Correspondence Neonatal meningitis due to Salmonella typhimurium treated with dprofloxadn
gress, although experiencing occasional left sided focal fits despite anticonvulsants. The route of administration was changed on the second day from oral to intravenous because of the high acidity (pH 3-5) of the iv preparation which was being administered orally. The CSF concentration measured by HPLC 2 h after the third oral dose of ciprofloxacin in our patient was 0-5 mg/1. He was discharged on the 29th day having had three culture-negative stool samples. The blood cultures and CSF specimen (with a cell count of 2140/cu mm with 60% polymorphs) repeated 24 h after commencing ciprofloxacin were sterile. Specimens cultured during chloramphenicol therapy were consistently positive for 5. typhimurium. The emergence of chloramphenicol resistance which is documented in salmonella species (Cherubin et a!., 1977), and the development of meningitis with the resistant organism narrowed the choice of antibiotics in this neonate. Ciprofloxacin with its well documented efficacy against salmonella species, and with very low MIC, became the drug of choice despite the age of the child. Various studies carried out to determine the penetration of ciprofloxacin into CSF (Wolff et al., 1987; Kitzes-Cohen et al., 1988) have suggested that a therapeutic concentration could be achieved with adequate dosage, in patients with inflamed meninges. Irreversible arthopathy as a long term effect of ciprofloxacin has been documented in young animals (Schluter, 1987). The manufacturer reports that in a multicentre study done in the UK between 1984 and 1986, there have been eight cases of joint-related disorder in children and six of them were reversible events (Bayer, personal communication). Acknowledgements We thank Mr D. Felmingham, University College Hospital, London for the ciprofloxacin assay, Dr A. J. Bint, Department of Microbiology, Royal Victoria Infirmary, Newcastle upon Tyne for chloramphenicol assays and the Division of Enteric Pathogens, Public Health Laboratory, Colindale, London for typing the isolates. P. L. RAGUNATHAN* D. V. POTKINS* J. G. WATSON* A. M. KEARNS* A. CARROLL' 'Department of Microbiology, Public Health Laboratory Service, Newcastle General Hospital; 'Department of Paediatrics, Newcastle General Hospital, Newcastle upon Tyne, UK
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Diego on June 7, 2015
Sir, A six-day-old baby boy born at term weighing 3-2 kg was admitted with a two-day history of profuse watery diarrhoea, and refusing feeds. There was no history of vomiting, fever or fits. On examination he was found to be dehydrated and moribund with sunken eyes and fontanelle. He was commenced on ampicillin and flucloxacillin iv and intravenous fluids. On the second day after admission Salmonella typhimurium Phage type (PT) 193 was isolated from stool, blood cultures and a heavily bloodstained CSF specimen. The isolate was sensitive to chloramphenicol (MIC of 4 mg/1 by agar dilution method), ceftazidime, gentamicin, ciprofloxacin and resistant to ampicillin and cephaloridine. He was commenced on chloramphenicol 25 mg/kg/day iv and the other antibiotics were omitted. Culture of the mother's stool revealed the presence of S. typhimurium PT 193 with the same antibiotic sensitivity pattern. The CSF isolate was considered to be a blood contaminant. The child became febrile and developed bilateral convulsions within 24 h of admission and responded to anticonvulsants and ventilatory support. He also developed disseminated intravascular coagulation (DIC) with gastro-intestinal haemorrhage and haematuria, which required considerable support with fresh frozen plasma, platelets and blood transfusion for ten days. A week after starting chloramphenicol therapy he had a recurrence of high fever and blood cultures showed 5. typhimurium with a similar pattern of sensitivity to the initial isolate, the MIC of chloramphenicol being 4 mg/1. During the next few days the pyrexia persisted, the child's clinical condition deteriorated, and a repeat lumbar puncture revealed a white cell count of 215/cu mm and the presence of a chloramphenicol-resistant S. typhimurium PT 193 (MIC 16 mg/1). The peak serum chloramphenicol levels measured 2 h post dose on three occasions by HPLC whilst he was on iv therapy were 16-1,11-7 and 8-2 mg/1 on days 6, 7 and 8, respectively. The declining serum concentration despite use of the recommended dosage might explain the emergence of resistance and treatment failure in this child. The MIC of ciprofloxacin for the chloramphenicol resistant isolate was 0-06 mg/1, so ciprofloxacin 25 mg bd was substituted for chloramphenicol and continued for .thirteen days, during which he made good clinical pro-
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Correspondence References
Treatment and prophylaxis of faldparum malaria Sir, The recent leading article on the treatment and prophylaxis of falcipanim malaria (Pithie & Ellis, 1990) contains a series of worrying statements. Many of these relate to a failure to distinguish between severe and uncomplicated falciparum malaria. The authors suggest that, because of drug resistance, physicians in temperate countries will now see an increase in the number of patients with severe falciparum malaria and negative blood smears resulting from partially effective chemoprophylaxis.... 'It follows that empirical treatment of patients with negative films will have to become more commonplace.' While this may apply to uncomplicated partially suppressed infections in which the infecting biomass of parasites is small (and therefore may be below the level of detection), I know of no evidence that it applies to severe malaria where the infecting biomass is large (White & Krishna, 1989). There is also no evidence that partially effective prophylactic antimalarial drugs alter the intravascular distribution of sequestered and circulating parasitized erythrocytes in falciparum malaria. In very rare synchronous infections, and in occasional severely ill patients who have received an effective treatment dose of antimalarial days previously and in whom the parasite burden has already declined, parasitaemia may be below the level of microscopic detection, but in the vast majority of patients with severe infections blood smears arc positive. I am worried that these statements could lead to severely ill patients who have returned from the tropics
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Diego on June 7, 2015
Chenibin, C , Neu, H. C , Rahal, J. J. & Sabath, L. D. (1977). Emergence of resistance to chloramphenicol in Salmonella. Journal of Infectious Diseases 135, 807-12. Kitzes-Cohen, R., Miter, A., Gilboa, A. & Harel, D. (1988). Penetration of ciprofloxacin into cerebrotpinal fluid. Reviews of Infectious Diseases 10, Suppl. 1. S256-7. Schluter, G. (1987). Ciprofloxacin: review of potential toxicologic effects. American Journal of Medicine 82, Suppl. 4A. 91-3. Wolff, M., Boutron, L., Singlas, E., Clair, B., Decazes, J. M. & Regnier, B. (1987). Penetration of ciprofloxacin into cerebrospinal fluid of patients with bacterial meningitis. Antimicrobial Agents and Chemotherapy 31, 899-902.
being diagnosed as 'blood smear-negative, severe falciparum malaria', when in fact they are suffering from a different treatable infection. The distinction between severe and uncomplicated malaria in the recommendation for treatment is also unclear. If patients remain severely ill and parasitaemic after 72 h of quinine treatment, the drug should be continued but the dose should be reduced by onethird to one-half to maintain plasma concentrations between 8 and 15mg/l (World Health Organization, 1986). The regimens suggested (three days quinine followed by an antibiotic) would be inappropriate in this situation., Tetracycline, a slow acting antimalarial, is contraindicated in renal failure, pregnancy and in children, and should not be started until the patient is well enough to take drugs by mouth, and clindamycin has not been evaluated in severe malaria. 'Mefloquine can be given as an aqueous suspension via a nasogastric tube to vomiting or unconscious patients.' Although mefloquine was absorbed rapidly in most patients with cerebral malaria following nasogastric instillation of a suspension of the hydrochloride salt (Chanthavanich et al., 1985), a review of subsequent studies suggests that oral bioavailability in cerebral malaria was probably much less than that in uncomplicated malaria (Karbwang & White, 1990). Furthermore the suspension is not commercially available. The oral bioavailability of the tablet formulation in severe malaria is unknown. Mefloquine should only be given by nasogastric tube in dire circumstances, i.e. if effective parenteral drugs are not available. It is not true that serious neuropsychiatric reactions occur in 1% of patients receiving a treatment dose of mefloquine, as is stated: the incidence is not known with certainty but is nearer 0.1%. However, lightheadedness, dizziness and vertigo are very common following administration of doses greater than 250 mg to healthy subjects (Patchen, Campbell & Williams, 1989; Nosten, F., Ter Kuile, F. & White, N. J., unpublished observations). Rare but serious acute neuropsychiatric reactions must be distinguished from this predictable minor nervous system toxicity (Karbwang & White, 1990). Over twenty severe neuropsychiatric reactions associated with the prophylactic use of mefloquine have now been observed in France and Thailand (although the denominator is unknown). Thus the true incidence of serious neuropsychiatric reactions following prophylactic administration of mefloquine is not
gress, although experiencing occasional left sided focal fits despite anticonvulsants. The route of administration was changed on the second day from oral to intravenous because of the high acidity (pH 3-5) of the iv preparation which was being administered orally. The CSF concentration measured by HPLC 2 h after the third oral dose of ciprofloxacin in our patient was 0-5 mg/1. He was discharged on the 29th day having had three culture-negative stool samples. The blood cultures and CSF specimen (with a cell count of 2140/cu mm with 60% polymorphs) repeated 24 h after commencing ciprofloxacin were sterile. Specimens cultured during chloramphenicol therapy were consistently positive for 5. typhimurium. The emergence of chloramphenicol resistance which is documented in salmonella species (Cherubin et a!., 1977), and the development of meningitis with the resistant organism narrowed the choice of antibiotics in this neonate. Ciprofloxacin with its well documented efficacy against salmonella species, and with very low MIC, became the drug of choice despite the age of the child. Various studies carried out to determine the penetration of ciprofloxacin into CSF (Wolff et al., 1987; Kitzes-Cohen et al., 1988) have suggested that a therapeutic concentration could be achieved with adequate dosage, in patients with inflamed meninges. Irreversible arthopathy as a long term effect of ciprofloxacin has been documented in young animals (Schluter, 1987). The manufacturer reports that in a multicentre study done in the UK between 1984 and 1986, there have been eight cases of joint-related disorder in children and six of them were reversible events (Bayer, personal communication). Acknowledgements We thank Mr D. Felmingham, University College Hospital, London for the ciprofloxacin assay, Dr A. J. Bint, Department of Microbiology, Royal Victoria Infirmary, Newcastle upon Tyne for chloramphenicol assays and the Division of Enteric Pathogens, Public Health Laboratory, Colindale, London for typing the isolates. P. L. RAGUNATHAN* D. V. POTKINS* J. G. WATSON* A. M. KEARNS* A. CARROLL' 'Department of Microbiology, Public Health Laboratory Service, Newcastle General Hospital; 'Department of Paediatrics, Newcastle General Hospital, Newcastle upon Tyne, UK
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Diego on June 7, 2015
Sir, A six-day-old baby boy born at term weighing 3-2 kg was admitted with a two-day history of profuse watery diarrhoea, and refusing feeds. There was no history of vomiting, fever or fits. On examination he was found to be dehydrated and moribund with sunken eyes and fontanelle. He was commenced on ampicillin and flucloxacillin iv and intravenous fluids. On the second day after admission Salmonella typhimurium Phage type (PT) 193 was isolated from stool, blood cultures and a heavily bloodstained CSF specimen. The isolate was sensitive to chloramphenicol (MIC of 4 mg/1 by agar dilution method), ceftazidime, gentamicin, ciprofloxacin and resistant to ampicillin and cephaloridine. He was commenced on chloramphenicol 25 mg/kg/day iv and the other antibiotics were omitted. Culture of the mother's stool revealed the presence of S. typhimurium PT 193 with the same antibiotic sensitivity pattern. The CSF isolate was considered to be a blood contaminant. The child became febrile and developed bilateral convulsions within 24 h of admission and responded to anticonvulsants and ventilatory support. He also developed disseminated intravascular coagulation (DIC) with gastro-intestinal haemorrhage and haematuria, which required considerable support with fresh frozen plasma, platelets and blood transfusion for ten days. A week after starting chloramphenicol therapy he had a recurrence of high fever and blood cultures showed 5. typhimurium with a similar pattern of sensitivity to the initial isolate, the MIC of chloramphenicol being 4 mg/1. During the next few days the pyrexia persisted, the child's clinical condition deteriorated, and a repeat lumbar puncture revealed a white cell count of 215/cu mm and the presence of a chloramphenicol-resistant S. typhimurium PT 193 (MIC 16 mg/1). The peak serum chloramphenicol levels measured 2 h post dose on three occasions by HPLC whilst he was on iv therapy were 16-1,11-7 and 8-2 mg/1 on days 6, 7 and 8, respectively. The declining serum concentration despite use of the recommended dosage might explain the emergence of resistance and treatment failure in this child. The MIC of ciprofloxacin for the chloramphenicol resistant isolate was 0-06 mg/1, so ciprofloxacin 25 mg bd was substituted for chloramphenicol and continued for .thirteen days, during which he made good clinical pro-
727
728
Correspondence References
Treatment and prophylaxis of faldparum malaria Sir, The recent leading article on the treatment and prophylaxis of falcipanim malaria (Pithie & Ellis, 1990) contains a series of worrying statements. Many of these relate to a failure to distinguish between severe and uncomplicated falciparum malaria. The authors suggest that, because of drug resistance, physicians in temperate countries will now see an increase in the number of patients with severe falciparum malaria and negative blood smears resulting from partially effective chemoprophylaxis.... 'It follows that empirical treatment of patients with negative films will have to become more commonplace.' While this may apply to uncomplicated partially suppressed infections in which the infecting biomass of parasites is small (and therefore may be below the level of detection), I know of no evidence that it applies to severe malaria where the infecting biomass is large (White & Krishna, 1989). There is also no evidence that partially effective prophylactic antimalarial drugs alter the intravascular distribution of sequestered and circulating parasitized erythrocytes in falciparum malaria. In very rare synchronous infections, and in occasional severely ill patients who have received an effective treatment dose of antimalarial days previously and in whom the parasite burden has already declined, parasitaemia may be below the level of microscopic detection, but in the vast majority of patients with severe infections blood smears arc positive. I am worried that these statements could lead to severely ill patients who have returned from the tropics
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Diego on June 7, 2015
Chenibin, C , Neu, H. C , Rahal, J. J. & Sabath, L. D. (1977). Emergence of resistance to chloramphenicol in Salmonella. Journal of Infectious Diseases 135, 807-12. Kitzes-Cohen, R., Miter, A., Gilboa, A. & Harel, D. (1988). Penetration of ciprofloxacin into cerebrotpinal fluid. Reviews of Infectious Diseases 10, Suppl. 1. S256-7. Schluter, G. (1987). Ciprofloxacin: review of potential toxicologic effects. American Journal of Medicine 82, Suppl. 4A. 91-3. Wolff, M., Boutron, L., Singlas, E., Clair, B., Decazes, J. M. & Regnier, B. (1987). Penetration of ciprofloxacin into cerebrospinal fluid of patients with bacterial meningitis. Antimicrobial Agents and Chemotherapy 31, 899-902.
being diagnosed as 'blood smear-negative, severe falciparum malaria', when in fact they are suffering from a different treatable infection. The distinction between severe and uncomplicated malaria in the recommendation for treatment is also unclear. If patients remain severely ill and parasitaemic after 72 h of quinine treatment, the drug should be continued but the dose should be reduced by onethird to one-half to maintain plasma concentrations between 8 and 15mg/l (World Health Organization, 1986). The regimens suggested (three days quinine followed by an antibiotic) would be inappropriate in this situation., Tetracycline, a slow acting antimalarial, is contraindicated in renal failure, pregnancy and in children, and should not be started until the patient is well enough to take drugs by mouth, and clindamycin has not been evaluated in severe malaria. 'Mefloquine can be given as an aqueous suspension via a nasogastric tube to vomiting or unconscious patients.' Although mefloquine was absorbed rapidly in most patients with cerebral malaria following nasogastric instillation of a suspension of the hydrochloride salt (Chanthavanich et al., 1985), a review of subsequent studies suggests that oral bioavailability in cerebral malaria was probably much less than that in uncomplicated malaria (Karbwang & White, 1990). Furthermore the suspension is not commercially available. The oral bioavailability of the tablet formulation in severe malaria is unknown. Mefloquine should only be given by nasogastric tube in dire circumstances, i.e. if effective parenteral drugs are not available. It is not true that serious neuropsychiatric reactions occur in 1% of patients receiving a treatment dose of mefloquine, as is stated: the incidence is not known with certainty but is nearer 0.1%. However, lightheadedness, dizziness and vertigo are very common following administration of doses greater than 250 mg to healthy subjects (Patchen, Campbell & Williams, 1989; Nosten, F., Ter Kuile, F. & White, N. J., unpublished observations). Rare but serious acute neuropsychiatric reactions must be distinguished from this predictable minor nervous system toxicity (Karbwang & White, 1990). Over twenty severe neuropsychiatric reactions associated with the prophylactic use of mefloquine have now been observed in France and Thailand (although the denominator is unknown). Thus the true incidence of serious neuropsychiatric reactions following prophylactic administration of mefloquine is not
