Michael E. Ellis

An EORTC International Multicenter Randomized Trial (EORTC Number 19923) Comparing Two Dosages of Liposomal Amphotericin B for Treatment of Invasive Aspergillosis

This is the first completed prospective randomized clinical efficacy trial of antifungals in the treatment of invasive aspergillosis (IA) and the first to compare the clinical efficacy of two dosages of liposomal amphotericin B (L-AmB) for IA in neutropenic patients with cancer or those undergoing bone marrow transplantation. Eighty-seven of 120 patients were eligible and evaluable. Clinical responses were documented for 26 (64%) of 41 patients receiving 1 mg/(kg.d) (L-AmB-1) and 22 (48%) of 46 receiving 4 mg/(kg.d) (L-AmB-4). Radiologic response rates were similar: 24 (58%) of the L-AmB-1 recipients and 24(52%) of the L-AmB-4 recipients. The six-month survival rates were 43% (L-AmB-1) and 37% (L-AmB-4). These differences were not significant. The numbers of deaths directly due to IA at 6 months were similar: 9 (22%) of 41 L-AmB-1 recipients and 9 (20%) of 46 L-AmB-4 recipients. No other variable independently influenced survival, apart from central nervous system IA. L-AmB is effective in treating approximately 50%-60% of patients who have IA. A 1-mg/(kg.d) dosage is as effective as a 4-mg/(kg.d) dosage, and no advantages to use of the higher, more expensive, dosage has been observed.

Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients

The efficacy and safety of oral fluconazole versus a polyene regimen in preventing mycoses in neutropenic patients was compared. Patients with haematological malignancy or bone marrow transplantation received as antifungal prophylaxis either fluconazole 200 mg daily or a regimen consisting of clotrimazole trouches 10 mg twice daily with mycostatin, 500,000 i.u. four times daily, benadryl and cepacol mouthwash. Ninety patients at risk for fungus infection were evaluable. Four of 42 patients (9.5 %; confidence interval 2 %–23 %) on fluconazole and 17 of 48 patients (35.4 %; confidence interval 22 %–52 %) (p<0.01) on the clotrimazole regimen developed a clinically significant fungal infection, including 3 (7.1 %) and 11 (22.9 %) patients respectively who had severe fungal infection, mainly pulmonary aspergillosis. Death directly due to a fungal infection within 100 days of the start of prophylaxis occurred in 2 of 42 patients (4.8 %) and 9 of 48 patients (18.8 %) respectively (p<0.06). Kaplan-Meier analysis showed that the chance of survival on fluconazole was statistically greater than for the clotrimazole regimen (p<0.04). A decrease of candidal colonisation of the gastrointestinal and genitourinary tracts occurred only in patients receiving fluconazole. No significant toxicity occurred. A 200 mg daily dose of fluconazole given to these patients thus appears to be well tolerated and to provide a protective effect against the development of fungal infection and death from severe fungal disease.

Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: A double-blind placebo-controlled study

Fluconazole 50 mg daily for 14-28 days was effective in the treatment of patients with AIDS and AIDS-related complex with severe oropharyngeal and oesophageal candidiasis. Of 24 patients entered, 17 (81%), including seven with oesophageal candidiasis, were clinically cured and two (9.5%) improved at the end of treatment. Following clinical cure, 14 patients were entered into the double-blind phase of the study, where fluconazole (150 mg) or placebo capsules were given once weekly. Treatment was double blind. Fluconazole 150 mg once weekly was found to be effective in maintaining patients both clinically and mycologically free of oropharyngeal candidiasis.

Chronic non-A, non-B hepatitis complicated by end-stage renal failure treated with recombinant interferon alpha

Chronic non-A, non-B hepatitis occurs in 50% of Saudi patients with end-stage renal failure and requires long-term hemodialysis since it is a contraindication to renal transplantation. Thirteen patients with biochemical and histological documented chronic non-A, non-B hepatitis (11 with HCV antibodies) entered a double-blind placebo controlled cross-over study, in which Roferon A 3 MU or placebo were administered subcutaneously 3 times weekly after hemodialysis for 6 months. The mean ALT fell significantly from pretreatment levels of 74.7 (95% confidence interval (CI) 54.7, 92.5) (13 patients in the 6-month run-in period) and 66.8 (CI 47.7, 85.8) (7 patients in the run-in period + 6 patients in the placebo period) (difference NS) to 37.6 (CI 21.0, 54.2) during interferon treatment (P < 0.005). In 10/13 patients (77%) ALT levels became normal. In the 6-month follow-up period immediately after therapy, the mean ALT was 45.2 (CI 28.0, 62.0). Although this change was not significant (P = 0.49), only 7 of these 10 patients sustained biochemical remission in the 6-month follow-up period. The corresponding total Histological Activity Index improved from 8.9 (CI 7.5, 10.3), 8.9 (CI 7.2, 10.7) (difference NS) to 6.2 (CI 3.9, 8.5) (P < 0.05; P = 0.052, respectively). Intralobular inflammation and periportal inflammation showed the most significant changes. Five of 13 (39%) and 2/13 patients (15%) had complete resolution of piecemeal necrosis and intralobular inflammation, respectively. Toxic effects of interferon were mild, early and self-limiting.(ABSTRACT TRUNCATED AT 250 WORDS)

Open Lung Biopsy Provides a Higher and More Specific Diagnostic Yield Compared to Broncho-Alveolar Lavage in Immunocompromised Patients

In order to examine the feasibility and safety of undertaking a larger prospective study to compare the diagnostic yield from concurrent open lung biopsy (OLB) and bronchoalveolar lavage (BAL) in febrile neutropenic patients with pulmonary infiltrates and the impact of such knowledge on clinical outcome, a pilot exploratory study was performed. 13 immunocompromised patients (mainly with haematological malignancy or bone marrow transplantation recipients) were investigated. At least one diagnostic finding in 12 of 13 patients was provided by OLB compared to 4 of 13 patients by BAL. BAL provided 7 specific diagnoses (pneumocystis 1, fungal infection 3, bacterial pneumonia 1, pulmonary haemorrhage 2) whilst OLB provided 12 specific diagnosis (CMV 2, pneumocystis 3, fungal infection 1, bacterial pneumonia 1, pulmonary haemorrhage 4, pulmonary embolism 1). Five patients with nonspecific interstitial/alveolar inflammation were diagnosed only by OLB. The concordance that the exact same specific diagnoses present in the OLB were found in the BAL was zero. There were 2 minor complications (1 wound infection by OLB, 1 moderate haemorrhage by BAL). Mortality at 28 days was 8 of 13 patients which in no case was related to either procedure. We suggest that OLB is a safe procedure in such patients, provides superior and more complete diagnostic information compared to BAL and a larger controlled study to investigate the impact of early OLB on the outcome of these patients appears to be justified.

High Proportion of Multi-drug Resistant Mycobacterium tuberculosis in Saudi Arabia

289 patients with TB, presented to a single tertiary care unit in Saudi Arabia between 1989 and 1994. The isolate from each patient was tested for in vitro susceptibility to rifampicin, isoniazid, ethambutol, pyrazinamide and streptomycin. 25 patients (8.7%) had isolates resistant to at least 1 anti-tuberculous drug. Single drug resistance (SDR)-mainly isoniazid-occurred in 14, and resistance to at least 2 drugs (multi-drug resistance-MDR) in 11, of which 8 were due to both isoniazid and rifampicin. Previous drug treatment occurred significantly more often in patients with MDR (8/11), than SDR (1/14) (p = 0.0021). A literature review of another 5571 patients from Saudi Arabia with TB revealed an incidence of resistance of M. tuberculosis isolates to at least 1 anti-tuberculous drug tested, of between 5.9% and 44%. The overall percentage of patients with resistant tuberculosis (including our own patients) was 14.9%. Resistance to streptomycin (8.9%), isoniazid (6.6%), and rifampicin (6.1%) were the commonest reported. There were as many patients with MDR as there were SDR. A history of previous anti-tuberculous treatment was found in over 40%. The high rate of anti-tuberculous resistance in Saudi Arabia may be due to poor supervision of anti-TB treatment, the embryonic healthcare system, over-the-counter antibiotic availability, treatment of endemic diseases such as brucella with rifampicin etc., a large migrant work force, and possibly increased toxicity of anti-tuberculous drugs secondary to the high incidence of chronic liver disease in the country.

Successful Combined Surgical and Medical Treatment of Fusarium Infection after Bone Marrow Transplantation

The usual management of opportunistic fusarium infection in the immunocompromized patient is with systemic antifungals, despite which little impact is made on the mortality which approaches 100%. We describe a case of fusarium infection of the foot in a bone marrow transplant recipient which was successfully managed with local wide excisional surgery and intravenous liposomal amphotericin B.

Systemic amphotericin B versus fluconazole in the management of antibiotic resistant neutropenic fever — preliminary observations from a pilot, exploratory study

A pilot exploratory study was undertaken to collect preliminary information relating to safety and overall outcome in using intravenous fluconazole (FLUC) for managing antibiotic resistant neutropenic fever (ARNF), with the objective of assessing feasibility of performing a larger prospective controlled study. Patients who were neutropenic from treatment for leukaemia or bone marrow transplantation, received either fluconazole (FLUC) or amphotericin B (AB). Eight of 16 patients (50%) on FLUC and 21 of 25 patients (84%) on AB defervesced; the mean time to defervescence was 11.0 +/- 10.0 days for FLUC compared to 7.7 +/- 6.3 days for AB, and a similar proportion in each treatment group defervesced within 5 days (50% vs. 52%), respectively. Six of 16 patients (37.5%) on FLUC and three of 25 patients (12%) on AB developed overt invasive fungal disease, including pulmonary aspergillosis (FLUC 4 cases, AB 2 cases) and invasive candidiasis (FLUC 2 cases, AB 0 cases). The mean time to these events was 19.5 +/- 13.4 (FLUC) and 9.0 +/- 3.6 (AB) days. The fungal related mortality rates were higher in the FLUC group: five of 16 patients (31%) vs. two of 25 patients (18%) died respectively; the time to fungal death was 43.2 +/- 18.2 (FLUC) and 25.0 +/- 18.4 (AB) days. This tendency towards a more favourable outcome in patients on AB may have been due to absence of prior fluconazole prophylaxis in patients subsequently receiving IV FLUC. Analysis of a small subgroup of patients who had all received prior prophylaxis with clotrimazole only, indicated that a greater number of patients subsequently receiving IV FLUC died from fungal disease (5/16 vs.0/6, P = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Histologically advanced chronic hepatitis C treated with recombinant alpha-interferon: a randomized placebo-controlled double-blind cross-over study

Chronic hepatitis C is common in Saudi Arabia and most often presents in an advanced stage. To assess the response of patients to interferon, a randomized placebo-controlled double-blind study was undertaken. All but 1 patient had cirrhosis or fibrosis before interferon. After a 24-week observation period patients received alpha 2a interferon, 3 mega units sc tiw or placebo for 24 weeks, then the opposite treatment for another 24 weeks followed by 24 weeks of observation. Liver biopsies were performed before and after each of the treatment phases. Twenty-two out of 24 patients completed the study. The mean alanine aminotransferase (ALT) levels fell from 150.7 +/- 118.7 units/l to 91.0 +/- 42.6 units/l after 6 months interferon treatment (P = 0.03) but only 3 patients (14%) had complete normalization of mean ALT levels and 4 (18%) had > 50% reduction. The mean hepatitis activity index fell from 12.2 +/- 2.6 immediately before to 11.6 +/- 2.5 just after interferon (P = 0.4). After interferon there was an insignificant raise in 6-month mean ALT. Hepatitis C virus-RNA was positive in all 17 patients tested and remained so after treatment. Side-effects were mild and well tolerated. Alpha interferon 3 mega units tiw for 24 weeks is not an effective treatment of histologically advanced chronic hepatitis C.

A clinical-radiological evaluation of benzimidazoles in the management of echinococcus granulosus cysts

Nine patients with complicated hydatid disease managed with surgery and mebendazole/albendazole are presented. Five patients received albendazole (1 treatment course) and 5 patients received mebendazole (3 had 2 treatment courses, 1 had a switch-over from mebendazole to albendazole). The mean durations of treatment and follow-up were respectively 7 +/- 2.5 months and 7 +/- 2.5 months (albendazole); 13 +/- 10 months and 29 +/- 31 months (mebendazole). A superior clinical and radiological response was seen in 1 patient with disseminated intra-abdominal disease on switching therapy from mebendazole to albendazole. Radiological improvement occurred in 3/5 courses of albendazole and in 2/8 courses of mebendazole. Clinical improvement occurred in 3/5 courses of albendazole and 0/8 courses of mebendazole. Radiological deterioration was demonstrated in 0/5 courses of albendazole and 2/8 courses of mebendazole. Although the impression was that albendazole was superior, good responses were also seen with mebendazole. The heterogeneity of the patients, their disease, short follow-up time, lack of more sensitive noninvasive assay techniques urges caution before firm conclusions can be drawn.