Combination of co-trimoxazole and ciprofloxacin as therapy of a patient with infective endocarditis caused by an enterococcus highly resistant to gentamicin.

Sir, Enterococci are currently amongst the most troublesome hospital pathogens and effective therapy of patients with infective endocarditis (IE) caused by these bacteria, especially those that are highly resistant to aminoglycosides, is particularly difficult and has not yet been standardized. Recently, Tripodi et al. reported that treat ment with co-trimoxazole, in combination with ciprofloxacin, cured a patient with IE caused by such a strain. This combination has also been shown to be bactericidal in vitro against five of seven strains of Enterococcus faecium and seven of nine of Enterococcus faecalis; the MICs of ciprofloxacin for all of the isolates were 4 mg/L. We describe here a patient with IE caused by a strain of E. faecalis exhibiting high-level resistance to gentamicin who was successfully treated with a regimen comprising cotrimoxazole and ciprofloxacin. A 25 year old female patient was admitted to our hospital with a history of pain in multiple joints (for 2 months) and fever (for 1 month). The fever was initially low-grade, but reached a peak of 39°C after a few days and exhibited a continuous or continuous–remittent pattern. On the basis of serological investigations (an antistreptolysin O (ASO) titre of 333 Todd units and a streptozyme (ASTZ) titre of 1:200), therapy comprising oral salicylate (150 mg/kg body weight/day) and procaine penicillin G 1.2 mU bd im was commenced. The fever fell slightly, but, after 1 week, a second physician, suspecting IE on the basis of the longstanding fever and pre-existing mitral and aortic valve disease, altered the antibiotic therapy to benzylpenicillin 20 mU/day, administered by the intravenous route, and gentamicin 80 mg tds im. This regimen was given for 1 week, during which time there was no improvement. Four blood cultures, obtained 3 days after discontinuing the antibiotics, were sterile and therapy with iv teicoplanin 400 mg bd for the first 2 days, followed by 200 mg bd on subsequent days, together with gentamicin, was initiated. After a further 3 days of treatment with this regimen, the patient complained of increasing malaise and she was transferred to our care for further evaluation. On examination, the right ankle, left knee and distal interphalangeal joints were tender. Slight swelling, redness and functional impairment of the knee joint were also noted. Examination of the heart showed sinus tachycardia, a third heart sound, a grade 2/6 pandiastolic murmur over the aortic area and a grade 3/6 systolic murmur at both Erb’s area and the apex which radiated to the axilla. Urinalysis revealed slight proteinuria and microscopic haematuria, while haematological and biochemical investigations showed mild anaemia, a normal leucocyte count, hypoalbuminaemia and mild hypergammaglobulinaemia. No vegetations were identified on a two-dimensional echocardiogram, but moderate mitral and slight aortic regurgitation were present on Doppler echocardiography. Because of persistent pyrexia, the antibiotic therapy was discontinued and, 3 days later, nine blood cultures were obtained. Six of these yielded a strain of E. faecalis. The susceptibilities of the isolate were determined by the microbroth dilution method according to a protocol issued by the National Committee for Clinical Laboratory Standards (NCCLS); the medium used was Mueller– Hinton broth and the inoculum was approximately 5 10 cfu/L. The MICs and MBCs of the agents tested were as follows: imipenem, MIC 1 mg/L, MBC 8 mg/L; vancomycin, MIC 1 mg/L, MBC 250 mg/L; ciprofloxacin, MIC 1 mg/L, MBC 8 mg/L; teicoplanin, MIC 0.004 mg/L, MBC 250 mg/L; co-trimoxazole, MIC 0.25 mg/L, MBC 250 mg/L; gentamicin, MIC and MBC 4000 mg/L; benzylpenicillin, MIC 0.25 mg/L, MBC 250 mg/L. Whilst awaiting the outcome of susceptibility testing, the teicoplanin and gentamicin were recommenced, but, when the results became available, the gentamicin was withdrawn and ciprofloxacin 200 mg bd iv was administered with the teicoplanin. Following 3 days of treatment with this regimen, the fever resolved. However, serumcidal studies (with Mueller–Hinton broth and an inoculum of 5 10 cfu/L) revealed an absence of both trough and peak bactericidal activities. We therefore evaluated various antibiotic combinations (ciprofloxacin and teicoplanin, ciprofloxacin and vancomycin and ciprofloxacin and co-trimoxazole) by the chequerboard method (again with Mueller–Hinton broth and an inoculum of 5 10 cfu/L). Of the combinations tested, only ciprofloxacin and co-trimoxazole exhibited synergic activity (bactericidal activity at concentrations equivalent to 0.25 MIC of each drug and fractional inhibitory concentration 0.5); the others exhibited indifferent activity. Co-trimoxazole 960 mg bd iv was therefore added to the ciprofloxacin and the teicoplanin discontinued. On the third day after starting this regimen, the patient’s trough and peak serumcidal titres were 1:16 and 1:32 respectively.