DRUGS FOR DIFFICULT BUGS: AN OVERVIEW OF NEW ANTIBACTERIAL AND ANTIVIRAL AGENTS

1House of Lords Select Committee on Science and Technology. Resistance to antibiotics and other antimicrobial agents. London: The Stationery Office;1998.

2Standing Medical Advisory Committee. Sub-group on Antimicrobial Resistance. The path of least resistance. Department of Health; 1998.

3The Scottish Office and Department of Health. Resistance to antibiotics and other antimicrobial agents. NHS MEL39. The Scottish Office; 1999.

4 Gold HS Moellering RC Jr. Antimicrobial-drug resistance. N Engl J Med 1996; 335:1445-53.

5 Livermore DM. ß-lactamases in laboratory and clinical resistance. Clin Micro Rev 1995; 8:557-84.

6 Hawkey PM. The origins and molecular basis of antibiotic resistance. BMJ 1998; 317:657-60.

7 Linden PK AW Pasculle Manez R Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium. Clin Infect Dis 1996; 22:663-70.

8 Soriano A JA Martinez Mensa J Pathogenic significance of methicillin resistance for patients with Staphylococcus aureus bacteremia. Clin Infect Dis 2000; 30:368-73.

9 Pallares R J Linares Vadillo M Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain [published erratum appears in N Engl J Med 1995; 333(24):1655]. N Engl J Med 1995; 333:474-80.

10 Fluit AC ME Jones Schmitz FJ Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Europe from the SENTRY antimicrobial surveillance program, 1997 and 1998. Clin Infect Dis 2000; 30:454-60.

11Felmingham D,Gruneberg RN. The Alexander Project 1996/7: latest susceptibility data from this international study of bacterial pathogens from community-acquired lower respiratory tract infections. J Antimicrob Chemother 2000; 45:191-203.

12 Jacobs M PC Appelbaum Felmingham D The Alexander Project 1998/9: Penicillin resistance in S. pneumoniae. 3rd European Congress of Chemotherapy, Madrid, Spain, 7–10 May, 2000. Abstract T185.

13 Johnson AP DC Speller George RC Prevalence of antibiotic resistance and serotypes in pneumococci in England and Wales: results of observational surveys in 1990 and 1995. BMJ 1996; 312:1454-6.

14 Hughes G N Andrews Catchpole M Investigation of the increased incidence of gonorrhoea diagnosed in genitourinary medicine clinics in England, 1994–6 [published erratum appears in Sex Transm Infect 2000; 76(2):148]. Sex Transm Infect 2000; 76:18-24.

15Scottish Centre for Infection and Environmental Health. Reports of gonorrhoea in Scotland continue to increase in 2000. SCIEH Wkly Rep 2000; 34:193.

16 Kaczmarski EB. Meningococcal disease in England and Wales: 1995. Commun Dis Rep CDR Rev 1997; 7:R55-59.

17 Felmingham D MJ Robbins Tesfaslasie Y Antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens isolated in the UK during the 1995-1996 cold season. J Antimicrob Chemother 1998; 41:411-5.

18 Mirza SH NJ Beeching Hart CA. Multi-drug resistant typhoid: a global problem. J Med Microbiol 1996; 44:317-9.

19 Threlfall EJ. Epidemic Salmonella typhimurium DT 104 – a truly international multiresistant clone. J Antimicrob Chemother 2000; 46:7-10.

20 Molbak K DL Baggesen Aarestrup FM An outbreak of multidrug-resistant, quinolone-resistant Salmonella enterica serotype typhimurium DT104. N Engl J Med 1999; 341:1420-5.

21 Thwaites RT Drug resistance in Campylobacter jejuni Frost JA. coli C. lari isolated from humans in north west England and Wales and C. , 1997. J Clin Pathol 1999; 52:812-4.

22Public Health Laboratory Service and Nosocomial Infection National Surveillance Scheme. Surveillance of hospital-acquired bacteraemia. London: Central Public Health Laboratory; 2000.

23 Reacher MH A Shah Livermore DM Bacteraemia and antibiotic resistance of its pathogens reported in England and Wales between 1990 and 1998: trend analysis. BMJ 2000; 320:213-6.

24 Hiramatsu K H Hanaki Ino T Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997; 40:135-6.

25 Smith TL ML Pearson Wilcox KR Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group. N Engl J Med 1999; 340:493-501.

26 Johnson AP. Intermediate vancomycin resistance in Staphylococcus aureus: a major threat or a minor inconvenience? J Antimicrob Chemother 1998; 42:289-91.

27 Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med 2000; 342:710-21.

28 Hobson RP FM MacKenzie Gould IM. An outbreak of multiply resistant Klebsiella pneumoniae in Grampian region of Scotland. J Hosp Infect 1996; 33:249-62.

29 MacKenzie FM KJ Forbes Dorai-John T Emergence of a carbapenem-resistant Klebsiella pneumoniae. Lancet 1997; 350:783.

30 Koh TH GS Babini Woodford N Carbapenemhydrolysing IMP-1 beta-lactamase in Klebsiella pneumoniae from Singapore. Lancet 1999; 353:2162.

31 Henwood C D Livermore James D Antimicrobial susceptibility of Pseudomonas aeruginosa – results of a UK study. 3rd European Congress of Chemotherapy, Madrid, Spain, 7–10 May, 2000. Abstract T117.

32 Senda K Y Arakawa Ichiyama S PCR detection of metallo-beta-lactamase gene (blaIMP) in gram-negative rods resistant to broad-spectrum beta-lactams. J Clin Microbiol 1996; 34:2909-13.

33 Woodford N MF Palepou Babini GS Carbapenemaseproducing Pseudomonas aeruginosa in UK. Lancet 1998; 352:546-8.

34 Pablos-Mendez A MC Raviglione Laszlo A Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization – International Union against Tuberculosis and Lung Disease Working Group on Anti- Tuberculosis Drug Resistance Surveillance [published erratum appears in N Engl J Med 1998; 339(2):139]. N Engl J Med 1998; 338:1641-9.

35Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons – Florida and New York, 1988–1991. MMWR Morb Mortal Wkly Rep 1991; 40:585-91.

36 Irish C J Herbert Bennett D Database study of antibiotic resistant tuberculosis in the United Kingdom, 1994–6. BMJ 1999; 318:497-8.

37 Goble M MD Iseman Madsen LA Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328:527-32.

38 Cocito C M Di Giambattista Nyssen E Inhibition of protein synthesis by streptogramins and related antibiotics. J Antimicrob Chemother 1997; 39(Suppl A):7-13.

39 Johnson AP M Warner Hallas G Susceptibility to quinupristin/dalfopristin and other antibiotics of vancomycin-resistant enterococci from the UK, 1997 to mid-1999. J Antimicrob Chemother 2000; 46:125-8.

40 Schmitz FJ J Verhoef Fluit AC. Prevalence of resistance to MLS antibiotics in 20 European university hospitals participating in the European SENTRY surveillance programme. SENTRY Participants Group. J Antimicrob Chemother 1999; 43:783-92.

41 Allignet J Diversity among the gram-positive acetyltransferases inactivating streptogramin A and structurally related compounds and characterization of a new staphylococcal determinant El Solh N. , vatB. Antimicrob Agents Chemother 1995; 39:2027-36.

42 Nichols RL DR Graham Barriere SL Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. Synercid Skin and Skin Structure Infection Group [published erratum appears in J Antimicrob Chemother 1999 44(4):585]. J Antimicrob Chemother 1999; 44:263-73.

43 Fagon J H Patrick Haas DW Treatment of gram-positive nosocomial pneumonia. Prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Nosocomial Pneumonia Group. Am J Respir Crit Care Med 2000; 161:753-62.

44 Moellering RC PK Linden Reinhardt J The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group. J Antimicrob Chemother 1999; 44:251-61.

45 Rubinstein E P Prokocimer Safety Talbot GH. of tolerability quinupristin/dalfopristin: administration guidelines. J Antimicrob Chemother 1999; 44(Suppl A):37-46.

46 Swaney SM H Aoki Ganoza MC The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 1998; 42:3251-5.

47 Johnson AP M Warner Livermore DM. Activity of linezolid against multi-resistant gram-positive bacteria from diverse hospitals in the United Kingdom. J Antimicrob Chemother 2000; 45:225-30.

48 Noskin GA F Siddiqui Stosor V In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci. Antimicrob Agents Chemother 1999; 43:2059-62.

49 Birmingham MC GS Zimmer Hafkin B Outcomes with Linezolid (LZD) from an ongoing compassionate use (CU) trial of patients with significant, resistant, grampositive infections. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 26–29 September, 1999. Abstract 1098.

50 Molinari M G Garrera Soler M Linezolid eradication rates for Staphylococcus aureus in patients with noscomial pneumonia. 3rd European Congress of Chemotherapy, Madrid, Spain, 7–10 May, 2000. Abstract M261.

51 Molinari M R Mangano Balda B Comparison of linezolid and oxacillin/dicloxacillin in the treatment of complicated skin infections: a subgroup analysis of European patients in a multinational phase III trial. 3rd European Congress of Chemotherapy, Madrid, Spain, 7–10 May, 2000. Abstract M291.

52 Chien JW ML Kucia Use of linezolid Salata RA. oxazolidinone an , in the treatment of multidrug-resistant gram-positive bacterial infections. Clin Infect Dis 2000; 30:146-51.

53 Blondeau JM. A review of the comparative in vitro activities of 12 antimicrobial agents, with a focus on five new ‘respiratory quinolones’. J Antimicrob Chemother 1999; 43 (Suppl B):1-11.

54 King A J May French G Comparative in vitro activity of gemifloxacin. J Antimicrob Chemother 2000; 45 (Suppl S1):1-12.

55 Pan XS gyrase Fisher LM. DNA are topoisomerase IV dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob Agents Chemother 1998; 42:2810-6.

56 Trigo-daporta M MA Alonso-Manzanares Yague-Guirao G In vitro activity of the older and newer fluoroquinolones against Streptococcus pneumoniae. Incidence of mutations in DNA gyrase and topoisomerase IV. 3rd European Congress of Chemotherapy, Madrid, Spain, 7–10 May, 2000. Abstract M146.

57 Milatovic D FJ Schmitz Brisse S In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8,796 clinical bacterial isolates. Antimicrob Agents Chemother 2000; 44:1102-7.

58 Dowell ME H Mayer Anderson A A randomized, double-blind, multicenter comparative study of gatifloxacin (GAT) 400 mg IV and PO versus ceftriaxone +/- erythromycin (CTX+/-ERY) in treatment of community-acquired pneumonia (CAP) requiring hospitalization. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 26–29 September, 1999. Abstract 2241.

59 Fogarty C C Grossman Williams J Efficacy and safety of moxifloxacin vs clarithromycin for community-acquired pneumonia. Infect Med 1999; 16:748-63.

60 Tremolieres F F de Kock Pluck N Trovafloxacin versus high-dose amoxicillin (1 g three times daily) in the treatment of community-acquired bacterial pneumonia. Eur J Clin Microbiol Infect Dis 1998; 17:447-53.

61 Wilson R R Kubin Ballin I Five day moxifloxacin therapy compared with seven day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1999; 44:501-13.

62 Leophonte P RJ Baldwin Pluck N. Trovafloxacin versus amoxicillin/clavulanic acid in the treatment of acute exacerbations of chronic obstructive bronchitis. Eur J Clin Microbiol Infect Dis 1998; 17:434-40.

63 von Keutz E Preclinical safety evaluation of moxifloxacin Schluter G. , a novel fluoroquinolone. J Antimicrob Chemother 1999; 43(Suppl B):91-100.

64 Henkel TJ D McKay Young C. Safety of gemifloxacin in adult patients with respiratory and urinary tract infections. 3rd European Congress of Chemotherapy, Madrid, Spain, 7–10 May, 2000. Abstract M130.

65 Welling LE CL Burke Tack KJ. Safety profile of clinafloxacin (CLX), a new fluoroquinolone antibiotic. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 26–29 September, 1999. Abstract 1764.

66 Pechere JC W Wilson Neu H. Laboratory assessment of antibacterial activity of zwitterionic 7-methoxyimino cephalosporins. J Antimicrob Chemother 1995; 36:757-71.

67 Wolff M. Comparison of strategies using cefpirome and ceftazidime for empiric treatment of pneumonia in intensive care patients. The Cefpirome Pneumonia Study Group. Antimicrob Agents Chemother 1998; 42:28-36.

68 Bonfitto P V Lamorgese De Vietro T A randomized trial of cefepime and ceftazidime for the treatment of community-acquired pneumonia. J Chemother 1999; 11:273-7.

69 Norrby SR AM Geddes Shah PM. Randomized comparative trial of cefpirome versus ceftazidime in the empirical treatment of suspected bacteraemia or sepsis. Multicentre Study Group. J Antimicrob Chemother 1998; 42:503-9.

70 Yamamura D R Gucalp Carlisle P Open randomized study of cefepime versus piperacillin-gentamicin for treatment of febrile neutropenic cancer patients. Antimicrob Agents Chemother 1997; 41:1704-8.

71 Barie PS SB Vogel Dellinger EP A randomized, double-blind clinical trial comparing cefepime plus metronidazole with imipenem-cilastatin in the treatment of complicated intra-abdominal infections. Cefepime Intra-abdominal Infection Study Group. Arch Surg 1997; 132:1294-302.

72 Livermore DM AP Johnson Warner M. Activity of cephalosporin RJW-54428 (MC-02,479) vs. multiresistant gram-positive cocci from England and Wales. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 26–29 September, 1999. Abstract 395.

73 Edwards JR Betts MJ. Carbapenems: the pinnacle of the ß-lactam antibiotics or room for improvement? J Antimicrob Chemother 2000; 45:1-4.

74 Jaccard C N Troillet Harbarth S Prospective randomized comparison of imipenem-cilastatin and piperacillin-tazobactam in nosocomial pneumonia or peritonitis [published erratum appears in Antimicrob Agents Chemother 1999; 43(3):726]. Antimicrob Agents Chemother 1998; 42:2966-72.

75 Brun-Buisson C JP Sollet Schweich H Treatment of ventilator-associated pneumonia with piperacillintazobactam/amikacin versus ceftazidime/amikacin: a multicenter, randomized controlled trial. VAP Study Group. Clin Infect Dis 1998; 26:346-54.

76 Cometta A S Zinner De Bock R Piperacillintazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Antimicrob Agents Chemother 1995; 39:445-52.

77 Kennedy N. New drugs for old: the continuing challenge of tuberculosis. CPD Infect 2000; 2:6-12.

78 Yang B H Koga Ohno H Relationship between antimycobacterial activities of rifampicin, rifabutin and KRM-1648 and rpoB mutations of Mycobacterium tuberculosis. J Antimicrob Chemother 1998; 42:621-8.

79 McGregor MM P Olliaro Wolmarans L Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med 1996; 154:1462-7.

80Hong Kong Chest Service/British Medical Research Council. A controlled study of rifabutin and an uncontrolled study of ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin and rifampicin. Tuberc Lung Dis 1992; 73:59-67.

81 Vernon A W Burman Benator D Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet 1999; 353:1843-7.

82 Kohno S H Koga Kaku M Prospective comparative study of ofloxacin or ethambutol for the treatment of pulmonary tuberculosis. Chest 1992; 102:1815-8.

83 Kennedy N L Berger Curram J Randomized controlled trial of a drug regimen which includes ciprofloxacin in the treatment of tuberculosis. Clin Infect Dis 1996; 22:827-33.

84 Lalande V C Truffot-Pernot Paccaly-Moulin A Powerful bactericidal activity of sparfloxacin (AT-4140) against Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother 1993; 37:407-13.

85 Miyazaki E M Miyazaki Chen JM Moxifloxacin (BAY12-8039), a new 8-methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob Agents Chemother 1999; 43:85-9.

86 Cynamon MH SP Klemens Sharpe CA Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother 1999; 43:1189-91.

87 Bryskier A. New research into macrolides and ketolides since 1997. Exp Opin Invest Drugs 1999; 8:1171-94.

88 Capobianco JO Z Cao Shortridge VD Studies of the novel ketolide ABT-773: transport, binding to ribosomes, and inhibition of protein synthesis in Streptococcus pneumoniae. Antimicrob Agents Chemother 2000; 44:1562-7.

89 Denis A C Agouridas Auger JM Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg Med Chem Lett 1999; 9:3075-80.

90 Jones RN SA Marshall Erwin ME. Antimicrobial activity and spectrum of SCH27899 (Ziracin) tested against grampositive species including recommendations for routine susceptibility testing methods and quality control. Quality Control Study Group. Diagn Microbiol Infect Dis 1999; 34:103-10.

91 Rybak MJ E Hershberger , MoldoVan T In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin-intermediate and -resistant strains. Antimicrob Agents Chemother 2000; 44:1062-6.

92 Fleming DM. The contribution of influenza to combined acute respiratory infections, hospital admissions, and deaths in winter. Commun Dis Public Health 2000; 3:32-8.

93 Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995; 267:483-9.

94 Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995; 333:450-1.

95British HIV Association (BHIVA). Guidelines for the treatment of HIV-infected adults with antiretroviral therapy. December 1999. Available from: URL: http://www.aidsmap.com/bhiva/bhivagd1299.htm

96Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available from: URL: http://www.hivatis.org/guidelines/adult/text/

97 Cabana M B Clotet Emergence Martinez MA. evolution genetic of HIV-1 variants with mutations conferring resistance to multiple reverse transcriptase and protease inhibitors. J Med Virol 1999; 59:480-90.

98 Hertogs K S Bloor Kemp SD Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6,000 sample. AIDS 2000; 14:1203-10.

99 Wong DK AM Cheung O’Rourke K Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993; 119:312-23.

100 Niederau C T Heintges Lange S Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996; 334:1422-7.

101Ince N,Wands JR. The increasing incidence of hepatocellular carcinoma. N Engl J Med 1999; 340:798-9.

102 Carithers RL Emerson SS. Therapy of hepatitis C: metaanalysis of interferon alfa-2b trials. Hepatology 1997; 26:83S-8S.

103Fife KH, Crumpacker CS, Mertz GJ Recurrence and resistance patterns of herpes simplex virus following cessation of > or = 6 years of chronic suppression with acyclovir. Acyclovir Study Group. J Infect Dis 1994; 169:1338-41.

104 Hill EL GA Hunter Ellis MN. In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1991; 35:2322-8.

105 Erice A. Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev 1999; 12:286-97.

106El Sahly HM, Atmar RL, Glezen WP Spectrum of clinical illness in hospitalized patients with ‘Common Cold’ virus infections. Clin Infect Dis 2000; 31:96-100.

107 Makela MJ K Pauksens Rostila T Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study. J Infect 2000; 40:42-8.

108 Treanor JJ FG Hayden Vrooman PS Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000; 283:1016-24.

109 Hayden FG RL Atmar Schilling M Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999; 341:1336-43.

110 Monto AS DP Robinson Herlocher ML Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282:31-5.

111 Tyring S RA Barbarash Nahlik JE Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med 1995; 123:89-96.

112 Beutner KR DJ Friedman Forszpaniiak C Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39:1546-53.

113 Diaz-Mitoma F RG Sibbald Shafran SD Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. JAMA 1998; 280:887-92.

114 Fife KH RA Barbarash Rudolph T Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, doubleblind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 1997; 24:481-6.

115 Pelosi E GB Mulamba Penciclovir Coen DM. phenotypes pathogenesis of drug-resistant Herpes simplex virus mutants. Antiviral Res 1998; 37:17-28.

116Studies of Ocular complications of AIDS Research Group, AIDS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Ann Intern Med 1997; 126:264-74.

117 Perry CM Balfour JA. Fomivirsen. Drugs 1999; 57:375-80.

118 Musch DC DF Martin Gordon JF Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Implant Study Group. N Engl J Med 1997; 337:83-90.

119 Brosgart CL TA Louis Hillman DW A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. Terry Beirn Community Programs for Clinical Research on AIDS. AIDS 1998; 12:269-77.

120 Drew WL D Ives Lalezari JP Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. Syntex Cooperative Oral Ganciclovir Study Group. N Engl J Med 1995; 333:615-20.

121 Gane E F Saliba Valdecasas GJ Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group [published erratum appears in the Lancet 1998; 351(9100):454]. Lancet 1997; 350:1729-33.

122 Limaye AP L Corey Koelle DM Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000; 356:645-9.

123Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348:283-91.

124 Hammer SM DA Katzenstein Hughes MD A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. N Engl J Med 1996; 335:1081-90.

125 Markowitz M M Saag Powderly WG A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995; 333:1534-9.

126 Hammer SM KE Squires Hughes MD A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725-33.

127 Cameron DW M Heath-Chiozzi Danner S Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998; 351:543-9.

128 Moyle G A Pozniak Opravil M The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues. Study of Protease Inhibitor Combinations in Europe. J Acquir Immune Defic Syndr 2000; 23:128-37.

129 Staszewski S J Morales-Ramirez Tashima KT Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999; 341:1865-73.

130 Squires K. The Atlantic Study: a randomized, openlabel trial comparing two protease inhibitor (pi)-sparing anti-retroviral strategies versus a standard pi-containing regimen, final 48 week data. XIII International AIDS Conference, Durban, South Africa, July 9–14, 2000. Abstract LbPeB7046.

131Palella FJ Jr, Delaney KM, Moorman AC Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853-60.

132 Egger M B Hirschel Francioli P Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective muticentre study. BMJ 1997; 315:1194-9.

133 Raboud JM JS Montaner Conway B Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy. AIDS 1998; 12:1619-24.

134 Perelson AS P Essunger Cao Y Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387:188-91.

135 Furtado MR DS Callaway Phair JP Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999; 340:1614-22.

136 Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis 2000; 30(Suppl 2):S135-S142.

137 Paterson DL S Swindells Mohr J Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133:21-30.

138 Baxter JD DL Mayers Wentworth DN A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS 2000; 14:F83-F93.

139 Durant J P Clevenbergh Halfon P Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial [published erratum appears in the Lancet 1999; 354(9184):1128]. Lancet 1999; 353:2195-9.

140 Garraffo R J Durant Clevenbergh P Independent benefit of sufficient drug levels and genotypic analysis in salvage therapy: pharmacological data of the Viradapt study. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 26–29 September, 1999. Abstract 1166.

141 Kilby JM S Hopkins Venetta TM Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998; 4:1302-7.

142 Staszewski S P Keiser Montaner J Abacavirlamivudine- zidovudine vs. indinavir-lamivudinezidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial. JAMA 2001; 285:1155-63.

143Davey RT Jr., Murphy RL, Graziano FM Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial. JAMA 2000; 284:183-9.

144 Birx DL LD Loomis-Price Aronson N Efficacy testing of recombinant human immunodeficiency virus (HIV) gp160 as a therapeutic vaccine in early-stage HIV-1-infected volunteers. rgp160 Phase II Vaccine Investigators. J Infect Dis 2000; 181:881-9.

145 Dienstag JL ER Schiff Wright TL Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999; 341:1256-63.

146 Lai CL RN Chien Nancy WY A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998; 339:61-8.

147 Poynard T P Marcellin Lee SS Randomised trial of interferon a2b plus ribavirin for 48 weeks or 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C. Lancet 1998; 352:1426-32.

148 McHutchison JG SC Gordon Schiff ER Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339:1485-92.

149EASL Consensus Panel. EASL international consensus conference on hepatitis C: Consensus statement. J Hepatol 1999; 30:956-61.

150Scottish Needs Assessment Programme. Hepatitis C. Glasgow: Office for Public Health in Scotland, 2000.

151National Institute for Clinical Excellence. Guidance on the use of ribavirin and interferon alpha for hepatits C. Technology Appraisal Guidance No. 14. London: October, 2000.

152 Heathcote J ML Shiffman Cooksley G Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343:1673-80.

153 Zeuzem S SV Feinman Rasenack J Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343:1666-72.

154 Trepo C. Phase III results of pegylated interferon alpha-2b. Program and abstracts of the 35th Meeting of the European Association for the Study of the Liver, Rotterdam, The Netherlands, April 30–May 3, 2000.

155 Manns MP JG McHutchison Gordon SG Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multi-center, multinational phase III randomized controlled trial [abstract]. Hepatology 2000;32:297A.

156 Brillanti S F Levantesi Masi L Triple antiviral therapy as a new option for patients with interferon nonresponsive chronic hepatitis C. Hepatology 2000; 32:630-4.

157 McHutchison JG G Giannelli Nyberg L A pilot study of daily subcutaneous interleukin-10 in patients with chronic hepatitis C infection. J Interferon Cytokine Res 1999; 19:1265-70.

158 Zhang H R Hanecak Brown-Driver V Antisense oligonucleotide inhibition of hepatitis C virus (HCV) gene expression in livers of mice infected with an HCVvaccinia virus recombinant. Antimicrob Agents Chemother 1999; 43:347-53.

159 Bartenschlager R. The NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy. J Viral Hepat 1999; 6:165-81.

160 Rotbart HA. Pleconaril treatment of enterovirus and rhinovirus infections. Infect Med 2000; 17:488-94.

161 Schiff GM Sherwood JR. Clinical activity of pleconaril in an experimentally induced coxsackievirus A21 respiratory infection. J Infect Dis 2000; 181:20-6.

162 Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992; 257:1050-5.