Carlos Seas

Treatment of Shigellosis: V. Comparison of Azithromycin and Ciprofloxacin: A Double-Blind, Randomized, Controlled Trial

Shigellosis is the most common cause of dysentery and a leading cause of death in the worlds poor countries [1, 2]. Treatment of it is currently hampered by the high prevalence of multidrug-resistant strains of Shigella [3-5]. Most infections with Shigella dysenteriae type 1, the most virulent serotype of Shigella, are caused by strains resistant to ampicillin and trimethoprim-sulfamethoxazole; until recently, these were the drugs of choice for treating shigellosis [3-6]. Resistance to these two agents is also common among other Shigella species [2-4]. Because of the high prevalence of multidrug-resistant strains of Shigella in Bangladesh and other poor countries, we have conducted a series of studies to identify antimicrobial agents for the treatment of shigellosis [7-10]. To be useful in poor countries, such agents should be available in an oral formulation (thereby facilitating outpatient treatment), safe for use in children, and inexpensive [6]. In an earlier study [7], we showed that nalidixic acid was effective in treating infections caused by Shigella strains that were resistant to ampicillin and trimethoprim-sulfamethoxazole. Resistance to nalidixic acid, however, usually becomes prevalent within a few years of the drugs introduction into a community for treatment of shigellosis [3-5]. An epidemic of infection with S. dysenteriae type 1 caused by a strain resistant to nalidixic acid, ampicillin, and trimethoprim-sulfamethoxazole was responsible for an estimated 30 000 deaths among Rwandan refugees in Goma, Zaire, in 1994 [11]. In clinical trials conducted in Bangladesh, India, Rwanda, and Peru, we and others have found that the fluoroquinolones and pivamdinocillin are effective agents for treating multidrug-resistant Shigella infections [8, 9, 12-17]. The fluoroquinolones, however, are not approved for use in children in many countries because of concerns about toxicity [18], and pivamdinocillin is not widely available. The oral form of the extended-spectrum cephalosporin cefixime, although active in vitro against multidrug-resistant Shigella strains, was ineffective in achieving clinical and bacteriologic cure when we evaluated it for treating adults with moderate to severe shigellosis [10]. Other orally administered cephalosporins have also been ineffective in the treatment of shigellosis despite in vitro activity [19, 20]. This lack of in vivo activity may be due in part to poor intracellular activity of the cephalosporins [21]. In this study, the fifth in our series, we evaluated the efficacy of the macrolide agent azithromycin for treating shigellosis. Although azithromycin has been used primarily to treat gram-positive infections, it is active in vitro against most Shigella strains [22, 23], attains high intracellular concentrations [24, 25], can be given once daily [26], and is approved for use in children [27]. Methods Patients The study was conducted at the Dhaka Diarrhoeal Treatment Centre of the International Centre for Diarrhoeal Disease Research, Bangladesh. Study methods were similar to those of our previous studies of antimicrobial therapy for shigellosis [7-10]. Eligible patients were men 18 to 60 years of age who had grossly bloody-mucoid stool on examination, tenesmus, and illness that had lasted 72 hours or less. Patients were excluded if they had taken an effective antimicrobial agent for the current illness, had a coexisting illness requiring antimicrobial therapy, or had trophozoites of Entamoeba histolytica present on microscopic examination of stool. Signed informed consent was required before study entry. Study Protocol The study protocol was approved by the Ethical Review Committee. Patients were randomly assigned to receive either 1) one 500-mg dose of azithromycin on study day 1, followed by one daily 250-mg dose on the next 4 days [a total of 5 doses] or 2) 500 mg of ciprofloxacin every 12 hours for 5 days (a total of 10 doses). On admission, patients were given a consecutive study number to which treatment had been randomly preassigned by use of a random-number table; a block randomization method with a block size of six was used. The randomization list was developed and kept by a person not involved in the care or evaluation of the patients or in data analysis. Blinding was achieved by use of a double-dummy technique. Patients received an active form of the drug to which they were assigned and a placebo formulation of the other drug. Both active drug and placebo were given according to the routine schedule for the two drugs. Thus, patients assigned to the azithromycin group were given azithromycin tablets every 24 hours and received placebo tablets identical in appearance to the active ciprofloxacin tablets every 12 hours. Patients assigned to the ciprofloxacin group were given ciprofloxacin tablets every 12 hours and received placebo tablets identical in appearance to the active azithromycin tablets every 24 hours. Study day 1 was considered to begin with the first administration of the study drug and to continue for the next 24 hours. Patients were asked to remain in the hospital for 6 full study days. On admission, a medical history was obtained and a physical examination was performed; each day thereafter, symptoms were reviewed and physical examination was done. Patients were asked to return for a follow-up visit 7 days after discharge; at this visit, an interval history was obtained and a physical examination was performed. Laboratory Studies and Evaluation of Stool Samples A stool sample was cultured for enteric bacterial pathogens on admission and on study day 3. Rectal swab samples for isolation of Shigella strains were obtained on admission, daily thereafter until discharge, and at the follow-up visit. On admission and on study days 3 and 5, microscopic examination of stool was done to enumerate leukocytes and erythrocytes and identify cysts and ova of parasites. Stools passed on each study day were enumerated; the stool was categorized as bloody-mucoid, watery, soft, or formed; and the macroscopic presence of blood or mucus was noted and recorded. Blood samples for determination of complete blood count, serum electrolyte levels, and total protein and creatinine levels were obtained on admission and thereafter if clinically indicated. All laboratory evaluations were done by using standard methods described elsewhere [7]. The minimum inhibitory concentration (MIC) of the study drugs for the Shigella isolates was determined by using the E-Test (AB Biodisk, Solna, Sweden). Serum and stool concentrations of the study drugs were determined by bioassay for the first 36 patients entered into the study before noon. Blood samples were taken 90 minutes, 3 hours, and 24 hours after the first dose of study drug; stool samples were obtained on study days 2 and 4. Evaluation of Outcome Treatment was considered to have failed clinically if, at the end of study day 3, a patient was having persistent dysentery or if, on study day 5, a patient was febrile (oral body temperature > 37.8 C), had passed more than six stools, had any bloody-mucoid stools, or had more than one watery stool. Treatment was considered to have failed bacteriologically if Shigella strains could be isolated from a stool or rectal swab sample on study day 3 or thereafter. Patients in whom therapy failed and who continued to have dysentery were treated with pivamdinocillin, 400 mg every 6 hours for 5 days; treatment assignment was still unknown at the time pivamdinocillin was administered. Determination of Sample Size For determination of the sample size, the rate of clinical cure in the ciprofloxacin group was assumed to be 95% [8]. With a power of 80% and an error of 0.05, each group had to have 33 patients in order to detect a difference of 30% in rates of clinical cure between ciprofloxacin and azithromycin treatment (that is, cure rate of 95% compared with cure rate of 65%). A larger sample size, which would have allowed greater power to detect smaller differences between the two groups, was precluded by limitations in funding. Statistical Analysis The significance of differences in proportions was tested by using the chi-square test; if the predicted size of any cell was five or less, the Fisher exact test was used. The significance of differences between continuous variables was assessed by using the Student t-test if the data were normally distributed or by using the Mann-Whitney U test if the data were not normally distributed. Differences in median values (along with 95% CIs for these differences) were calculated as the median of all possible differences. All tests of significance were two tailed. The initial data analysis was done without knowledge of treatment assignment. Data were entered into a computer by using StatPac Gold, version 3.0 (Walonick Associates, Minneapolis, Minnesota), and were analyzed by using the Statistical Package for the Social Sciences, version 6.0 for Windows (SPS, Inc., Chicago, Illinois), and EpiInfo version 6.0 (USD, Inc., Stone Mountain, Georgia). We used Confidence Interval Analysis, version 1.0 (British Medical Journal, London, United Kingdom), to calculate CIs. Role of Industry Sponsor The authors were solely responsible for designing the study; gathering, analyzing, and interpreting the data; writing the manuscript; reporting the results of the study; and determining whether, and where, the manuscript should be submitted for publication. Results Patients Eighty-five patients were enrolled in the study between February 1995 and March 1996. No Shigella strains were isolated from an admission stool or rectal swab culture of 9 patients; these patients were not included in the analysis. An additional 6 patients (4 in the azithromycin group and 2 in the ciprofloxacin group) were excluded from the analysis because they withdrew before completion of the study (3 on study day 2, 2 on study day 3, and 1 on study day 4); thus, efficacy of therapy could not be determined. Of

Evolution of methicillin-resistant Staphylococcus aureus clones in Latin America

OBJECTIVES Methicillin-resistant Staphylococcus aureus (MRSA) is a prominent nosocomial bacterial pathogen, associated with significant morbidity and mortality. The global incidence is increasing, and Latin America is no exception. This article reviews MRSA clonal distribution in Latin America and implications for clinical practice. DESIGN A PubMed literature search (1966-2008) identified 32 articles that characterized MRSA clones in Latin America. RESULTS Data from these articles show that since 1990, several epidemic MRSA clones have spread in Latin America. The multidrug-resistant Brazilian clone is widespread, especially in Brazil and Argentina, but more recently clones with susceptibility to a range of antibiotics have been detected in Brazil, whereas in Argentina, as in Chile, Colombia and Paraguay, the multidrug-resistant Cordobes/Chilean clone prevails. In Mexico, the New York/Japan clone is most frequent. Data were not available from every country and, despite the increasing prevalence of community MRSA infections, most were collected from tertiary care centers. CONCLUSIONS A variety of epidemic MRSA clones are circulating in Latin America, some of which harbor genes that encode multidrug resistance or enhanced pathogenicity. Continued collection and reporting of epidemiological data is crucial for effective prevention and treatment.

Foxp3+ regulatory T cells in antiretroviral-naive HIV patients

We characterized regulatory T cells from antiretroviral-naive HIV patients by flow cytometry. The proportion of CD4 cells positive for CD25 and Foxp3 was increased, mainly in those with CD4 cell counts less than 200 cells/μl. The total number of Foxp3-positive cells correlated with the CD4 cell count. Further studies are needed on whether Foxp3-positive cell numbers or function explain the susceptibility to autoimmune and inflammatory diseases seen in some patients with advanced HIV.

Etiologies and Manifestations of Persistent Diarrhea in Adults with HIV-1 Infection: A Case-Control Study in Lima, Peru

UNLABELLED OBJECTIVE We sought to determine the etiologies, manifestations, and risk factors for persistent (> or =7 days) diarrhea in human immunodeficiency virus type 1 (HIV-1)-infected persons in Peru. DESIGN The present study is a case-control study of 147 HIV-1-infected case subjects with persistent diarrhea and 147 HIV-1-infected control subjects without diarrhea. METHODS We obtained clinical, demographic, and exposure data, CD4 lymphocyte counts, and stool samples for detection of enteric parasitic and bacterial pathogens and rotavirus. RESULTS One or more enteric pathogen was identified in 55% of case subjects and 21% of control subjects (odds ratio adjusted for CD4 lymphocyte count, 3.8; 95% confidence interval, 2.2-6.5). The median CD4 lymphocyte count was highest with pathogen-free diarrhea and lowest with Cryptosporidium infection. Cryptosporidium species (the most frequent pathogen), Giardia lamblia, Aeromonas species, Campylobacter species, and rotavirus were all significantly associated with diarrhea. Bacterial pathogens were significantly associated with G. lamblia and rotavirus infection. Of the bacterial pathogens (Aeromonas, Campylobacter, Salmonella, and Vibrio species and enterotoxigenic Escherichia coli), only 24% were susceptible to cotrimoxazole, whereas 90% were susceptible to ciprofloxacin. In no case did the sensitivity or positive predictive value of specific clinical and laboratory findings for curable enteric infections exceed 50%. CONCLUSIONS Several enteric pathogens were associated with diarrhea in HIV-1-infected case subjects in Peru, especially among those who were heterosexual. Clinical findings were poor predictors of detectable microbial etiology. The guidelines for initial management of chronic diarrhea with sulfamethoxazole-trimethoprim in HIV-1-infected persons require revision, at least in settings where prophylaxis with this agent is common.

Durability of Initial Antiretroviral Therapy in a Resource-Constrained Setting and the Potential Need for Zidovudine Weight-Based Dosing

Background:Whereas access to antiretroviral therapy (ART) for HIV-infected individuals in the developing world is increasing, data on factors impacting initial regimen durability are lacking. Methods:Retrospective review patients starting initial ART at Instituto de Medicine Tropical (Lima, Peru) April 1, 2004 to December 30, 2007. Survival methods (Kaplan-Meier, Cox proportional hazard) assessed factors associated with regimen durability including an interaction term between nucleoside reverse transcriptase inhibitor backbone and time. Results:Decreased initial regimen durability was observed with weight <60 kg [hazards ratio (HR) = 1.77; 95% confidence interval (CI) = 1.25-2.51], CD4 <200 (HR = 1.73; 95% CI = 1.03-2.91), and zidovudine (AZT) use at <120 days (HR = 2.09; 95% CI = 1.22-3.57). In contrast, after 120 days, AZT use decreased risk of discontinuation (HR = 0.52; 95% CI = 0.28-0.95). Early (<120 days) toxicity-related discontinuation of AZT containing regimens was observed in 44% of patients <50 kg at baseline vs. 14% of those >70 kg. An increased risk of early toxicity-related discontinuation of AZT-containing regimens was observed for baseline weight <60 kg (HR = 2.52; 95% CI = 1.46-4.35). Conclusions:Lower baseline weight and lower CD4 values at ART initiation were associated with decreased regimen durability. Compared with didanosine/stavudine, AZT use initially increased, then subsequently (>120 days) lowered hazards for regimen discontinuation. Weight <60 kg was associated with an increased risk of toxicity-related AZT discontinuation. As ART use expands globally, further study into maximally durable, least toxic regimens, and the role of weight-based AZT dosing is imperative.BACKGROUND Anal intraepithelial neoplasia (AIN), particularly AIN 3 is a precursor to anal cancer. Most cases of AIN are intraanal, but few treatments for intraanal AIN are currently available. Topical 85% trichloroacetic acid (TCA) is an inexpensive method used to treat perianal condyloma, a form of AIN 1, but its efficacy to treat intraanal AIN as first-line therapy is unknown. METHODS Retrospective review of medical records was performed for all patients with AIN treated at the University of California San Francisco Anal Neoplasia Clinic with TCA as the first-line therapy from January 2000 to December 2004. Clearance was defined as the absence of AIN confirmed by high-resolution anoscopy and cytology after up to 4 TCA treatments. RESULTS Thirty-five HIV-positive men and 19 HIV-negative men met the enrollment criteria. In multivariate analysis, greater clearance was seen in patients 41-48 years of age versus >49 years [odds ratio (OR): 8.4, confidence interval (CI): 1.1 to 94, P: 0.04]. Among HIV-positive men, those with 2 or fewer lesions showed greater clearance (OR: 14.3, CI: 1.5 to 662, P: 0.01). 32% of patients with AIN 2/3 cleared to no lesions. On a per lesion basis, 73% of AIN 1 and 71% AIN 2/3 cleared to no lesion or AIN 1 or less, respectively. CONCLUSIONS Topical 85% TCA was safe and well tolerated. It was more effective in younger patients and among HIV-positive patients, those with 2 or fewer lesions. A high proportion of AIN 2/3 lesions responded to TCA treatment.

Epidemiology of meticillin-resistant Staphylococcus aureus (MRSA) in Latin America

Methicillin-resistant Staphylococcus aureus (MRSA) has become a serious threat to public health worldwide. Ongoing surveillance is essential to support infection control committees and clinicians in the prevention and treatment of infection. However, in Latin America, resources for monitoring the changing epidemiology of MRSA remain limited. In this article, we review the current situation of MRSA in Latin America in order to highlight the need for a more harmonised effort to improve its management. Literature in the PubMed and SciELO databases as well as the website of the Pan American Health Organization were searched for articles and information about the epidemiology of MRSA in Latin America. MRSA is already the leading cause of nosocomial infection in the Latin American region, and the number of reports of community-acquired MRSA infections is also rising. However, the extent of the problem is not fully understood, especially since data tend to come from large hospitals whereas much of the population is served by small community healthcare centres that do not have extensive facilities for performing microbiological surveillance. In conclusion, wider-reaching and co-ordinated programmes to provide regular MRSA surveillance reports are required across the Latin American region.

Successful treatment of Balamuthia mandrillaris amoebic infection with extensive neurological and cutaneous involvement.

Granulomatous amoebic encephalitis caused by Balamuthia mandrillaris is an uncommon infection for which there is no optimal therapy. We describe a young, female patient who presented with extensive cutaneous and neurological involvement and who recovered after receiving prolonged treatment with miltefosine, fluconazole, and albendazole.

Sexual behavior of international travelers visiting Peru

Background Sexual behavior of travelers to Latin America and the sexual behavior of US travelers in general are poorly characterized. Goal The goal of the study was to evaluate sexual risk factors of travelers to Peru. Study Design Anonymous written questionnaires were administered to 442/507 (87%) of the individuals approached in the international departures area of the Lima airport. Results Of the 442 respondents, 54 (12.2%) had new sex partners during their stay. Sex with a local partner (35/52; 67.3%) was more frequent than sex with other travelers (18/52; 34.6%) or with sex workers (4/52; 7.7%). Risk factors for a new sex partner included male sex (relative risk, 1.94), single marital status (relative risk, 2.59), duration of stay longer than 30 days (relative risk, 5.05), traveling alone or with friends (relative risk, 2.88), and bisexual orientation (relative risk, 4.94). Frequency of sexual activity among US travelers was greater than that among travelers from other countries (15.2% [22/145] versus 10.6% [30/282]; NS). Condoms were consistently used by 12/50 (24%) and sometimes used by 10/50 (20%), including 8/20 United States travelers and 13/29 travelers from other countries. Conclusion Behaviors and risk factors are similar to those described for travelers to Africa, Asia, and Eastern Europe. Behavior of US travelers did not differ from that of other travelers.

Sexual behavior in travelers visiting Cuzco.

BACKGROUND In South America, little is known about sexual behavior and risk factors for acquiring sexually transmitted diseases (STDs) among travelers and among local people sexually interacting with travelers. There is evidence that, in Peru, significant sexual interaction between these groups exists. METHOD An anonymous written questionnaire was administered to travelers in the airport and bus stations before they left Cuzco. RESULTS Of the travelers,5.6% engaged in sexual activity with a new partner during their stay in Cuzco. Sexual intercourse with other travelers was most common (76/140, 54.3%), followed by sex with local partners (57/140, 40.7%), and with commercial sex workers (3/140, 2.15%). Consistent condom use was reported by 97/140 (69.3%). In the multivariate analysis, the following variables were independently associated with casual sex: male gender, single marital status, age between 15 and 35 years, non-United States travelers (NUSTs), traveling alone or with friends, length of stay more than 30 days, homosexual or bisexual orientation, and expectation of having sex before traveling. Homosexual and bisexual travelers had 3 or more new sexual partners more frequently than heterosexual travelers (4/8, 18/129, OR=6.17 (1.16<OR<33.5)). NUSTs received more pretravel advice (698/1587, 210/718, OR=1.86 (1.54<OR<2.24)) and engaged in more sexual activity (100/1,587, 25/722, OR=1.86 (1.20<OR<2.93)) than United States travelers (USTs). CONCLUSION Travelers visiting Cuzco engage in sexual activities that put them at risk of acquiring STD and transmitting it, both in their home country and in Peru. We recommend the inclusion of Peru and possibly other Latin American countries in the list of destinations where there is substantial risk of transmission of STD and the provision of pretravel advice regarding this issue to travelers to Peru.

Metabolic syndrome in HIV-infected patients receiving antiretroviral therapy in Latin America

OBJECTIVE To evaluate the prevalence of and the associated factors for metabolic syndrome (MS) among Latin American HIV-infected patients receiving antiretroviral therapy (ART) using baseline data from the RAPID II study. METHODS A longitudinal study to evaluate the metabolic profile, cardiovascular disease (CVD) risk and associated treatment practices to reduce this risk has been conducted in seven Latin American countries (the RAPID II study). Adult HIV patients with at least six months of RT were enrolled. MS was defined following ATP-III criteria. Demographic and anthropometric data, serum biochemical and clinical parameters were compared in patients with and without MS using bivariate and multivariate analysis. RESULTS A total of 4,010 patients were enrolled, 2,963 (74%) were males. Mean age (SD) was 41.9 (10.0) years. The prevalence of MS was 20.2%. Females had higher prevalence of MS than males (22.7% vs. 19.4%, p = 0.02). MS was driven by high triglycerides, low HDL-cholesterol and high blood pressure (HBP). Patients with MS had higher 10 year CVD risk: 22.2% vs. 7.4%, p < 0.001. Age (OR: 1.05 per year), female gender (OR: 1.29), family history of CVD (OR: 1.28), CD4 cell count (OR: 1.09 per 100 cell increase), and protease inhibitor based-ART (OR: 1.33) correlated with MS in the multivariate analysis. CONCLUSIONS Prevalence of MS in this setting was similar to that reported from developed countries. MS was driven by high triglycerides, low-HDL and HBP, and it was associated with higher risk of CVD. Traditional risk factors, female gender, immune reconstitution, and protease inhibitor based-ART correlated with MS.