Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

Rheumatological lesions in individuals with human immunodeficiency virus infection.

One hundred and twenty-three patients with human immunodeficiency virus infection have been referred to rheumatologists at our hospitals between October 1985 and April 1989 because of musculoskeletal symptoms. Thirty-four homosexual men presented with acute, peripheral, non-erosive arthritis (mean number of four joints affected) with the knees being involved in 23. Other features developing concurrently with arthritis included psoriasis, keratoderma blenorrhagica, plantar fasciitis, urethritis, conjunctivitis and anterior uveitis. Four of five patients investigated were HLA-B27-positive; none of 15 patients tested had raised titres of rheumatoid or antinuclear factors. Various infections were associated with the onset of arthritis and two patients with a recent history of diarrhoea had serological evidence of yersinia infection. No micro-organisms were identified within the joint except for HIV itself. At the time of onset of arthritis four of these individuals had the acquired immunodeficiency syndrome (AIDS); 11 were not known to be HIV-positive before testing which was performed following referral for arthritis. Six patients have since developed AIDS and four have died. In 15 individuals, including those who progressed to AIDS, joint symptoms have been severe, persistent and poorly responsive to non-steroidal anti-inflammatory drugs. In only five patients has the arthritis been known to resolve. Synovitis has also been seen in two women: in one of these HIV infection was thought to have been acquired through intravenous drug abuse. Other rheumatic lesions included myalgia/myositis, non-inflammatory peripheral arthritis, spinal pain, soft tissue lesions, arthralgia or myalgia of unknown cause and infective lesions including septic arthritis and bony infection due to histoplasmosis and atypical mycobacterial infection. It appears likely that HIV infection is a risk factor for the development of seronegative arthritis and other rheumatic lesions.

Non-cryptosporidial diarrhoea in human immunodeficiency virus (HIV) infected patients.

Thirty of 81 consecutive HIV antibody positive patients referred with non-cryptosporidial diarrhoea had no potential infectious cause; most had AIDS related complex rather than the full blown syndrome. Opportunistic infections with cytomegalovirus (CMV), mycobacterium avium-intracellulare (MAI), and herpes simplex virus (HSV), which allowed a diagnosis of AIDS to be made, were found in 19 patients and were the presenting features of AIDS in five. Other potential pathogenic species included entamoeba, giardia, campylobacter, and salmonella (without septicaemia). Cytomegalovirus infection was often accompanied by abdominal pain. Severe weight loss (greater than 10 kg) at presentation was found in patients with CMV infection and MAI. Bloody diarrhoea was confined to the group with HSV procitis. Malignant causes of diarrhoea were rare. Two patients developed a squamous carcinoma of the anorectal margin and one a non-Hodgkin's lymphoma. In only two of 12 patients who had Kaposi's sarcoma was this considered as a cause of diarrhoea. Rigid sigmoidoscopy showed macroscopic abnormalities in over a third (32) of the 81 patients with non-cryptosporidial diarrhoea. Most commonly this was severe inflammation (17) or discrete ulceration (four) [three of whom had CMV colitis]. Kaposi's sarcoma was identified in 11 patients. Non-specific inflammation was seen histologically in 40 of the 60 patients with no sigmoidoscopic inflammatory changes. Barium enema only revealed an abnormality in a minority of the patients and a colonoscopy only revealed information additional to rigid sigmoidoscopy in two patients--one with CMV ulcers in the transverse colon and the other with evidence of Kaposi's sarcoma not seen in the rectum. Ten patients had a rectal biopsy examined by electron microscopy as no infective cause of diarrhoea was uncovered. In four of these microtubular structures which are commonly seen in viral infections were found and two had prelymphomatous changes and in one of these frank lymphoma has developed. We recommend multiple stool analysis, sigmoidoscopy and rectal biopsy as the initial investigations in these patients reserving tests of malabsorption, colonoscopy, and barium enema for the small number of more difficult cases.

Unsuccessful treatment of non-gonococcal urethritis with rosoxacin provides information on the aetiology of the disease.

In a controlled trial of rosoxacin in patients with non-gonococcal urethritis (NGU), 150 mg of the antibiotic given twice daily for 10 days was compared with 300 mg triple tetracycline (Deteclo) given twice daily for the same period. Only six (19%) of 31 patients treated with rosoxacin were free of urethritis after 10 days; Chlamydia trachomatis was reisolated from 12 (92%) of 13 patients who were chlamydia positive originally, and Ureaplasma urealyticum was reisolated from 12 (80%) of 15 patients who were ureaplasma positive originally. In contrast, 18 (58%) of 31 patients treated with triple tetracycline were cured clinically after 10 days; C trachomatis was not reisolated from any of 10 patients who were chlamydia positive originally, and U urealyticum was reisolated from only three (17%) of 18 patients who were ureaplasma positive originally. These results were consistent with the antimicrobial inactivity of rosoxacin in vitro and they cannot be reconciled with previous reports of successful use of this antibiotic in NGU. Ureaplasmas were isolated more frequently and in larger numbers from chlamydia negative than from chlamydia positive patients, but it is probable that ureaplasmas resistant to tetracycline were not responsible for persistent urethritis.