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Use of moxalactam for bacterial meningitis
Volume 1O0 Number 5
Use of moxalactam for bacterial meningitis To the Editor: We read ~ith interest the paper by Thirumoorthi et al, ~ concerning the unpredictability of moxalactam penetration into the cerebrospinal fluid (CSF) of children with bacterial meningitis. We, as well as other investigators, have demonstrated excellent penetration of moxalactam into the CSF of children with bacterial meningitis34 The authors propose that the difference in results might be explained by the methods used to measure moxalactam in biological fluids. They suggest that by our bioassay of moxalactam, " . . . the possibility of a synergistic interaction of various concentrations of multiple antibiotics on the test organism cannot be excluded. This may lead to detection of antimicrobial activity erroneous!y attributed to moxalactam." In our bioassay, we used a Serratia marcescens resistant to ampici!lin (greater than 100 ~zg/ml) and chloramphenicol (greater than 100 ~g/ml) as the test organism. We stated that 30 tzg/ml of ampicillin and 50 t*g/ml of chloramphenicol, both alone or in combination, did not interfere with expected assay values of moxalactam in mock samples. Furthermore, in our study, 16 children were studied after three 50 mg/kg/doses of moxalactam given every eight hours. Five of the children had completed routine antimicrobial therapy, six were receiving ampieillin alone, one was receiving chloramphenicol alone, and only three were receiving bot h ampicillin and chloramphenicol together at the time that the CSF was obtained for moxalactam concentrations. We also have reported an additional 20 children with bacterial meningitis who received a 100 rag/ kg/loading dose followed by two 50 mg/kg/doses of moxalactam every six hours prior to obtaining CSF for moxalactam determinations? Eleven of these children bad completed antibiotic therapy, seven were receiving ampicillin or penicillin alone, and only two were receiving both ampicillin and chloramphenicol together at the time the CSF was obtained. In every instance, moxalactam concentrations were detected in the CSF (mean + 1 SD = 3.8 _+ 4.7 #g/ml, range 0.9 to 22.6 ~g/ml). Thus, in a total of 36 children with bacterial meningitis, we have Observed excellent and consistent penetration into the CSF ~of moxalactam after three intravenous doses. We cannot explain the difference in results of Thirumoorthi et al compared to our own as well as other investigators. Since the microbiologic assay and the high pressure liquid chromatography assay for moxalactam in biological fluids have been shown to be very comparable, we do not believe the differences are on the basis of the assays? Many patients with gram-negative enteric meningitis have been successfully treated with moxalactam. 7 Currently, we are comparing moxalactam to ampicillin or chloramphenicol in the treatment of Haemophilus influenzae type b meningitis in a randomized study. Thus far, we have found that moxalactam is equivalent to ampicillin or chloramphenicol for treating this disease. Further studies are obviously required. However, it does appear that moxalactam will be very useful for treating bacterial meningitis due to gram-negative enteric organisms and H. influenzae type b. Lastly, we would like to address the point raised by Thirumoorthi et al with their anecdotal case of a child who developed "pneumococcal meningitis during moxalactam treatment for peri-
Editorial correspondence
843
orbital cellulitis." It is not clear whether this child had a CSF examination prior to moxalactam therapy. Thus, since CSF sterility was not documented prior to moxalactam therapy, there is the possibility that this child had pneumococcal meningitis before he ever received moxalactam. Sheldon L. Kaplan, M.D. Assistant Professor o f Pediatrics Infectious Diseases Section Edward O. Mason, Jr., Ph.D. Assistant Professor o f Pediatrics Infectious Diseases Section Ralph D. Feigin, M.D. Professor and Chairman Department of Pediatrics Baylor College o f Medicine Texas Medical Center Houston, TX 77030 REFERENCES
1. Thirumoorthi MC, Buckley JA, Araviad MK, Kauffman RE, and Dajani AS: Diffusion of moxalactam into the cerebrospinal fluid of children with bacterial meningitis, J PEDIATR 99:975, 1981, 2. Kaplan SL, Mason EO, Garcia H, Kvernland S J, Loiselle EM, Anderson DC, Mintz AA, and Feigin RD: Pharmacokinetics and cerebrospinal fluid penetration of moxalactam in children with bacterial meningitis, J PEDIATR 98:152, 1981. 3. Schaad UB, McCracken GH Jr, Threlkeld N, and Thomas ML: Clinical evaluation of a new broad-spectrum oxabeta-lactam antibiotic, moxalactam, in neonates and infants, J PEDIATR98:129, 1981. 4. Landesman SH, Corrado ML, Cherubin CC, Gombert M, and Cleri D: Diffusion of a new beta-lactam (LY 127935) into cerebrospinal fluid, Am J Med 69:92, 1980. 5. Kaplan SL, Mason EO, Kverntand S J, Loisetle EM, and Feigin RD: Pharmacology, cerebrospinal fluid penetration and dose recommendations of moxalactam in children, presented at the International Symposium on the N e w Generation of Beta-lactam Antibiotics, May 7, 1981, London, England. 6. Miner D J, Coleman DL, Shepherd AMM, and Hardin TC: Determination of moxalactam in human body fluids by liquid chromatographic and microbiological methods, Antimicrob Agents Chemother 20:252, 1981. 7. Kammer RS: Moxalactam-clinical summary, efficacy and safety, International Symposium on the New Generation of Beta-Lactam Antibiotics, London, 1981, (abstr).
Reply To the Editor: The possibility of synergy cannot be excluded from the data presented by Drs. Kaplan, Mason, and Feigin in their manuscript. Unless a checkerboard titration is dofie using varying concentrations of moxalactam and chloramphenicol (or ampicillin), synergy (or antagonism) cannot be demonstrated. Dr. Kaplan and colleagues used 30 #g/ml of ampiciltin and 50 ~zg/ml of chloramphenicol only. These concentrations are considerably higher than can be measured in CSF of patients receiving these drugs.
Use of moxalactam for bacterial meningitis To the Editor: We read ~ith interest the paper by Thirumoorthi et al, ~ concerning the unpredictability of moxalactam penetration into the cerebrospinal fluid (CSF) of children with bacterial meningitis. We, as well as other investigators, have demonstrated excellent penetration of moxalactam into the CSF of children with bacterial meningitis34 The authors propose that the difference in results might be explained by the methods used to measure moxalactam in biological fluids. They suggest that by our bioassay of moxalactam, " . . . the possibility of a synergistic interaction of various concentrations of multiple antibiotics on the test organism cannot be excluded. This may lead to detection of antimicrobial activity erroneous!y attributed to moxalactam." In our bioassay, we used a Serratia marcescens resistant to ampici!lin (greater than 100 ~zg/ml) and chloramphenicol (greater than 100 ~g/ml) as the test organism. We stated that 30 tzg/ml of ampicillin and 50 t*g/ml of chloramphenicol, both alone or in combination, did not interfere with expected assay values of moxalactam in mock samples. Furthermore, in our study, 16 children were studied after three 50 mg/kg/doses of moxalactam given every eight hours. Five of the children had completed routine antimicrobial therapy, six were receiving ampieillin alone, one was receiving chloramphenicol alone, and only three were receiving bot h ampicillin and chloramphenicol together at the time that the CSF was obtained for moxalactam concentrations. We also have reported an additional 20 children with bacterial meningitis who received a 100 rag/ kg/loading dose followed by two 50 mg/kg/doses of moxalactam every six hours prior to obtaining CSF for moxalactam determinations? Eleven of these children bad completed antibiotic therapy, seven were receiving ampicillin or penicillin alone, and only two were receiving both ampicillin and chloramphenicol together at the time the CSF was obtained. In every instance, moxalactam concentrations were detected in the CSF (mean + 1 SD = 3.8 _+ 4.7 #g/ml, range 0.9 to 22.6 ~g/ml). Thus, in a total of 36 children with bacterial meningitis, we have Observed excellent and consistent penetration into the CSF ~of moxalactam after three intravenous doses. We cannot explain the difference in results of Thirumoorthi et al compared to our own as well as other investigators. Since the microbiologic assay and the high pressure liquid chromatography assay for moxalactam in biological fluids have been shown to be very comparable, we do not believe the differences are on the basis of the assays? Many patients with gram-negative enteric meningitis have been successfully treated with moxalactam. 7 Currently, we are comparing moxalactam to ampicillin or chloramphenicol in the treatment of Haemophilus influenzae type b meningitis in a randomized study. Thus far, we have found that moxalactam is equivalent to ampicillin or chloramphenicol for treating this disease. Further studies are obviously required. However, it does appear that moxalactam will be very useful for treating bacterial meningitis due to gram-negative enteric organisms and H. influenzae type b. Lastly, we would like to address the point raised by Thirumoorthi et al with their anecdotal case of a child who developed "pneumococcal meningitis during moxalactam treatment for peri-
Editorial correspondence
843
orbital cellulitis." It is not clear whether this child had a CSF examination prior to moxalactam therapy. Thus, since CSF sterility was not documented prior to moxalactam therapy, there is the possibility that this child had pneumococcal meningitis before he ever received moxalactam. Sheldon L. Kaplan, M.D. Assistant Professor o f Pediatrics Infectious Diseases Section Edward O. Mason, Jr., Ph.D. Assistant Professor o f Pediatrics Infectious Diseases Section Ralph D. Feigin, M.D. Professor and Chairman Department of Pediatrics Baylor College o f Medicine Texas Medical Center Houston, TX 77030 REFERENCES
1. Thirumoorthi MC, Buckley JA, Araviad MK, Kauffman RE, and Dajani AS: Diffusion of moxalactam into the cerebrospinal fluid of children with bacterial meningitis, J PEDIATR 99:975, 1981, 2. Kaplan SL, Mason EO, Garcia H, Kvernland S J, Loiselle EM, Anderson DC, Mintz AA, and Feigin RD: Pharmacokinetics and cerebrospinal fluid penetration of moxalactam in children with bacterial meningitis, J PEDIATR 98:152, 1981. 3. Schaad UB, McCracken GH Jr, Threlkeld N, and Thomas ML: Clinical evaluation of a new broad-spectrum oxabeta-lactam antibiotic, moxalactam, in neonates and infants, J PEDIATR98:129, 1981. 4. Landesman SH, Corrado ML, Cherubin CC, Gombert M, and Cleri D: Diffusion of a new beta-lactam (LY 127935) into cerebrospinal fluid, Am J Med 69:92, 1980. 5. Kaplan SL, Mason EO, Kverntand S J, Loisetle EM, and Feigin RD: Pharmacology, cerebrospinal fluid penetration and dose recommendations of moxalactam in children, presented at the International Symposium on the N e w Generation of Beta-lactam Antibiotics, May 7, 1981, London, England. 6. Miner D J, Coleman DL, Shepherd AMM, and Hardin TC: Determination of moxalactam in human body fluids by liquid chromatographic and microbiological methods, Antimicrob Agents Chemother 20:252, 1981. 7. Kammer RS: Moxalactam-clinical summary, efficacy and safety, International Symposium on the New Generation of Beta-Lactam Antibiotics, London, 1981, (abstr).
Reply To the Editor: The possibility of synergy cannot be excluded from the data presented by Drs. Kaplan, Mason, and Feigin in their manuscript. Unless a checkerboard titration is dofie using varying concentrations of moxalactam and chloramphenicol (or ampicillin), synergy (or antagonism) cannot be demonstrated. Dr. Kaplan and colleagues used 30 #g/ml of ampiciltin and 50 ~zg/ml of chloramphenicol only. These concentrations are considerably higher than can be measured in CSF of patients receiving these drugs.