Archive for September 22, 2008

Community Infections Caused by Extended-Spectrum β-Lactamase–Producing Escherichia coli

Archives of Internal Medicine  Sept 22, 2008  V.168  N.17  p.1897-1902

Jesús Rodríguez-Baño, MD, PhD; Juan C. Alcalá, MD; Jose M. Cisneros, MD, PhD; Fabio Grill, MD; Antonio Oliver, PhD; Juan P. Horcajada, MD, PhD; Teresa Tórtola, MD; Beatriz Mirelis, MD, PhD; Gemma Navarro, MD; María Cuenca, MD; María Esteve, MD; Carmen Peña, MD; Ana C. Llanos, MD; Rafael Cantón, PhD; Alvaro Pascual, MD, PhD

Sección de Enfermedades Infecciosas (Dr Rodríguez-Baño) and Servicio de Microbiología (Drs Alcalá and Pascual), Hospital Universitario Virgen Macarena, Seville, Spain; Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocío, Seville (Drs Cisneros and Llanos); Servicios de Enfermedades Infecciosas (Dr Grill) and Microbiología (Dr Cantón), Hospital Universitario Ramón y Cajal, Madrid, Spain; Servicio de Microbiología, Hospital Son Dureta, Palma de Majorca, Spain (Dr Oliver); Servicio de Enfermedades Infecciosas, Hospital Clinic, Barcelona, Spain (Dr Horcajada); Servicio de Microbiología, Hospital Vall d’Hebrón, Barcelona (Dr Tórtola); Servicio de Microbiología, Hospital Santa Creu i San Pau, Barcelona (Dr Mirelis); Unidad de Epidemiología, Corporación Sanitaria Parc Taulí, Sabadell, Spain (Dr Navarro); Servicio de Microbiología, Hospital de la Ribera, Alcira (Valencia), Spain (Dr Cuenca); Unidad de Medicina Preventiva, Hospital Universitario Germans Trias i Pujol, Badalona, Spain (Dr Esteve); and Servicio de Enfermedades Infecciosas, Hospital Universitario de Bellvitge, Barcelona (Dr Peña). Dr Horcajada is now with the Sección de Enfermedades Infecciosas, Hospital del Mar, Barcelona.

Background  Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is an increasingly important group of community pathogens worldwide. These organisms are frequently resistant to many of the antimicrobial agents usually recommended for the treatment of infections caused by E coli, such as penicillins, cephalosporins, fluoroquinolones, and trimethoprim-sulfamethoxazole. Data concerning risk factors, clinical features, and therapeutic options for such infections are scarce.

Methods  A case-control study was performed to investigate the risk factors for all types of community-acquired infections caused by ESBL-producing E coli in 11 Spanish hospitals from February 2002 to May 2003. Controls were randomly chosen from among outpatients with a clinical sample not yielding ESBL-producing E coli. The clinical features of these infections were investigated in the case patients. The efficacy of fosfomycin tromethamine and amoxicillin-clavulanate potassium was observationally studied in patients with cystitis.

Results  A total of 122 cases were included. Risk factors selected by multivariate analysis included the following: age older than 60 years; female sex; diabetes mellitus; recurrent urinary tract infections (UTIs); previous invasive procedures of the urinary tract; follow-up in outpatient clinic; and previous receipt of aminopenicillins, cephalosporins, and fluoroquinolones. Urinary tract infections accounted for 93% of the cases; 6% of the patients were bacteremic and 10% needed hospitalization. The cure rate of patients with cystitis was 93% with fosfomycin therapy (all isolates were susceptible); among patients treated with amoxicillin-clavulanate, cure rates were 93% for those with susceptible isolates (minimum inhibitory concentration ≤8 µg/mL) and 56% for those with intermediate or resistant isolates (minimum inhibitory concentration ≥16 µg/mL) (P = .02).

Conclusions  In predisposed patients, ESBL-producing E coli is a notable cause of community-acquired infection, and particularly UTI. Fosfomycin and amoxicillin-clavulanate appear to be effective for cystitis caused by susceptible isolates.


September 22, 2008 at 11:43 pm Leave a comment

Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection: 2008 Recommendations of an International AIDS Society–USA Panel

Clinical Infectious Diseases  15 July 2008  V.47  N.2  p.266-285


Martin S. Hirsch,1 Huldrych F. Günthard,9 Jonathan M. Schapiro,10 Françoise Brun-Vézinet,11 Bonaventura Clotet,12 Scott M. Hammer,2 Victoria A. Johnson,3,4 Daniel R. Kuritzkes,1 John W. Mellors,5 Deenan Pillay,13 Patrick G. Yeni,11 Donna M. Jacobsen,6 and Douglas D. Richman7,8

1Harvard Medical School, Boston, Massachusetts; 2Columbia University College of Physicians and Surgeons, New York, New York; 3Birmingham Veterans Affairs Medical Center and the 4University of Alabama at Birmingham School of Medicine, Birmingham, Alabama; 5University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 6International AIDS Society–USA, San Francisco, and 7University of California–San Diego and 8Veterans Affairs San Diego Healthcare System, San Diego, California; 9University Hospital of Zürich, Zürich, Switzerland; 10Sheba Medical Center, Tel Aviv, Israel; 11Hôpital Bichat-Claude Bernard, Paris, France; 12Hospital Universitari Germans Trias i Pujol, irsi Caixa Foundation, Barcelona, Catalonia, Spain; and 13Royal Free and University College Medical School, London, United Kingdom

Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society–USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non–subtype B strains of HIV will become increasingly important.



September 22, 2008 at 5:38 pm Leave a comment

Update of the Drug Resistance Mutations in HIV-1

Topics in HIV Medicine  March/Apr 2008  V.16  N.1

International AIDS Society – USA

Victoria A. Johnson, MD, Françoise Brun-Vézinet, MD, PhD, Bonaventura Clotet, MD, PhD, Huldrych F. Günthard, MD, Daniel R. Kuritzkes, MD, Deenan Pillay, MD, PhD, Jonathan M. Schapiro, MD, and Douglas D. Richman, MD


Revisión en español
Websites about HIV Drug Resistance Mutations Resource List

September 22, 2008 at 5:37 pm Leave a comment

Comparison of a Rule-Based Algorithm with a Phenotype-Based Algorithm for the Interpretation of HIV Genotypes in Guiding Salvage Regimens in HIV-Infected Patients by a Randomized Clinical Trial: The Mutations and Salvage Study

Clinical Infectious Diseases  15 May 2006  V.42  N.10  p.1470-1480

Nicola Gianotti,1 Vincenzo Mondino,4 Maria Cristina Rossi,5 Elisabetta Chiesa,2 Ivano Mezzaroma,6 Nicoletta Ladisa,8 Giovanni Guaraldi,9 Carlo Torti,10 Pierluigi Tarquini,11 Paula Castelli,12 Aldo Di Carlo,7 Enzo Boeri,3 Wilco Keulen,13 Paula Mc Kenna,14 and Adriano Lazzarin,1 on behalf of the Mutations and Salvage (MuSa) Study Groupa

1Clinica di Malattie Infettive, Università Vita-Salute San Raffaele, 2Clinica di Malattie Infettive, Ospedale “Luigi Sacco,” and 3Diagnostica & Ricerca San Raffaele, Milan, 4Divisione di Malattie Infettive, Ospedali Riuniti di Pallanza, Verbania, 5Divisione di Malattie Infettive, Ospedale Ca’ Foncello, Treviso, 6Dipartimento di Medicina Clinica, Università di Roma “La Sapienza,” and 7Unità Operativa AIDS Rome 71, Istituto di Ricovero e Cura a Carattere Scientifico Dermosifilopatico S. Maria e S. Gallicano, Roma, 8Clinica di Malattie Infettive, Policlinico di Bari, 9Clinica di Malattie Infettive e Tropicali Università di Modena e Reggio Emilia, 10Clinica di Malattie Infettive e Tropicali, Spedali Civili di Brescia, 11Unità Operativa Malattie Infettive, Ospedale G. Mazzini, Teramo, and 12Reparto di Malattie Infettive, Ospedale di Macerata, Italy; 13Virology Education, Utrecht, The Netherlands; and 14Virco, Mechelen, Belgium

Background.  There is still considerable uncertainty as to the best algorithm for interpreting human immunodeficiency virus (HIV) genotyping results.

Methods.  A total of 318 subjects with HIV RNA levels of >1000 copies/mL were enrolled in 41 centers throughout Italy from 2001 through 2003, stratified on the basis of their drug history, randomized (1:1) to 2 arms to have their treatments modified on the basis of the results of HIV genotyping (as interpreted by virtual phenotype analysis or with use of a rule-based interpretation system), and followed up for 48 weeks. At least 1 nucleoside reverse-transcriptase inhibitor and 1 protease inhibitor had to be included in any new regimen; nonnucleoside reverse-transcriptase inhibitor–naive patients were also prescribed a nonnucleoside reverse-transcriptase inhibitor. Only drugs licensed in Italy were allowed. The primary end point was a decrease in HIV RNA level to <400 copies/mL by week 12 according to on-treatment analysis.

Results.  The mean (± standard deviation) values at baseline were as follows: HIV RNA level,  log10 copies/mL; CD4+ T lymphocyte count,  cells/μL; reverse-transcriptase mutations,  ; and protease mutations,  . There were 133 patients (41.8%) who were nonnucleoside reverse-transcriptase inhibitor naive and protease inhibitor experienced, 63 patients (19.8%) who were nonnucleoside reverse-transcriptase inhibitor experienced and protease inhibitor naive, and 122 patients (38.4%) who were 3-class experienced. A total of 192 patients completed 12 weeks of the treatment regimen assigned at baseline; at 12 weeks, 66.3% of patients in the virtual phenotype arm and 71.3% of patients in the rule-based interpretation arm had HIV RNA levels of <400 copies/mL ( ). No statistically significant difference between arms was observed by intention-to-treat analysis.

Conclusion.  Both the virtual phenotype and rule-based interpretation methods of HIV genotyping can guide the selection of effective antiretroviral drugs for a salvage regimen.



September 22, 2008 at 11:33 am Leave a comment

A Randomized Controlled Trial to Evaluate Antiretroviral Salvage Therapy Guided by Rules-Based or Phenotype-Driven HIV-1 Genotypic Drug-Resistance Interpretation With or Without Concentration-Controlled Intervention: The Resistance and Dosage Adapted Regimens (RADAR) Study

Clinical Infectious Diseases  15 Jun 2005  V.40  N.12  p.1828-1836

Carlo Torti,1 Eugenia Quiros-Roldan,1 Mario Regazzi,3 Andrea De Luca,5 Francesco Mazzotta,7 Andrea Antinori,6 Nicoletta Ladisa,8 Valeria Micheli,9 Anna Orani,10 Andrea Patroni,1,4 Paola Villani,3 Sergio Lo Caputo,7 Francesca Moretti,1 Simona Di Giambenedetto,5 Filippo Castelnuovo,2 Paolo Maggi,8 Carmine Tinelli,4 Giampiero Carosi,1 and the RADAR-MASTER Study Groupa

Background.  It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy.

Methods.  In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study.

Results.  Among 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response.

Conclusions.  The present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations.



September 22, 2008 at 11:28 am Leave a comment

Prevalence of Antiretroviral Drug Resistance Mutations in Chronically HIV–Infected, Treatment-Naive Patients: Implications for Routine Resistance Screening before Initiation of Antiretroviral Therapy

Clinical Infectious Diseases  1 Feb 2005  V.40  N.3  p.468-474

Richard M. Novak,1 Li Chen,2 Rodger D. MacArthur,3 John D. Baxter,4 Kathy Huppler Hullsiek,2 Grace Peng,2 Ying Xiang,2 Christopher Henely,5 Barry Schmetter,6 Jonathan Uy,1 Mary van den Berg-Wolf,7 Michael Kozal,8 and the Terry Beirn Community Programs for Clinical Research on AIDS 058 Study Team

1University of Illinois, Chicago; 2University of Minnesota, Minneapolis; 3Wayne State University, Detroit, Michigan; 4University of Medicine and Dentistry of New Jersey, Camden, and 5Southern New Jersey AIDS Clinical Trials, Belmar, New Jersey; 6Social and Scientific Systems, Silver Springs, Maryland; 7Temple University, Philadelphia, Pennsylvania; and 8Yale University, New Haven, Connecticut

Background.  The prevalence of drug resistance among persons with newly acquired human immunodeficiency virus (HIV) infection is well documented. However, it is unclear to what extent these mutations persist in chronically infected, treatment-naive patients.

Methods.  Prevalence of and factors associated with genotypic drug resistance were analyzed retrospectively in a subset of 491 chronically HIV-infected, antiretroviral-naive patients enrolled at 25 cities in the Terry Beirn Community Programs for Clinical Research on Acquired Immune Deficiency Syndrome (AIDS) Flexible Initial Retrovirus Suppressive Therapies trial during 1999–2001. Resistance was defined on the basis of the International AIDS Society 2003 definition, as well as the presence of additional mutations at codons 215 (C/D/E/S) and 69 (A/N/S) in the pol gene. Prevalence of mutations was estimated by use of techniques for stratified random samples. Logistic regression models were used to determine factors associated with resistance.

Results.  Among the 491 chronically HIV-infected patients (mean CD4 cell count, 269 cells/mm3; 31% of patients had a prior AIDS diagnosis), 57 (11.6%) had 1 resistance mutation, resulting in an estimated prevalence for the cohort of 10.8% (95% confidence interval [CI], 9.5%–12.1%). The prevalence was 8.8% if the 118I mutation was excluded. By drug class, the estimated prevalence of mutations conferring resistance to nucleoside reverse-transcriptase inhibitors was 7.8%, and the prevalence was 3.0% for nonnucleoside reverse-transcriptase inhibitors and 0.7% for protease inhibitors. In a multiple logistic regression analysis, non-Hispanic white subjects were twice as likely than African American subjects to have resistance (odds ratio [OR], 2.1; 95% CI, 1.1–4.1;  ), and there was a 40% increase per year in prevalence of mutations by later year of enrollment (OR, 1.4; 95% CI, 1.0–2.1;  ).

Conclusions.  These results demonstrate the persistence of drug resistance mutations in chronically HIV-infected patients and an increasing prevalence of resistance over time, and they support genotyping of virus at baseline for chronically HIV-infected patients.



September 22, 2008 at 11:23 am Leave a comment

Should Resistance Testing Be Performed for Treatment-Naive HIV-Infected Patients? A Cost-Effectiveness Analysis

Clinical Infectious Diseases  1 Nov 2005  V.41  N.9  p.1316-1323

Paul E. Sax,1 Runa Islam,2 Rochelle P. Walensky,1,2,3 Elena Losina,2,5 Milton C. Weinstein,4 Sue J. Goldie,4 Sara N. Sadownik,2 and Kenneth A. Freedberg2,3,4,5

1Division of Infectious Diseases, Brigham and Women’s Hospital, Divisions of 2General Medicine and 3Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, 4Harvard Center for Risk Analysis, Harvard School of Public Health, and 5Departments of Biostatistics and Epidemiology, Boston University School of Public Health, Boston, Massachusetts

Background.  Data from the United States and Europe show a population prevalence of baseline drug resistance of 8%–10% among human immunodeficiency virus (HIV)–infected patients who are antiretroviral naive. Our objective was to determine the clinical impact and cost-effectiveness of genotype resistance testing for treatment-naive patients with chronic HIV infection.

Methods.  We utilized a state-transition model of HIV disease to project life expectancy, costs, and cost-effectiveness in a hypothetical cohort of antiretroviral-naive patients with chronic HIV infection. On the basis of a US survey of treatment-naive patients from the Centers for Disease Control and Prevention, we used a baseline prevalence of drug resistance of 8.3%.

Results.  A strategy of genotype-resistance testing at initial diagnosis of HIV infection increased per-person quality-adjusted life expectancy by 1.0 months, with an incremental cost-effectiveness ratio of $23,900 per quality-adjusted life-year gained, compared with no genotype testing. The cost-effectiveness ratio for resistance testing remained less than $50,000 per quality-adjusted life-year gained, unless the prevalence of resistance was 1%, a level lower than those reported in most regions of the United States and Europe. In sensitivity analyses, the cost-effectiveness remained favorable through wide variations in baseline assumptions, including variations in genotype cost, prevalence of resistance overall and to individual drug classes, and sensitivity of resistance testing.

Conclusions.  Genotype-resistance testing of chronically HIV-infected, antiretroviral-naive patients is likely to improve clinical outcomes and is cost-effective, compared with other HIV care in the United States. Resistance testing at the time of diagnosis should be the standard of care.



September 22, 2008 at 11:16 am Leave a comment

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