Clarithromycin and pseudomembranous enterocolitis

mention ototoxicity due to azithromycin, but no detailed information is provided. Pfizer’s package insert in the US (1992) for azithromycin does not mention this potentially serious problem. We describe our experience of ototoxicity with azithromycin used as M avium therapy. Beginning in 1992, we used a 3-drug combination:

Figure: Histological slide of right gonad Tubules with small Sertoli cells lined by a fine basement membrane, containing voluminous germ cells centrally localised, which are similar to oogoma (indicated by arrow). Numerous Leydig cells and small round cells are present in the interstitium ( x 400).

ng/mL), dehydroepiandrosterone (0-65 ng/mL), and 11desoxycortisol (0-38 ng/mL) were normal, excluding adrenal hyperplasia. The normal plasma in the mother (0-25 ng/mL) excluded secondary virilisation of the fetus. The ultrasound examination at 24 weeks did not exclude the possibility of a small uterus behind the bladder. The parents decided to interrupt the pregnancy at 27 weeks of amenorrhoea. The external genitalia of the 1250 g fetus were normal. Neither kidney malformation nor Mullerian ducts were observed. The right gonad had a testicular structure. However, the tubules were less numerous than in a normal XY testis of corresponding age and were occasionally observed in a ring or network organisation. Two types of germ cells were observed. At the periphery of the tubules apparently normal spermatogonia were present. In the centre germ cells, similar in appearance to oogonia (large nucleus and cytoplasm), were observed; one of them appeared to be undergoing meiosis (figure). The left gonad had a testicular appearance. However, the tubular organisation was again abnormal. No ovarian structures were observed. Mosaicism was excluded since Y-chromosome sequences (determined by polymerase chain reaction amplification) including the testis-determining gene SRY, were not detected in tissue samples, not even those from the testes. We conclude that complete male development can occur in the absence of the SRY gene. A mutation in an autosomal gene or X-linked gene could explain such a phenotype.2

congenital

testosterone

azithromycin (500 mg orally per day), clofazimine (100 mg orally per day), and ethambutol (15 mg/kg per day as a single oral dose). In the first 9 months of use of this regimen, 3 patients spontaneously reported hearing loss; in 2 cases the deficit markedly interfered with normal conversation before azithromycin was discontinued. All 3 patients had bilateral sensorineural hearing loss documented by audiological assessments (air conduction and bone conduction testing at 250-12 000 Hz). An audiologist rated their impairments as moderately severe in 2 cases and as mild in the third case. Hearing loss developed 30-90 days after beginning azithromycin and resolved 2-4 weeks after azithromycin was stopped. Follow-up audiological testing was essentially normal on all 3 patients. 1 patient was rechallenged with azithromycin after his hearing had returned to baseline, and within 14 days he noted a marked decline in his auditory acuity. He again stopped his azithromycin and noted a return to normal hearing over 10-15 days. These patients represented 14% of the 21 patients treated for disseminated M avium with the regimen containing azithromycin in 1992 and early 1993. Since early 1993, we have treated M avium with a 3-drug regimen of clarithromycin (1-5-2-0 g orally in 2 divided doses), clofazamine, and ethambutol. This change of therapy was made because of the azithromycin ototoxicity and lower cost of clarithromycin. None of the 26 patients followed on clarithromycin for 2-12 months has reported any ototoxicity. Although not mentioned in the US package insert, ototoxicity appears to be a frequent and often dose-limiting toxic effect of azithromycin when used at a dose of 500 mg daily long term. Clinicians should consider this when selecting regimens for the therapy of M avium. Patients receiving azithromycin on a long term basis should be monitored for new hearing problems. Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program sponsored this report #84-16-1968-450, as required by HSETCINST 6000.41. Mark R

Departments of Internal Medicine (Infectious Diseases), Pharmacy, Otolaryngology (Audiology), and Clinical Investigation, Naval Medical Center, San Diego, CA 92134-5000, USA 1

E Vilain, B Le Fiblec, N Morichon-Delvallez, R Brauner, M Dommergues, Y Dumez, F Jaubert, C Boucekkine, K McElreavey, M Vekemans, M Fellous Centre Hôpitalier de Saint Brieuc, St Brieuc; Laboratoire d’Immunogénétique Humaine, Institut Pasteur, 75724 Paris, France, and Hôpital Necker-Enfants Malades, Paris

1

De la

2

3

Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. N EnglJ Med 1993; 329: 898-904. Inderlied CB, Kemper CA, Bermudez LM. The Mycobacterium avium complex. Clin Microbiol Rev 1993; 6: 266-310. Benson CA, Ellner JJ. Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis 1993; 17: 7-20.

Chapelle A. The etiology of maleness in XX men. Hum Genet

1981; 58: 105-16. 2 McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M. A regulatory cascade of hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl Acad Sci U S A 1993; 90: 3368-72.

Ototoxicity with azithromycin SIR-2

Wallace, Larry K Miller, Minh-Thu Nguyen, Anne R Shields

azithromycin and excellent clarithromycin, possess activity against Mycobacterium avium complex. These agents are used in most multidrug regimens for the therapy of disseminated M avium complex in AIDS.1-3 2 recent reviews1,2 of M avium therapy new

macrolide

antibiotics,

Clarithromycin

and

pseudomembranous

enterocolitis SIR—Pseudomembranous enterocolitis is a serious disease, caused most often by toxins produced by Clostridium difficile.1 The disorder is almost always associated with antibiotic treatment. Among antibacterial agents implicated are ampicillin, amoxycillin, other penicillins, clindamycin, cephalosporins, and co-trimoxazole. However, the macrolide clarithromycin has not been incriminated in antibioticassociated diarrhoea so far. We report a 26-month-old girl who developed fever and severe diarrhoea with mucus causing dehydration and lethargy 241

while being treated with a 10-day course of clarithromycin for otitis media. Clostridium difficile toxin B was identified by tissue culture assay. Pseudomembranous enterocolitis was suspected, clarithromycin was stopped, and vancomycin was given orally at a dose of 150 mg four times daily (50 mg/kg per day) for 7 days. Diarrhoea improved within 2 days and no relapse was observed within 4 weeks. It is important to note that clarithromycin can trigger pseudomembranous enterocolitis because this macrolide is increasingly used in immunocompromised patients, including HIV-infected subjects, for treatment of non-tuberculous mycobacteriosis.2 Diarrhoea occurs frequently in HIVinfected patients, and the cause often remains unknown.3 Patients with HIV infection and clarithromycin treatment must therefore be monitored for Clostridium difficile and its toxins in the stool as soon as diarrhoea develops.

Christian P Braegger, David Nadal

Figure: Coomassie blue stained SDS PAGE gel

Department of Paediatrics, University of Zürich, Kinderspital, 8032 Zurich, Switzerland

Lane 1 = B recurrentis; 2 = B hermsii strain HS1 ; 3 = hermsii strain Manl; 4 = B hermsii strain Conl; 5 = B turicatae; 6 =B burgdorferi strain 831; 7 = B garinii; 8 = B burgdorferi strain VS461; 9 =B burgdorferi UK isolate.

1

2

3

LaMont JT. Bacterial infections of the colon. In: Tadataka Y, Alpers DH, Owyang C, Powell DW, Silverstein FE, eds. Textbook of gastroenterology. New York: J B Lippincott, 1991. Nadal D, Caduff R, Kraft R, et al. Invasive infection with Mycobacterium genavense in three children with the acquired immunodeficiency syndrome. Eur J Clin Microbiol Infect Dis 1993; 12: 37-43. Ullrich R, Heise W, Bergs C, L’age M, Riecken EO, Zeitz M. Gastrointestinal symptoms in patients infected with human immunodeficiency virus: relevance of infective agents isolated from gastrointestinal tract. Gut 1992; 33: 1080-84.

Successful in-vitro cultivation of Borrelia recurrentis SIR—Sundnes and Tekle Haimanot report (Nov 13, p 1213) louse-borne relapsing fever in Ethiopia. We have successfully cultivated a strain of Borrelia recurrentis isolated from a patient with louse-borne relapsing fever in Addis Ababa. A 24-year-old seaman who had been resident in Addis Ababa for two months was admitted to the Black Lion Hospital, as part of a study of louse-borne relapsing fever. He gave a 3-day history of fever, chills, headache, dizziness, cough, chest pain, musculoskeletal aches, abdominal pain, anorexia, nausea, and vomiting. He had 14 000 spirochaetes per µL in blood. His serum was cultured in Kelly’sl growth medium for B recurrentis and in BSK II medium, for growth of Lyme borreliae.2 Cultures were incubated at 35°C and examined by dark-field microscopy. BSK II medium yielded an isolate that has now survived eighteen in vitro passages, producing a growth yield of 107 organisms per mL with a generation time of 8-9 h. Although Obermeier first described B recurrentis in 1867, attempts to maintain this spirochaete in culture have failed.1,3 Pulsed-field electrophoresis of the isolate showed a chromosome of about 1 megabase and six plasmids of 184-3, 54-56, 46, 39-6, 30-2, and a faint band at 15-6 kilobase. This pattern was distinct from that of other borrelial species tested including B hermsii, B turicatae, and B burgdorferi (data not shown). Similarly, the Coomassie blue stained protein profile of the strain was distinct from that of other borreliae tested with a major band detected at 47 kDa (figure). Serum samples from 16 patients with louse-borne relapsing fever were highly reactive with an isolate of both B recurrentis and B burgdorferi when tested by immunoblotting. These samples would have been falsely reported as positive in Lyme borreliosis serological tests with B burgdorferi antigens.’ This finding should be considered when investigating patients from relapsing fever endemic regions for Lyme borreliosis (see Fry and Kenny,

Sept 11, p 689). 242

This strain was highly susceptible to penicillin (minimum inhibitoryconcentration [MIC] 0-2 µg/mL ; minimum bactericidal concentration [MBC] 0-75 µg/mL), tetracycline (MIC and MBC 0 06 µg/mL), and erythromycin (MIC 0 04 µg/mL ; MBC ::::; 0.02 µg/mL). This finding contrasts with values for tetracycline and tick-borne relapsing fever strains which gave MICs of 1-4 µg/mL (three B hermsii and one B turicatae), whereas B burgdorferi gave MICs of 0.12-0.5 ltg/mL for tetracycline (low and high passage strain B31); MBC values ranged from 2-4 µg/mL for tick-borne relapsing fever and 0-25 to 1 µg/mL for B burgdorferi. The exquisite antibiotic susceptibility of this isolate supports the use of single dose treatment of louse-borne relapsing fever. We thank the Well come Trust for

a

travel grant.

S J Cutler, D Fekade, K Hussein, K A Knox, A Melka, K Cann, Emilianus, D Warrell, D J M Wright

AR

Department of Medical Microbiology, Charing Cross Hospital, London W6 8RF, UK; Department of Internal Medicine, Black Lion Hospital, Addis Ababa, Ethiopia; and Centre for Tropical Medicine, University of Oxford, John Radcliffe Hospital, Oxford

2

Kelly RT. Cultivation and physiology of relapsing fever borreliae. In: Johnson RC, ed. The biology of parasitic spirochaetes. New York: Academic Press, 1976: 87-94. Barbour AG. Isolation and cultivation of Lyme disease spirochetes.

3

Yale J Biol Med 1984; 54: 521-25. Dodge RW. Culture of Ethiopian strains of Borrelia recurrentis. Appl

1

4

Microbiol 1973; 25: 935-39. Cutler SJ, Wright DJM. Predictive value of serology for Lyme borreliosis. J Clin Pathol (in press).

diagnosing

Chronic

fatigue syndrome or myalgic encephalitis SIR—Although we agree with David and Wessely (Nov 13, 1247) that the term benign myalgic encephalomyelitis (ME) is no longer accurate, we do not share their enthusiasm for the suggested replacement, chronic fatigue syndrome (CFS). CFS means different things in different countries. In Australia, it is synonymous with ME; in America, it covers several disorders, including ME, chronic fatigue and immune dysfunction syndrome, giardiasis, fibromyalgia, and masked depression, whereas in the UK it has become a dustbin diagnosis for all cases of unexplained chronic fatigue. In a sense, ME is to CFS what migraine is to headaches: it is much more disabling, it is aetiologically more complex, and it is p

often

more

difficult

to treat.

The confusion between ME and