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Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin
Journal of Infection (1992) 24, 317-32o
CASE REPORT Treatment
of Haemophilus aphrophilus endocarditis with
ciprofloxacin S u s a n J. D a w s o n * $ a n d Lucy A. W h i t e r
* Department of Microbiology and Public Health Laboratory, Southampton General Hospital, Southampton and t Medical Department, Lymington Hospital, Lymington, U.K. Accepted for publication 23 October 1991 Summary A patient with Haemophilus aphrophilus endocarditis was successfully treated with ciprofloxacin. The response to treatment with cefotaxime and netilmicin for 12 days was poor but was satisfactory to a 6 weeks' course of ciprofloxacin.
Introduction In one study of infective aetiological agents in about aphrophilus endocarditis was been reported since. I, 3-7 We
endocarditis, Haemophilus species were the 5 %.i T h e first recorded case of Haemophilus described by Khariat in 194o, 3 but several have present here another case.
Case report A 43-year-old man presented with a 3 weeks' history of rigors, anorexia and lethargy. Previously he had suffered from cardiomyopathy of ischaemic origin. This had led to cardiac dilatation and heart failure. Investigation by a cardiologist had revealed mitral regurgitation and an apical thrombus which were demonstrated by angiography and echocardiography. Four months before his admission to hospital, a dental procedure (recapping of a tooth plus scaling and polishing) had been performed after the patient had received prophylactic oral amoxycillin 3 g. Examination on admission to hospital revealed fever of 39 ~ pulse rate Ioo/min, three splinter haemorrhages, poor dentition, and a pansystolic m u r m u r at the cardiac apex similar to that recorded in the past. T h e haemoglobin concentration was IO g/dl, white blood cell count I3"9x lO9/1, erythrocyte sedimentation rate I o o m m / h and a C reactive protein concentration of 3o7 rag/1. Microscopy revealed red blood cells in the urine. An echocardiogram showed left ventricular dilatation and a dyskinetic apical segment with a probably organised thrombus. T h e valves appeared normal without evidence of vegetations. A clinical diagnosis of infective endocarditis having been made, treatment began empirically with intravenous benzylpenicillin 1.2 g 4-hourly, fluclox$ Address correspondence to: Dr S.J. Dawson, Department of Microbiology and Public Health Laboratory, Southampton General Hospital, Tremona Road, Southampton SO9 4XY, U.K.
o163-4453/92/o3o3 ~7+ 04 $03.00/0
9 1992 The British Society for the Study of Infection
318
S. J. D A W S O N
AND
L . A. W H I T E
acillin 2 g 6-hourly and netilmicin Ioo mg I2-hourly. A total of six blood cultures (I2 bottles) grew a Gram-negative cocco-bacillus, subsequently identified as Haemophilus aphrophilus at the National Collection of T y p e Cultures (NCTC), Central Public Health Laboratory, Colindale, London ( N C T C results: catalase - , onpg + ; sugar fermentation tests: glucose + , lactose + , maltose + , mannose + , sucrose + and mannitol - ) . Initial antibiotic testing by means of Stokes' method showed sensitivity to ampicillin, cefotaxime and ciprofloxacin. Testing for beta lactamase production by means of an ' I N T R A L A C T A M ' paper strip (Mast Diagnostics) was negative. Therapy was changed to cefotaxime 2 g 8-hourly and netilmicin 80 mg x2hourly. Serum netilmicin concentrations were monitored throughout so as to ensure maintenance of a i h ' p e a k ' concentration of 4-6 mg/1. Blood cultures (six bottles) after treatment began were negative. After t5 days, the patient still had intermittent fever and felt unwell. T h e pansystolic m u r m u r had become louder and more harsh, but this was thought to be related to worsening anaemia. Drug fever was considered but examination of the skin did not reveal a rash. A further echocardiogram did not show any change in the appearance of the mitral valve or in the degree of regurgitation. An apical thrombus was again seen, but without evidence of vegetations. T h e haemoglobin concentration had fallen to 8"5 g/dl, the white blood cell count was I I'7 x Io9/1 and the erythrocyte sedimentation rate had risen to I2O m m / h but the C reactive protein concentration had fallen to 75"3 mg/1. An orthopantomogram excluded a dental abscess and upper abdominal ultrasound examination failed to show signs of an infective focus. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations [MBC] for the various antibiotics were--ampicillin: M I C 0"5 mg/1, M B C I mg/1; cefotaxime: M I C o'I25 mg/1, MBC o'I25 rag/l; netilmicin: M I C 0"5 mg/1, MBC 0"5 mg/1; and for ciprofloxacin: M I C 0"03 mg/1 and M B C o'I25 mg/1. These were determined by means of a broth-dilution technique with the organism in the log phase of growth from an enrichment broth with added N A D and haemin. Doubling dilutions of the test antibiotic in enriched broth were dispensed into wells of a microtitre plate and then the bacterial inoculum (I x io 5 C F U / m l ) added. T h e plate was incubated for 24 h at 37 ~ aerobically with 5 % CO2, and the MBC reported as that of the highest dilution showing, after subculture, at least 99% killing of the organism. Serum bactericidal titres (SBT) were determined on samples of serum taken immediately before and I h after simultaneous dosing with cefotaxime and netilimicin. T h e titres were both 4. T h e y were obtained by double-diluting each sample of serum in wells of a microtitre plate, then adding an equal volume of an enrichment broth with N A D and haemin and containing the patient's organism in the log phase of growth at an inoculum of I • I O 5 C F U / m l . T h e plates were incubated at 37 ~ aerobically with 5 % COs for 24 h. T h e bactericidal titre was recorded as the reciprocal of the highest dilution showing, after subculture, at least 99 % killing of the organism. It was not known whether the patient's continuing fever and lack of clinical response were related to persistence of infection or possibly drug allergy. Combining these facts with the poor SBT results, it was decided to change
H. aphrophilus endocarditis
319
therapy to ciprofloxacin 200 m g iv I2-hourly. After 5 days treatment with ciprofloxacin the patient had improved clinically and the fever had completely resolved. Pre- and I h post-dose ciprofloxacin concentrations were o'7 and 1.2 mg/1 respectively, while the corresponding SBTs were both satisfactory at 32 . After a further lO days of iv treatment, therapy was changed to oral ciprofloxacin 75o mg i2-hourly. Serum pre- and I h post-dose concentrations were I'9 mg/1 and 6.I mg/1, respectively; corresponding SBTs were 256 and 1024 . T h e patient was discharged from hospital to complete a 6 weeks' course of ciprofloxacin treatment at home. When he was reviewed as an outpatient I month after stopping treatment, he remained well and blood cultures taken then were negative. Discussion
Haemophilus aphrophilus may be part of the normal oral flora of adults. One study found it to be present in one third of them. s T h e organism has fastidious growth requirements. It was originally described as being X-factor-dependent. 2 Later tests, however, have not confirmed this finding (although the tests included use of subcultured organisms). 9 It grows best in a COs-enriched atmosphere 5 but also grows in moist air. 6 Growth in liquid m e d i u m is initially granular adhering to the tube walls, but can become turbid with a ropy sediment on subculture. Antibiotic sensitivity testing in vitro has shown poor correlation between the results of disc tests and the MIC. ~ T u b e dilution tests, however, are considered to be more reliable than disc diffusion studies but serum bactericidal assays may be difficult or impossible to accomplish due to inadequate bacterial growth. 1~ We encountered similar problems, the granular growth in particular making the reading of tests troublesome. This again emphasises the problems with performing in vitro tests on a fastidious organism, and hence their unreliability for predicting or monitoring a clinical response. Testing growth of H. aphrophilus on trypticase soy agar with 5 % rabbit blood and incorporating two-fold dilutions of antibiotics has shown t h e . organism to be susceptible to streptomycin, tetracycline and chloramphenicol, with variable susceptibility to penicillin and ampicillin. ~ T r e a t m e n t recommended for endocarditis caused by Haemophilus spp. is ampicillin with or without an aminoglycoside. 1~ Geraci et al. x recommended I2 g daily of ampicillin for 3 weeks. For ampicillin-resistant strains of Haemophilus spp., the choice of therapy is not clear. 1 A second- or thirdgeneration cephalosporin, 11 with or without an aminoglycoside, might be used 1~ or fosfomycin and gentamicin as used in a penicillin-allergic patient. ~2 Our patient was treated with cefotaxime and netilmicin for I2 days but the symptoms and fever persisted. On changing to ciprofloxacin there was a marked clinical response with defervescence. We therefore think it would be worth while considering ciprofloxacin for patients with H. aphrophilus infections who are allergic to beta lactam antibiotics.
320
S. J. DAWSON AND L. A. W H I T E
(We thank D r R. Dathan for permission to report this case and M r H. Malnick of the National Collection of T y p e Cultures, Colindale, L o n d o n , for identifying the organism.)
References x. Geraci JE, Wilkowske CJ, Wilson WR, Washington II JA. Haemophilus endocarditis, report of I4 patients, Mayo Clin Proc I977; 52: 2o9-2I 5. 2. Khairat O. Endocarditis due to a new species of Haemophilus. J Patho! Bacteriol I94O; 50 :
497-505.
3. Elster SK, Mattes LM, Meyers BR, Jurado RA. Haemophilus aphrophilus endocarditis: review of 23 cases. Am J Cardiol I975; 35: 72-79. 4. Bieger RC, Brewer NS, Washington II JA. I-laemophilus aphrophilus: A microbiologic and clinical review and report of 42 cases. Medicine I978; 57: 345-355. 5. Page MI, King EO. Infection due to Actinobacillus actinomycetemcomitans and Haemophilus aphrophilus. N Engl J Med x966; 275: I8I-I88. 6. Sutter VL, Finegold SM. I-Iaemophilus aphrophilus infections: clinical and bacteriologic studies. Ann N Y Acad Sci I97o; x74: 468-487. 7. Webb CH, Hogg GM. Haemophilus aphrophilus endocarditis. Br J Clin Pract I99o; 44: 329-33I. 8. Kraut MS, Attebery HR, Finegold SM, Sutter VL. Detection of Haemophilus aphrophilus in the human oral flora with a selective medium. J Infect Dis I972; x26: I89-x92. 9. King EO, Tatum HW. Actinobacillus actinomycetemcomitans and Haemophilus aphrophilus. J Infect Dis x962; xxx: 85-94. xo. Lee Hand W. Haemophilus species chapter 2o2. In: Mandell GL, Douglas RG, Bennett JE, Eds. Principles and practice of infectious diseases 3rd ed. New York: Churchill Livingston, I99o: I729-x733. 11. Calio AJ, Cusumano S, Ullman RF, Tjioe DY, Cunha BA. Haemophilus parainfluenzae endocarditis. Heart Lung I987; x6:222-223. x2. Moreno S, Ezpeleta C, Parras F, Barros C, Martinez Beltran J, Buzon L. Cure of a case of Haemophilus aphrophilus endocarditis with a combination of fosfomycin and gentamicin. J Antimicrob Chemother I986; xS: 77x-772.
CASE REPORT Treatment
of Haemophilus aphrophilus endocarditis with
ciprofloxacin S u s a n J. D a w s o n * $ a n d Lucy A. W h i t e r
* Department of Microbiology and Public Health Laboratory, Southampton General Hospital, Southampton and t Medical Department, Lymington Hospital, Lymington, U.K. Accepted for publication 23 October 1991 Summary A patient with Haemophilus aphrophilus endocarditis was successfully treated with ciprofloxacin. The response to treatment with cefotaxime and netilmicin for 12 days was poor but was satisfactory to a 6 weeks' course of ciprofloxacin.
Introduction In one study of infective aetiological agents in about aphrophilus endocarditis was been reported since. I, 3-7 We
endocarditis, Haemophilus species were the 5 %.i T h e first recorded case of Haemophilus described by Khariat in 194o, 3 but several have present here another case.
Case report A 43-year-old man presented with a 3 weeks' history of rigors, anorexia and lethargy. Previously he had suffered from cardiomyopathy of ischaemic origin. This had led to cardiac dilatation and heart failure. Investigation by a cardiologist had revealed mitral regurgitation and an apical thrombus which were demonstrated by angiography and echocardiography. Four months before his admission to hospital, a dental procedure (recapping of a tooth plus scaling and polishing) had been performed after the patient had received prophylactic oral amoxycillin 3 g. Examination on admission to hospital revealed fever of 39 ~ pulse rate Ioo/min, three splinter haemorrhages, poor dentition, and a pansystolic m u r m u r at the cardiac apex similar to that recorded in the past. T h e haemoglobin concentration was IO g/dl, white blood cell count I3"9x lO9/1, erythrocyte sedimentation rate I o o m m / h and a C reactive protein concentration of 3o7 rag/1. Microscopy revealed red blood cells in the urine. An echocardiogram showed left ventricular dilatation and a dyskinetic apical segment with a probably organised thrombus. T h e valves appeared normal without evidence of vegetations. A clinical diagnosis of infective endocarditis having been made, treatment began empirically with intravenous benzylpenicillin 1.2 g 4-hourly, fluclox$ Address correspondence to: Dr S.J. Dawson, Department of Microbiology and Public Health Laboratory, Southampton General Hospital, Tremona Road, Southampton SO9 4XY, U.K.
o163-4453/92/o3o3 ~7+ 04 $03.00/0
9 1992 The British Society for the Study of Infection
318
S. J. D A W S O N
AND
L . A. W H I T E
acillin 2 g 6-hourly and netilmicin Ioo mg I2-hourly. A total of six blood cultures (I2 bottles) grew a Gram-negative cocco-bacillus, subsequently identified as Haemophilus aphrophilus at the National Collection of T y p e Cultures (NCTC), Central Public Health Laboratory, Colindale, London ( N C T C results: catalase - , onpg + ; sugar fermentation tests: glucose + , lactose + , maltose + , mannose + , sucrose + and mannitol - ) . Initial antibiotic testing by means of Stokes' method showed sensitivity to ampicillin, cefotaxime and ciprofloxacin. Testing for beta lactamase production by means of an ' I N T R A L A C T A M ' paper strip (Mast Diagnostics) was negative. Therapy was changed to cefotaxime 2 g 8-hourly and netilmicin 80 mg x2hourly. Serum netilmicin concentrations were monitored throughout so as to ensure maintenance of a i h ' p e a k ' concentration of 4-6 mg/1. Blood cultures (six bottles) after treatment began were negative. After t5 days, the patient still had intermittent fever and felt unwell. T h e pansystolic m u r m u r had become louder and more harsh, but this was thought to be related to worsening anaemia. Drug fever was considered but examination of the skin did not reveal a rash. A further echocardiogram did not show any change in the appearance of the mitral valve or in the degree of regurgitation. An apical thrombus was again seen, but without evidence of vegetations. T h e haemoglobin concentration had fallen to 8"5 g/dl, the white blood cell count was I I'7 x Io9/1 and the erythrocyte sedimentation rate had risen to I2O m m / h but the C reactive protein concentration had fallen to 75"3 mg/1. An orthopantomogram excluded a dental abscess and upper abdominal ultrasound examination failed to show signs of an infective focus. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations [MBC] for the various antibiotics were--ampicillin: M I C 0"5 mg/1, M B C I mg/1; cefotaxime: M I C o'I25 mg/1, MBC o'I25 rag/l; netilmicin: M I C 0"5 mg/1, MBC 0"5 mg/1; and for ciprofloxacin: M I C 0"03 mg/1 and M B C o'I25 mg/1. These were determined by means of a broth-dilution technique with the organism in the log phase of growth from an enrichment broth with added N A D and haemin. Doubling dilutions of the test antibiotic in enriched broth were dispensed into wells of a microtitre plate and then the bacterial inoculum (I x io 5 C F U / m l ) added. T h e plate was incubated for 24 h at 37 ~ aerobically with 5 % CO2, and the MBC reported as that of the highest dilution showing, after subculture, at least 99% killing of the organism. Serum bactericidal titres (SBT) were determined on samples of serum taken immediately before and I h after simultaneous dosing with cefotaxime and netilimicin. T h e titres were both 4. T h e y were obtained by double-diluting each sample of serum in wells of a microtitre plate, then adding an equal volume of an enrichment broth with N A D and haemin and containing the patient's organism in the log phase of growth at an inoculum of I • I O 5 C F U / m l . T h e plates were incubated at 37 ~ aerobically with 5 % COs for 24 h. T h e bactericidal titre was recorded as the reciprocal of the highest dilution showing, after subculture, at least 99 % killing of the organism. It was not known whether the patient's continuing fever and lack of clinical response were related to persistence of infection or possibly drug allergy. Combining these facts with the poor SBT results, it was decided to change
H. aphrophilus endocarditis
319
therapy to ciprofloxacin 200 m g iv I2-hourly. After 5 days treatment with ciprofloxacin the patient had improved clinically and the fever had completely resolved. Pre- and I h post-dose ciprofloxacin concentrations were o'7 and 1.2 mg/1 respectively, while the corresponding SBTs were both satisfactory at 32 . After a further lO days of iv treatment, therapy was changed to oral ciprofloxacin 75o mg i2-hourly. Serum pre- and I h post-dose concentrations were I'9 mg/1 and 6.I mg/1, respectively; corresponding SBTs were 256 and 1024 . T h e patient was discharged from hospital to complete a 6 weeks' course of ciprofloxacin treatment at home. When he was reviewed as an outpatient I month after stopping treatment, he remained well and blood cultures taken then were negative. Discussion
Haemophilus aphrophilus may be part of the normal oral flora of adults. One study found it to be present in one third of them. s T h e organism has fastidious growth requirements. It was originally described as being X-factor-dependent. 2 Later tests, however, have not confirmed this finding (although the tests included use of subcultured organisms). 9 It grows best in a COs-enriched atmosphere 5 but also grows in moist air. 6 Growth in liquid m e d i u m is initially granular adhering to the tube walls, but can become turbid with a ropy sediment on subculture. Antibiotic sensitivity testing in vitro has shown poor correlation between the results of disc tests and the MIC. ~ T u b e dilution tests, however, are considered to be more reliable than disc diffusion studies but serum bactericidal assays may be difficult or impossible to accomplish due to inadequate bacterial growth. 1~ We encountered similar problems, the granular growth in particular making the reading of tests troublesome. This again emphasises the problems with performing in vitro tests on a fastidious organism, and hence their unreliability for predicting or monitoring a clinical response. Testing growth of H. aphrophilus on trypticase soy agar with 5 % rabbit blood and incorporating two-fold dilutions of antibiotics has shown t h e . organism to be susceptible to streptomycin, tetracycline and chloramphenicol, with variable susceptibility to penicillin and ampicillin. ~ T r e a t m e n t recommended for endocarditis caused by Haemophilus spp. is ampicillin with or without an aminoglycoside. 1~ Geraci et al. x recommended I2 g daily of ampicillin for 3 weeks. For ampicillin-resistant strains of Haemophilus spp., the choice of therapy is not clear. 1 A second- or thirdgeneration cephalosporin, 11 with or without an aminoglycoside, might be used 1~ or fosfomycin and gentamicin as used in a penicillin-allergic patient. ~2 Our patient was treated with cefotaxime and netilmicin for I2 days but the symptoms and fever persisted. On changing to ciprofloxacin there was a marked clinical response with defervescence. We therefore think it would be worth while considering ciprofloxacin for patients with H. aphrophilus infections who are allergic to beta lactam antibiotics.
320
S. J. DAWSON AND L. A. W H I T E
(We thank D r R. Dathan for permission to report this case and M r H. Malnick of the National Collection of T y p e Cultures, Colindale, L o n d o n , for identifying the organism.)
References x. Geraci JE, Wilkowske CJ, Wilson WR, Washington II JA. Haemophilus endocarditis, report of I4 patients, Mayo Clin Proc I977; 52: 2o9-2I 5. 2. Khairat O. Endocarditis due to a new species of Haemophilus. J Patho! Bacteriol I94O; 50 :
497-505.
3. Elster SK, Mattes LM, Meyers BR, Jurado RA. Haemophilus aphrophilus endocarditis: review of 23 cases. Am J Cardiol I975; 35: 72-79. 4. Bieger RC, Brewer NS, Washington II JA. I-laemophilus aphrophilus: A microbiologic and clinical review and report of 42 cases. Medicine I978; 57: 345-355. 5. Page MI, King EO. Infection due to Actinobacillus actinomycetemcomitans and Haemophilus aphrophilus. N Engl J Med x966; 275: I8I-I88. 6. Sutter VL, Finegold SM. I-Iaemophilus aphrophilus infections: clinical and bacteriologic studies. Ann N Y Acad Sci I97o; x74: 468-487. 7. Webb CH, Hogg GM. Haemophilus aphrophilus endocarditis. Br J Clin Pract I99o; 44: 329-33I. 8. Kraut MS, Attebery HR, Finegold SM, Sutter VL. Detection of Haemophilus aphrophilus in the human oral flora with a selective medium. J Infect Dis I972; x26: I89-x92. 9. King EO, Tatum HW. Actinobacillus actinomycetemcomitans and Haemophilus aphrophilus. J Infect Dis x962; xxx: 85-94. xo. Lee Hand W. Haemophilus species chapter 2o2. In: Mandell GL, Douglas RG, Bennett JE, Eds. Principles and practice of infectious diseases 3rd ed. New York: Churchill Livingston, I99o: I729-x733. 11. Calio AJ, Cusumano S, Ullman RF, Tjioe DY, Cunha BA. Haemophilus parainfluenzae endocarditis. Heart Lung I987; x6:222-223. x2. Moreno S, Ezpeleta C, Parras F, Barros C, Martinez Beltran J, Buzon L. Cure of a case of Haemophilus aphrophilus endocarditis with a combination of fosfomycin and gentamicin. J Antimicrob Chemother I986; xS: 77x-772.