/dl and glucose of 73 mg/dl. Because of a history of rash with penicillin, the patient was treated with cefamandole 100 mg/kg/day in four divided doses. Subsequently, the blood and tissue aspirate cultures grew H. influenzae type b, beta-lactamase negative (HIB lac-neg), sensitive by broth dilution (inoculum approximately 10~ cfu/mt) to cefamandole (M1C/MBC = 0.5/0.5 b~g/ml) and ampicillin (MIC/MBC = 0.5/0.5/~g/ml).
CASE R E P O R T S Patient 1. A previously well 8-month-old boy was hospitalized with a ten-hour history of fever and refusal to bear weight on his left leg. The patient was alert but irritable and had a temperature of 40.7~ there was soft tissue swelling, warmth, and tenderness over the left ankle. The remainder of the physical examination was r~ormal, including the neurologic system. A roentgenogram of the left ankle was normal. The peripheral white blood cell count was 11,600/mm ~ with 38% neutrophils. An aspirate of the soft tissue over the left ankle contained numerous red blood cells "and neutrophils, but no bacteria. The cerebrospinal fluid had no bacteria on smear and culture, 386 red blood cells/ram a, and From the Department of Pediatrics, University of Oklahoma Health Sciences Center. *Reprint address: University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190.
0022-3476/81/0601003+03500.30/0 9 1981 The C. V. Mosby Co.
Abbreviations used HIB lac-neg: H. influenzae type b, beta lactamase MIC: minimal inhibitory concentration MBC: minimal bactericidal concentration
See related articles, pp. 910 and 995.
The patient had daily fevers of 39.5~ to 40.7~ with minimal clinical improvement over the next four days; no further cultures were obtained during that time. On the fifth hospital day he was more irritable and developed nuchal rigidity. Lumbar CSF contained protein 235 mg/dl and glucose 30 mg/dl; Gram stain showed 2 to. 3 WBC/hpf and gram-negative pleomorphic rods. Cefamandole therapy was discontinued and chloramphenicol was given (75 mg/kg/day) in four divided doses. Culture of the
1 004
Brief clinical and laboratory observations
CSF grew 8 x 10" HIB lac-neg/ml; the blood culture was also positive. The organism was the same biotype (type 1) as the original isolate and was still sensitive to cefamandole (MIC/ MBC = 0.25/0.5 #g/ml), ampicillin (M1C = 0.25 /~g/ml), and chloramphenicol (MIC/MBC = 1.0/2.0 #g/ml). Inoculum studies on this isolate showed resistance (MIC > 16 ~tg/ml) only at 108 cfu/ml; a beta lactamase-positive strain was res!stant at 10~ cfu/ml. The patient's fever declined and there was clinical improvement over the next 72 hours. Repeat CSF and blood cultures were negative. He was treated for ten days and was discharged with a normal physical and neurologic examination. Patient 2. A 6-month-old hemophiliac was hospitalized with a 24-hour histOry of fever, lethargy, and left elbow swelling. He was alert with a temperature of 38.2~ Physical examination revealed bilateral otitis media plus swelling, tenderness,' and erythema over the left elbow. Results Of the neurologic examination were normal. The peripheral white blood cell count was 20,800/mm ~with 43% neutrophils and 10% band forms. The CSF had no bacteria on smear or culture, one mononuclear cell/mm 3, five red blood cells/mm ~, and normal glucose and protein concentrations. The patient was treated with cefamandole; 100 mg/kg/day.IV, in six divided doses. Admission blood and joint fluid cultures subsequently grew HIB lac-neg. The organism was sensitive to ampicillin (MIC/MBC = 0.5/0.5 ~g/ml) and chloramphenicol (MIC = 1.0/~g/ml) by the microtiter method, and to cefamandole by Kirby-Bauer disc diffusion. Within 36 hours there was clinical improvement and the fever decreased. On the following day, however, the child developed increasing lethargy and nuchal rigidity. Lumbar puncture revealed cloudy CSF with gram-negative pleomorphic rods on smear and 6,500 white blood cells/mm a (97% neutrophils); the glucose concentration was 65 mg/dl and protein 42 mg/dl. Cefamandole was discontinued and treatment with chloramphenicol, 100 mg/kg/day IV, was begun. Cultures of the CSF and blood grew H1B lac-neg with antibiotic sensitivities identical to those of the previous isolate. The patient became afebrile and clinically improved within 24 hours of changing therapy. He was treated for 11 more days and had a normal physical and neurologic examination at the time of discharge. DISCUSSION Cefamandole is active in vitro against gram-positive and gram-negative bacteria, including HIB. Mean MICs for HIB are 0.4 and 0.8 t~g/ml for beta lactamase-negative and positive strains, respectively. 1-4 Cefamandole cerebrospinal fluid concentrations infrequently equal or surpass these levels, and then only when serum concentrations exceed 20/~g/ml in the presence of intense meningeal inflammation. 8, 8, ~ Moreover, cefamand01e activity is decreased in the presence of high concentrations of HIB (_> 107 bacteria/ml), sometimes seen in meningitis. This effect is more c o m m o n with beta lactamase-positive strains,', 7 Treatment failures and relapses have been reported with cefamandole therapy of HIB meningitiS. Steinberg et
The Journal of Pediatrics June 1981
aP treated three children with meningitis caused by HIB with cefamandole (200 m g / k g / d a y ) . Two of the three remained culture-positive for three to four days after the initiation of treatment. The third patient's C S F was sterile 24 hours into therapy but relapsed on the seventh day. R0driguez et aP reported a patient who developed HIB meningitis during cefamandole therapy for periorbital cellulitis. Although admission blood and soft tissue cultures were positive, the initial CSF was sterile. It was not stated whether the organism was beta-lactamase positive or negative. Cefamandole was undetectable in the C S F at the time the meningitis was diagnosed (3.5 hours after an iv dose). Azimi and Chase 8 recently described a patient who developed meningitis while being treated with cefamandole for HIB lac-pos empyema. Our patients, unlike Azimi and Chase's, represent the first involving documented beta-lactamase-negative organisms. These reports also demonstrate that a sterile C S F at the beginning of therapy may not ensure the safety o f cefamandole alone in treating systemic HIB disease in young children. We conclude that cefamandole alone is inadequate earl), therapy for systemic Haemophitus disease in small children, regardless o f whether the organism is betalactamase positive or negative. The study of patients with such infections should always include blood and C S F cultures. Antibiotic therapy should include chloramphenicol (75 m g / k g / d a y ) with close monitoring of blood concentrations to avoid toxicity and to document adequate values. 9" 4o
REFERENCES
1. Steinberg EA, Overturf GD, Wilkins J, Baraff LJ, Streng JM, and Leedom JM: Failure of cefamandole in treatment of meningitis due to Haemophilus influenzae Type b, J Infect Dis 137:S180, 1978. 2. Kaiser GV, Gorman M, and Webber JA: Cefamandole--a review of chemistry and microbiology, J Infect Dis 137:S 10, 1978. 3. Rodriguez WJ, Ross S, Khan WN, and Goldenberg R: Clinical and laboratory evaluation of cefamandole in infants and children, J Infect Dis 137:S150, 1978. 4. Azimi PH: Clinical and laboratory investigation of cefamandole therapy of infections in infants and children, J Infect Dis 137:S155, 1978. 5. Korzeniowski OM, Carvalho EM, Rocha H, and Sande MA: Evaluation of cefamandole therapy of patients with bacterial meningitis, J Infect Dis 137:S169, 1978. 6. Steinberg EA, Overturf GD, Baraff LJ, and Wilkins J: Penetration of cefamandole into spinal fluid, Antimicrob Agents Chemother 11:933, 1977. 7. Eickhoff TC, and Ehret JM: In vitro comparison of cefoxitin, cefamandole, cephalexin, and cephalothin, Antimicrob Agents Chemother 9:944, 1976. 8. Azimi PH, and Chase P: The role of cefamandole in
Volume 98 Number 6
treatment of Haemophilus influenzae infections in infants and children, 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1980 (ABS). 9. Tuomanen E, Smith-A, Powell KR, and Marks MI: Oral chloramphenicol pharmacokinetics in H. influenzae b
Brief cl&ical and laboratory observations
10 0 5
meningitis, 20th International Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1980 (ABS). 10. Pickering LK, Hoecker JL, Kramer WG, K o h l S, and Cleary TG: Clinical pharmacology of two chloramphenicol preparations in children: sodium succinate (iv) and palmitate (oral) esters, J PEDIATR 96:757, 1980.
Brief clinical and laboratory observations
therapy could easily lead to s u b t h e r a p e u t i c peak c h l o r a m phenicol concentrations, which would be particularly dangerous in treating infections of the central nervous system, in which cerebrospinal fluid c h l o r a m p h e n i c o l concentrations m a y be only 30 to 50% of s e r u m values? This case illustrates the n e e d for close m o n i t o r i n g o f c h l o r a m p h e n i c o l s e r u m concentrations for the d u r a t i o n o f therapy, particularly w h e n concomitantly using drugs which m a y i n d u c e hepatic microsomal enzymes.
5. 6.
7.
8.
,REFERENCES 1. Meissner HC, and Smith AL: The current status of chloramphenicol, Pediatrics 64:348, 1979. 2. Conney AH: Pharmacological implications of microsomal enzyme induction, Pharmacol Rev 19:317, 1967. 3. Nahata MC, and Powell DA: Simultaneous determination of chloramphenicol and its succinate ester by high performance liquid chromatography, J Chromatogr 223:247, 1981. 4. Sack CM, Koup JR, and Smith AL: Chloramphenicol
9.
10.
1 0 03
pharmacokinetics in infants and young children, Pediatrics 66:579, 1980. Vincent FM, Mills L, and Sullivan JK: Choramphenicolinduced phenytoin intoxication, Ann Neurol 3:469, 1978. Bloxham RA, Durbin GM, Johnson T, et al: Chloramphenicol and phenobarbitone: A drug interaction, Arch Dis Child 54:76, 1979. Koup JR, Gibaldi M, McNamara P, et al: Interaction of chloramphenicol with phenytoin and phenobarbital: Case report, Clin Pharmacol Ther 24:571, 1978. Windorfer A, and Pringsheim W: Studies on the concentrations of chloramphenicol in the serum and cerebrospinal fluid of neonates, infants and small children. Reciprocal reactions between chl0ramphenicol , penicillin and phenobarbitone, Eur J Pediatr 124:129, 1977. Durbin GM, and Winterborn MH: Chloramphenicol and phenobarbitone: A drug interaction, Arch Dis Child 54:564, 1979. Buchanan NN, and Moodley GP: Interaction between chloramphenicol and paracetamol, Br Med J 2:307, 1979.
Development of Haemophilus influenzae meningitis in patients treated with cefamandole Stephen A. Chartrand, M.D., Melvin I. Marks, M.D.,* Rosemary Roberts, M.D., David P. Jubelirer, M.D., and Daniel C. Plunket, M.D., Oklahoma City, and Tulsa, Okla.
BECAUSE o f its in vitro activity against gram-positive cocci a n d Haemophilus influenzae, c e f a m a n d o l e is widely used to treat septic arthritis, cellulitis, a n d p n e u m o n i a in infants a n d children. O u r experience with two patients who developed Haemophilus meningitis while o n cefam a n d o l e t h e r a p y provides a w a r n i n g against this practice.
protein concentration of 17 mg/dl and glucose of 73 mg/dl. Because of a history of rash with penicillin, the patient was treated with cefamandole 100 mg/kg/day in four divided doses. Subsequently, the blood and tissue aspirate cultures grew H. influenzae type b, beta-lactamase negative (HIB lac-neg), sensitive by broth dilution (inoculum approximately 10~ cfu/mt) to cefamandole (M1C/MBC = 0.5/0.5 b~g/ml) and ampicillin (MIC/MBC = 0.5/0.5/~g/ml).
CASE R E P O R T S Patient 1. A previously well 8-month-old boy was hospitalized with a ten-hour history of fever and refusal to bear weight on his left leg. The patient was alert but irritable and had a temperature of 40.7~ there was soft tissue swelling, warmth, and tenderness over the left ankle. The remainder of the physical examination was r~ormal, including the neurologic system. A roentgenogram of the left ankle was normal. The peripheral white blood cell count was 11,600/mm ~ with 38% neutrophils. An aspirate of the soft tissue over the left ankle contained numerous red blood cells "and neutrophils, but no bacteria. The cerebrospinal fluid had no bacteria on smear and culture, 386 red blood cells/ram a, and From the Department of Pediatrics, University of Oklahoma Health Sciences Center. *Reprint address: University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190.
0022-3476/81/0601003+03500.30/0 9 1981 The C. V. Mosby Co.
Abbreviations used HIB lac-neg: H. influenzae type b, beta lactamase MIC: minimal inhibitory concentration MBC: minimal bactericidal concentration
See related articles, pp. 910 and 995.
The patient had daily fevers of 39.5~ to 40.7~ with minimal clinical improvement over the next four days; no further cultures were obtained during that time. On the fifth hospital day he was more irritable and developed nuchal rigidity. Lumbar CSF contained protein 235 mg/dl and glucose 30 mg/dl; Gram stain showed 2 to. 3 WBC/hpf and gram-negative pleomorphic rods. Cefamandole therapy was discontinued and chloramphenicol was given (75 mg/kg/day) in four divided doses. Culture of the
1 004
Brief clinical and laboratory observations
CSF grew 8 x 10" HIB lac-neg/ml; the blood culture was also positive. The organism was the same biotype (type 1) as the original isolate and was still sensitive to cefamandole (MIC/ MBC = 0.25/0.5 #g/ml), ampicillin (M1C = 0.25 /~g/ml), and chloramphenicol (MIC/MBC = 1.0/2.0 #g/ml). Inoculum studies on this isolate showed resistance (MIC > 16 ~tg/ml) only at 108 cfu/ml; a beta lactamase-positive strain was res!stant at 10~ cfu/ml. The patient's fever declined and there was clinical improvement over the next 72 hours. Repeat CSF and blood cultures were negative. He was treated for ten days and was discharged with a normal physical and neurologic examination. Patient 2. A 6-month-old hemophiliac was hospitalized with a 24-hour histOry of fever, lethargy, and left elbow swelling. He was alert with a temperature of 38.2~ Physical examination revealed bilateral otitis media plus swelling, tenderness,' and erythema over the left elbow. Results Of the neurologic examination were normal. The peripheral white blood cell count was 20,800/mm ~with 43% neutrophils and 10% band forms. The CSF had no bacteria on smear or culture, one mononuclear cell/mm 3, five red blood cells/mm ~, and normal glucose and protein concentrations. The patient was treated with cefamandole; 100 mg/kg/day.IV, in six divided doses. Admission blood and joint fluid cultures subsequently grew HIB lac-neg. The organism was sensitive to ampicillin (MIC/MBC = 0.5/0.5 ~g/ml) and chloramphenicol (MIC = 1.0/~g/ml) by the microtiter method, and to cefamandole by Kirby-Bauer disc diffusion. Within 36 hours there was clinical improvement and the fever decreased. On the following day, however, the child developed increasing lethargy and nuchal rigidity. Lumbar puncture revealed cloudy CSF with gram-negative pleomorphic rods on smear and 6,500 white blood cells/mm a (97% neutrophils); the glucose concentration was 65 mg/dl and protein 42 mg/dl. Cefamandole was discontinued and treatment with chloramphenicol, 100 mg/kg/day IV, was begun. Cultures of the CSF and blood grew H1B lac-neg with antibiotic sensitivities identical to those of the previous isolate. The patient became afebrile and clinically improved within 24 hours of changing therapy. He was treated for 11 more days and had a normal physical and neurologic examination at the time of discharge. DISCUSSION Cefamandole is active in vitro against gram-positive and gram-negative bacteria, including HIB. Mean MICs for HIB are 0.4 and 0.8 t~g/ml for beta lactamase-negative and positive strains, respectively. 1-4 Cefamandole cerebrospinal fluid concentrations infrequently equal or surpass these levels, and then only when serum concentrations exceed 20/~g/ml in the presence of intense meningeal inflammation. 8, 8, ~ Moreover, cefamand01e activity is decreased in the presence of high concentrations of HIB (_> 107 bacteria/ml), sometimes seen in meningitis. This effect is more c o m m o n with beta lactamase-positive strains,', 7 Treatment failures and relapses have been reported with cefamandole therapy of HIB meningitiS. Steinberg et
The Journal of Pediatrics June 1981
aP treated three children with meningitis caused by HIB with cefamandole (200 m g / k g / d a y ) . Two of the three remained culture-positive for three to four days after the initiation of treatment. The third patient's C S F was sterile 24 hours into therapy but relapsed on the seventh day. R0driguez et aP reported a patient who developed HIB meningitis during cefamandole therapy for periorbital cellulitis. Although admission blood and soft tissue cultures were positive, the initial CSF was sterile. It was not stated whether the organism was beta-lactamase positive or negative. Cefamandole was undetectable in the C S F at the time the meningitis was diagnosed (3.5 hours after an iv dose). Azimi and Chase 8 recently described a patient who developed meningitis while being treated with cefamandole for HIB lac-pos empyema. Our patients, unlike Azimi and Chase's, represent the first involving documented beta-lactamase-negative organisms. These reports also demonstrate that a sterile C S F at the beginning of therapy may not ensure the safety o f cefamandole alone in treating systemic HIB disease in young children. We conclude that cefamandole alone is inadequate earl), therapy for systemic Haemophitus disease in small children, regardless o f whether the organism is betalactamase positive or negative. The study of patients with such infections should always include blood and C S F cultures. Antibiotic therapy should include chloramphenicol (75 m g / k g / d a y ) with close monitoring of blood concentrations to avoid toxicity and to document adequate values. 9" 4o
REFERENCES
1. Steinberg EA, Overturf GD, Wilkins J, Baraff LJ, Streng JM, and Leedom JM: Failure of cefamandole in treatment of meningitis due to Haemophilus influenzae Type b, J Infect Dis 137:S180, 1978. 2. Kaiser GV, Gorman M, and Webber JA: Cefamandole--a review of chemistry and microbiology, J Infect Dis 137:S 10, 1978. 3. Rodriguez WJ, Ross S, Khan WN, and Goldenberg R: Clinical and laboratory evaluation of cefamandole in infants and children, J Infect Dis 137:S150, 1978. 4. Azimi PH: Clinical and laboratory investigation of cefamandole therapy of infections in infants and children, J Infect Dis 137:S155, 1978. 5. Korzeniowski OM, Carvalho EM, Rocha H, and Sande MA: Evaluation of cefamandole therapy of patients with bacterial meningitis, J Infect Dis 137:S169, 1978. 6. Steinberg EA, Overturf GD, Baraff LJ, and Wilkins J: Penetration of cefamandole into spinal fluid, Antimicrob Agents Chemother 11:933, 1977. 7. Eickhoff TC, and Ehret JM: In vitro comparison of cefoxitin, cefamandole, cephalexin, and cephalothin, Antimicrob Agents Chemother 9:944, 1976. 8. Azimi PH, and Chase P: The role of cefamandole in
Volume 98 Number 6
treatment of Haemophilus influenzae infections in infants and children, 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1980 (ABS). 9. Tuomanen E, Smith-A, Powell KR, and Marks MI: Oral chloramphenicol pharmacokinetics in H. influenzae b
Brief cl&ical and laboratory observations
10 0 5
meningitis, 20th International Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1980 (ABS). 10. Pickering LK, Hoecker JL, Kramer WG, K o h l S, and Cleary TG: Clinical pharmacology of two chloramphenicol preparations in children: sodium succinate (iv) and palmitate (oral) esters, J PEDIATR 96:757, 1980.