Efficacy and safety of an intravenous induction therapy for treatment of disseminated Mycobacterium avium complex infection in AIDS patients: a pilot study

Pierre-Marie Rogera,*, Michel Carlesa, Isabelle Agussol-Foina, Liliana Pandianib, Olivia Keïta-Persea, Veronique Mondaina, Francine De Salvadora and Pierre Dellamonicaa

a Service des Maladies Infectieuses et Tropicales, Hôpital de l’Archet I, BP 79, 06202 Nice cedex 3; b Laboratoires Marcel Mérieux, BP 7322, 69357 Lyon cedex 07, France


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Monotherapy with macrolides for the treatment of disseminated Mycobacterium avium complex (MAC) bacteraemia leads to drug resistance and relapse of bacteraemia. Gastrointestinal intolerance is a common reason for treatment withdrawal of multidrug regimens. We have assessed the efficacy and safety of initial parenteral therapy together with a macrolide, for disseminated MAC infection, defined as two positive blood cultures, in AIDS patients. Patients received a daily infusion of amikacin 15 mg/kg + ethambutol 20 mg/kg + ciprofloxacin 400 mg/day, for 1 month, together with a macrolide by oral route. Fifteen patients were included and 13 (86%) achieved negative culture before the end of parenteral therapy.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Macrolides are currently the cornerstone of treatment for disseminated Mycobacterium avium complex (MAC) infection. 1,2 However, monotherapy leads to the emergence of drug resistance and bacteraemia relapse. 2 Multidrug regimens lower the burden of MAC in the blood and improve symptoms in AIDS patients. 1,2 These drug combinations increase toxicity, and gastrointestinal intolerance is a common cause of discontinuation of treatment. 2,3 In addition, Gordon et al. 4 demonstrated that serum levels of oral antimycobacterial agents such as ethambutol, clofazimine, rifampicin and ciprofloxacin are low because of impaired drug absorption in HIV-infected patients, even without gastrointestinal manifestations. These observations led us to assess the efficacy and safety of an initial induction parenteral combination therapy associated with a macrolide to avoid selection of resistant strains and to optimize bioavailability and observance.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was performed in the Infectious Diseases and Tropical Medicine Department of the Nice University Hospital from July 1994 to March 1998. Human immunodeficiency virus (HIV)-infected patients with disseminated MAC infection were considered for enrolment after informed consent if they already had a central venous catheter for another parenteral treatment and/or if they had gastrointestinal intolerance to medications other than antimycobacterials. Disseminated MAC infection was defined as two positive blood cultures for M. avium. All patients received a daily infusion, including amikacin 15 mg/kg, ethambutol 20 mg/kg and ciprofloxacin 400 mg, for 1 month, and a macrolide, clarithromycin 500 mg bid or 1000 mg bid, or azithromycin 500 mg od. By the end of 1994, all patients received 1000 mg/day of clarithromycin. For outpatients, treatment was started in the daycare unit of our department. After a month of the regimen, patients were given a macrolide and ethambutol by the oral route. Blood culture was by the radiometric BACTEC system with Bactec 12B media (Becton Dickinson Diagnostic Instrument Systems, Towson, MD, USA). The speciation of M. avium was confirmed by a DNA hybridization technique (Gen-Probe, San Diego, CA, USA). Blood cell counts and a biochemical profile were assessed weekly during the first month and monthly subsequently. Blood cultures for detection of mycobacterial infection were taken weekly for the first month and then every 2 weeks for the following 6 weeks. After 10 weeks, blood cultures were obtained only in case of clinical events. The chart from each consecutively enrolled patient was studied retrospectively until 10 March 1998. The impact of our treatment was assessed through bacteriological clearance, and time to relapse defined as time to one new positive blood culture.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 15 patients was included. None of them had received any prophylaxis against M. avium. Patient 5 received the experimental regimen for a relapse of disseminated MAC infection. He received as an initial treatment rifabutine and clofazimine for 4 weeks and had been off therapy for 6 weeks because of gastrointestinal intolerance.

Antibacterial efficacy is shown in the Table. All patients but one with associated highly active antiretroviral therapy (HAART) had a CD4 % T-cell count recovery of <150/µL. Duration of parenteral therapy was 29 ± 13 days according to tolerance and patient’s request. After parenteral therapy, treatment consisted of a macrolide plus ethambutol in 11 cases and a macrolide plus ciprofloxacin in one case of intolerance to ethambutol. Eleven patients (73%) had negative blood cultures by the end of the first 2 weeks of treatment and 13/15 (86%) patients achieved negative blood cultures by the end of their parenteral therapy. No catheter-related complications were observed. Five patients had adverse effects during the period of clinical follow-up that resulted in therapeutic discontinuation (one cutaneous allergy and one digestive adverse effect with clarithromycin; one altered colour vision with ethambutol; one serum creatinine increase with amikacin and one thrombocytopenia with ciprofloxacin). All adverse effects resolved after drug discontinuation. Four relapses were diagnosed at days 60, 105, 160 and 330. The median survival time was 12 ± 10 months (range 1-30 months) and 10 patients died during the study period.


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Table. Results of parenteral therapy on disseminated MAC infection in 15 HIV-infected patients
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Antiretroviral therapy has dramatically changed since 1996 with the introduction of protease inhibitors, which have resulted in increased survival. Opportunistic infections, especially M. avium infection, currently have poor prognosis 5 and so it is important that the treatment of such infections is optimized. Clarithromycin, ethambutol and rifabutin is the standard treatment for M. avium infection in patients with AIDS. 1 However, rifabutin increases the metabolism of protease inhibitors, while clarithromycin and rifabutin interact and the introduction of three new drugs in patients who already receive so many other drugs may lead to poor compliance.

Our study shows that the combination of an initial parenteral regimen with a macrolide for therapy of disseminated MAC infection results in early mycobacterial blood culture negativity, in 11/15 cases in <2 weeks of treatment. In another pilot study using oral clarithromycin and ciprofloxacin plus parenteral amikacin (7.5 mg/kg/day), the first negative culture was obtained within 4.3 ± 1.4 weeks. 6 Chiu et al. 3 reported resolution of bacteraemia in only 3/10 patients after 12 weeks of a four-drug regimen including oral ciprofloxacin, ethambutol and rifampicin together with parenteral amikacin (7.5 mg/kg/day). In this study, the commonest reason for early drug withdrawal was gastrointestinal intolerance. Two of our patients clearly required longer treatment to achieve blood culture negativity; this could have been caused by a higher mycobacterial blood load in these patients. One limitation of our study is that we did not perform quantitative blood cultures to determine mycobacterial load.

Adverse drug effects were mild and disappeared with drug discontinuation. Survival was comparable to that for other treatments, 1,3 although 80% of our patients presented with AIDS disease. When we looked for late relapse of disseminated MAC infection, which is not undertaken in most studies, 1,3 only four patients showed relapse. For prevention of relapse with clarithromycin-resistant isolates, preliminary studies have shown that a macrolide plus ethambutol is an effective combination. 7

Our regimen is not much more expensive than the standard treatment. In December 1996 in France, the cost of parenteral therapy followed by a two-drug regimen for 1 year, including a nurse at home, was estimated to be FF 33,000, as compared with FF 28,500 for the treatment proposed by Shafran et al. 1 (with the lower dose of rifabutin).

Drugs used to treat mycobacterial diseases in patients with AIDS are associated with frequent side effects, and changes to therapeutic regimens are often required. Our 15 enrolled patients accounted for nearly 15% of all patients with a new diagnosis of disseminated MAC infection during the period of clinical follow-up attending our department. For most of these patients, our therapeutic regimen appeared to be safe and effective.

In conclusion, our therapeutic regimen is useful with current antiretroviral therapies. It improves quality of life for HIV-infected patients with gastrointestinal disorders and seems to improve antibacterial efficacy. Use of clinical parameters as well as bacteriological determination of mycobacterial blood load for a better determination of bacterial efficacy are needed to define precisely the role of this therapeutic approach.


    Notes
 
* Corresponding address. Services des Maladies Infectieuses, Hôpital de l’Archet 1, BP7932, 06202 Nice, France. Fax: +33-(0)4-93-96-54-54. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Shafran, S. D., Singer, J., Zarowny, D., Phillips, P., Salit, I., Walmsley, S. L. et al. (1996). A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. New England Journal of Medicine 335, 377–83.[Abstract/Free Full Text]

2 . Heifets, L. (1996). Susceptibility testing of Mycobacteriumavium complex isolates. Antimicrobial Agents and Chemotherapy 40, 1759–67.[Free Full Text]

3 . Chiu, J., Nussbaum, J., Bozette, S., Tilles, J. G., Young, L. S., Leedom, J. et al. (1990). Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin and ciprofloxacin. Annals of Internal Medicine 113 , 358–61.[ISI][Medline]

4 . Gordon, S. M., Horsburgh, C. R., Peloquin, C. A., Havlik, J. A., Metchock, B., Heifets, L. et al. (1993). Low serum levels of oral antimycobacterial agents in patients with disseminated Mycobacterium avium complex disease. Journal of Infectious Diseases 168, 1559 –62.[ISI][Medline]

5 . Jacobson, M. A. & French, M. (1998). Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy. AIDS 12, Suppl. A, S157–63.[Medline]

6 . De Lalla, F., Maserati, R., Scarpellini, P., Marone, P., Nicolin, R., Caccamo F. et al. (1992). Clarithromycin-ciprofloxacin-amikacin for therapy of Mycobacterium avium-Mycobacterium intracellulare bacteremia in patients with AIDS. Antimicrobial Agents and Chemotherapy 36, 1567 –9.[Abstract]

7 . Bermudez, L. E., Nash, K. A., Petrofsky, M., Young, L. S. & Inderlied, C. B. (1996). Effect of ethambutol on emergence of clarithromycin-resistant Mycobacterium avium complex in the beige mouse model. Journal of Infectious Diseases 174, 1218–22.[ISI][Medline]

Received 19 May 1998; returned 16 September 1998; revised 26 October 1998; accepted 30 January 1999





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