Atzori, C.

Marchetti, G.

Maserati, R.

Novati, S.

Olliaro, P.

Orani, A.

Orso, M.

Scaglia, M.

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1ID 1994; 170 (November) Correspondence 1349phism is accumulating more rapidly than simple nucleotide vari-ation. Also, restricted allelic diversity means that it is probablethat only nominal amino acid variation will occur in proteinsthat are of potential immunoprophylaxis or virulence interest.To gain further insight into the molecular evolutionary geneticsof M. tuberculosis, it will be necessary to determine the level ofsequence variation present in the other closely allied membersof the M. tuberculosis complex (M. bovis. Mycobacterium afri-canum. and Mycobacterium microti) and the related slowlygrowing pathogen Mycobacterium leprae. for which there is areport of limited chromosomal diversity based on restriction en-donuclease analysis [14].Vivek Kapur, Thomas S. Whittam, and James M. MusserSection of Molecular Pathobiology. Department of Pathology, BaylorCollege ojMedicine. Houston, Texas; Institute ofMolecular EvolutionaryGenetics, Pennsylvania State University, University ParkReferencesI. Bloom BR, Murray CJL. Tuberculosis: commentary on a reemergentkiller. Science 1992;257: 1055-64.2. Ayvazian LF. History of tuberculosis. In: Reichman LB, Hershfield ES,eds. Tuberculosis: a comprehensive international approach. New'York: Marcel Dekker, 1993:1-20.3. Salo WL, Aufderheide AC, Buikstra J, Holcomb T A. Identification ofMycobacterium tuberculosis DNA in a pre-Columbian Peruvianmummy. Proc Natl Acad Sci USA 1994;91:2091-4.4. van Embden JDA, van Soolingen D, Small PM, Hermans PWM. Ge-netic markers for the epidemiology of tuberculosis. Res Microbiol1992; 143:385-91.5. You-ng D, Lathigra R, Hendrix R, Sweetser D, Young RA. Stress pro-Effectiveness of Aminosidine (Paromomycin) Sulfate inChronic Cryptosporidium Diarrhea in AIDS Patients:An Open, Uncontrolled, Prospective Clinical TrialColleagues-All treatments for cryptosporidial diarrhea to datehave given poor results, including the use of antidiarrheal, anti-microbial, antiparasitic, and immunomodulatory compounds.By contrast, aminosidine (paromomycin), a non-orally absorb-able aminoglycoside antibiotic, was shown to be effective in vi-tro at concentrations achievable in the bowel [I. 2] as well as inexperimentally infected animals [3]. Data from various patientseries and noncomparative trials have indicated that symptom-This study was conducted when P.O. was employed at Farmitalia CarloErba, Research & Development Antiinfectives, Milan; no financial supportwas received for the study, but aminosidine was provided by FarmitaliaCarlo Erba under compassionate plea.Informed consent was obtained for all patients.Presented in part: joint annual meeting of the American Society ofTropi-cal Medicine and Hygiene and the American Society of Parasitologists, At-lanta, 31 October to 4 November 1993 (abstract 645).Reprints or correspondence: Prof. M. Scaglia, Institute for Infectious Dis-eases, University-IRCCS S. Matteo, 27100 Pavia, Italy.The Journal of Infectious Diseases 1994;170:1349-50© 1994 by The University of Chicago. All rights reserved.0022-1899/94/7005-0055$01.00teins are immune targets in leprosy and tuberculosis. Proc Natl AcadSci USA 1988;85:4267-70.6. Davis EO. Jenner PJ, Brooks Pc, Colston MJ, Sedgwick SG. Proteinsplicing in the maturation of M. tuberculosis RecA protein: a mecha-nism for tolerating a novel class of intervening sequence. Cell1992;71 :20 1-10.7. Telenti A, Imboden P, Marchesi F, et al. Detection of rifampicin-resis-tance mutations in Mycobacterium tuberculosis. Lancet 1993;341:647-50.8. Kapur V. Li LL, lordanescu S. et al. Characterization by automatedDNA sequencing of mutations in the gene (rpoB) encoding the RNApolymerase (3subunit in rifampin-resistant Mycobacterium tuberculo-sis strains from New York City and Texas. J Clin Microbiol1994;32: 1095-8.9. David HL, Newman CM. Some observations on the genetics of isonia-zid resistance in the tubercle bacilli. Am Rev Respir Dis1971; I04:508-15.10. Li WH, Wu CI, Luo Cc. A new method for estimating synonymous andnonsynonymous rates ofnucleotide substitution considering the rela-tive likelihood of nucleotide and codon changes. Mol BioI Evol1985;2: 150-74.II. Sharp PM. Determinants of DNA sequence divergence between Esche-richia coli and Salmonella tvphimurium: codon usage, map position,and concerted evolution. J Mol Evol 1991;33:23-33.12. Ochman H, Wilson AC. Evolutionary history of enteric bacteria. In:Neidhardt FC, Ingraham JL. Low KB, Magasanik B, Schaechter M,Umbarger HE. eds. Escherichia coli and Salmonella typhimurium:cellular and molecular biology. Washington. DC: American Societyfor Microbiology. 1987: 1649-54.13. Webb GB. Tuberculosis. New York: Hoeber, 1936.14. Williams DL, Gillis TP. Portaels F. Geographically distinct isolates ofMycobacterium leprae exhibit no genotypic diversity by restrictionfragment-length polymorphism analysis. Mol Microbiol 1990;4:1653-9.atic benefits and suppression of parasite growth are associatedwith the use of oral aminosidine [I, 4-10].Various aminoglycoside antibiotics belonging to the catenu-lin group were marketed in the late 1950s and originally thoughtto be separate entities. The identity of those compounds wasclarified later. Oral formulations ofaminosidine (paromomycin)are available with different trade names, but the source of theraw material is the same. Therefore, although referred to byeither name in the various publications, paromomycin andaminosidine are synonymous.On the basis of encouraging preliminary results and of theavailability of comprehensive information on the tolerability oforal aminosidine for treating intestinal protozoan and helminthinfections, we set up a prospective, uncontrolled trial in humanimmunodeficiency virus-infected patients with chronic crypto-sporidial diarrhea.Forty-one AIDS patients met the eligibility criteria (chronicdiarrhea caused by Crvptosporidium parvum, three or morebowel movements per day, lasting for at least I month) andreceived aminosidine (Gabbroral; Farmitalia Carlo Erba, Milan)at 2000 mg for 4 weeks and at 1000 mg for the subsequent 4weeks. No concomitant antidiarrheal or antiviral therapies wereallowed. Mean age was 31.2 years; most patients were male (n =32) and intravenous drug users (n = 28). CD4 cell counts aver-aged 39.3/mm3 (range, 4-208) at baseline and remained un-changed during treatment.1350 Correspondence JlD 1994; 170 (November)At the start of aminosidine treatment, I I patients had con-comitant extraintestinal opportunistic infections, includingPneumocystis carinii pneumonia, atypical disseminated myco-bacteriosis, neurotoxoplasmosis, cerebral abscess, and bacterialpneumonia; 3 had a concomitant intestinal parasitic infection(en tarnebiasis, giardiasis, trichocephalosis) and 4 had gastrointes-tinal bacterial infections (i.e., due to Helicobacter pylori, Proteusspecies, Clostridium difficile. nontuberculous mycobacteria).Thirty-five patients were deemed evaluatable for efficacy, and22 (62.8%) completed the 8-week treatment course. The clinicaland parasitologic status improved dramatically in most patients(table I).With the initial dose, a complete response to therapy (parasi-tologic plus clinical) was achieved in 7 (20%) of the 35 patientsin 7-28 days. The result was confirmed by duodenal biopsy andremained consistently negative in 3 patients at 12 weeks of fol-low-up. Of the remaining 4 patients, 2 relapsed parasitologicallyand clinically after treatment discontinuation, and 2 recru-desced when the dosage was reduced to 1000 mg/day.An additional 15 patients (42.8%) had a partial response, 3patients died, and 10 (28.5%) did not respond to the aminosi-dine treatment (4 worsened, 6 showed inadequate response). Ofthe latter, 2 had extraintestinal C. parvum infection. In no casewas death or treatment interruption attributed to the use ofaminosidine.When the aminosidine dosage was reduced to 1000 rug/day,symptoms gradually reappeared or increased in 9 of the 15 par-tial responders and in 2 complete responders. Resumption ofthe original dosage (2000 mg/day) in recrudescent patients for28-42 days (mean, 31.6) restored the previous clinical statusand reduced the number of oocysts in the stools of 9 of the 17patients. In the case of treatment failure, the addition of symp-tomatic antidiarrheals (loperamide, octreotide) did not lead toany substantial improvement.Concomitant intestinal parasitic infections were also defini-tively cured.All responders had significantly better baseline conditionsthan those who did not respond to therapy: CD4 cell countsTable 1. Change from baseline in parasitologic and clinical pa-rameters in patients receiving aminosidine therapy.No. (%) of patients whoRemainedParameter Worsened constant ImprovedBowel movements* 6(17.2) 3 (8.6) 26 (74.2)Consistency of stool 6 (17.2) 6 (17.2) 23 (65.5)Volume of stools 6 (17.2) 5(14.2) 24(68.6)No. of oocysts" 3 (8.5) 8 (22.9) 24 (68.6)Body weight 8 (22.9) 9 (25.7) 18 (51.4)Abdominal pain 8 (22.9) 9(27.7) 18 (51.4)Nausea or vomiting 5 (14.2) 8 (22.9) 22 (62.9)* Ten patients had normal bowel movements after a mean of 5.3 days oftherapy (range. 3-18): 6 reported constipation (one movement every sec-ond or third day) after a mean of6.1 (5-16) days of treatment with 2 g/day.t Mean/TO microscopic fields X 1000 (modified Ziehl-Nielsen staining).Ten patients cleared oocysts after a mean of-l8.6 days of therapy; completeparasitologic cure was confirmed in 3 by duodenal biopsy at 12 weeks offollow-up.> 150/mm3, mean of four or fewer bowel movements/day, ~5oocysts/rnicroscopic field X 1000.Treatment was well tolerated: 6 patients reported transientconstipation on the higher dosage. No significant change wasobserved in the clinical laboratory parameters. -Like prior studies, the present trial has limitations due to theopen, uncontrolled nature of the trial and the relatively smallsize. However, the results indicate a role for aminosidine incryptosporidial diarrhea and are substantiated by a randomized,placebo-controlled study [8].Consistent with findings in other patients, administration ofaminosidine was associated in most patients with suppression ofparasite growth rather than killing, and the effect was dose-re-lated. Some patients with less advanced disease and lower para-site load were definitively cured, thus indicating the advantageof early diagnosis and intervention and suggesting a possiblepreventive role of aminosidine for cryptosporidiosis [3]. More-over, the broad spectrum of activity, encompassing protozoaand helminths, makes aminosidine a drug of potential interestfor wide coverage of noninvasive intestinal parasitic infectionsin immunocompromised patients.M. Scaglia, C. Atzori, G. Marchetti, M. Orso, R. Maserati,A. Orani, S. Novati, and P. Olliaro*Institute for Infectious Diseases. University-lRCcS S. Matteo. Pavia,Infectious Diseases Unit. Busto Arsizio, Infectious Diseases Unit. CaGranda Hospital. Milan. and Infectious Diseases Unit, Lecco, Italy* Present affiliation: United Nations Development Programme/WorldBank/World Health Organization Special Programme for Research andTraining in Tropical Diseases. Geneva.ReferencesI. Datry A. Rogeaux O. Caurnes E. et al. Effects ofaminosidine sulfate onCrvptosporidium in cell culture and in AIDS patients [abstract P175].In: Proceedings of the 3rd European Conference on HIV Infection,Paris. 1992.2. Marshall RJ. Flanigan TP. Paromomycin inhibits Cryptosporidium in-fection ofa human enterocyte cell line. J Infect Dis 1992; 165:772-4.3. Fayer R. Ellis W. Paromomycin is effective as prophylaxis for crypto-sporidiosis in dairy calves. J Parasitol 1993;79:771-4.4. Clezy K. Gold J. Blaze J. Jones P. Paromomycin for the treatment ofcryptosporidial diarrhoea in AIDS patients. AIDS 1991;5: 1146-7.5. Drake J. Olliaro P. Catterall L. et al. Efficacy and tolerability of oralaminosidine (Gabbroral) for the treatment of cryptosporidialdiarrhoea in patients with AIDS. AIDS 1992;6(suppl I ):P45. S27.6. Armitage K. Flanigan T. Carey J. et al. Treatment of cryptosporidiosiswith paromomycin. A report of five cases. Arch Intern Med1992: 152:2497-9.7. Fichtenbaum CJ. Ritchie DJ. Powderly GW. Use of paromomycin fortreatment of cryptosporidiosis in patients with AIDS. Clin Infect Dis1993; 16:298-300.8. Kanyok TP. Novak RM, Danziger LH. Preliminary results ofa random-ized. blinded. control study ofparomomycin vs. placebo for the treat-ment of Crvptosporidium diarrhea in AIDS patients [abstract PoBIO-1508]. In: Program and abstracts: IX International Conference onAIDS (Berlin). London: Wellcome Foundation. 1993.9. Wallace MR, Nguyen MT. Newton JA. Use of paromomycin for thetreatment of cryptosporidiosis in patients with AIDS. Clin Infect Dis1993; 17: 1070-1.10. Bissuel F. Corte L. Rabodonirina M, Rougier p. Piens MA, Trepo C.Paromomycin: an effective treatment for cryptosporidial diarrhea inpatients with AIDS. Clin Infect Dis 1994; 18:447-9.

Effectiveness Of Aminosidine (Paromomycin) Sulfate In Chronic Cryptosporidium Diarrhea In Aids Patients: An Open, Uncontrolled, Prospective Clinical Trial

Effectiveness Of Aminosidine (Paromomycin) Sulfate In Chronic Cryptosporidium Diarrhea In Aids Patients: An Open, Uncontrolled, Prospective Clinical Trial

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