Resumo em Inglês:

OBJECTIVES: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. METHODS: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40% of the dosing interval. RESULTS: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90% cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20% lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90% CFR against bloodstream and respiratory isolates of K. pneumoniae. CONCLUSIONS: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra-abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials.

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OBJECTIVE: The present study was undertaken to characterize CTX-M ESBL-producing Klebsiella pneumoniae collected from hospitals in different cities of Brazil. MATERIAL AND METHODS: Eighty-five K. pneumoniae strains isolated from hospitalized patients in six different hospitals of three cities of Brazil were analyzed. ESBL production was confirmed by the standard double-disk synergy test and the Etest®. The MIC50 and MIC90 for ESBL-producing isolates were determined by the Etest® method. The antimicrobial susceptibilities of bacterial isolates were determined using the agar diffusion method according to the CLSI. Screening for blaTEM, blaSHV, blaCTX-M genes and class 1 integron was performed by PCR amplification. To determine the genomic diversity of CTX-M-producers, isolates were analyzed by macrorestriction profile analysis following PFGE. RESULTS AND DISCUSSION: Seventy-one K. pneumoniae isolates were ESBL-producing. PCR and sequencing experiments detected 38 CTX-M-producing K. pneumoniae belonged to groups CTX-M 1, CTX-M 2, CTX-M 8 and CTX-M 9. The association of different types ESBL (CTX-M, SHV and TEM) was frequent. All K. pneumoniae isolates carried class 1 integron. PFGE analysis revealed thirty-one clonal types among CTX-M-producing isolates. The data presented herein illustrate the diversity of genotypes of CTX-M producing K. pneumoniae among Brazilians hospitals.

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OBJECTIVES: Both total antimicrobial use and specific antimicrobials have been implicated as risk factors for healthcare-associated methicillin-resistant Staphylococcus aureus (HCA-MRSA) infection. The aims of this study were: (I) to explore predictors of a new HCA-MRSA infection in comparison with a new healthcare-associated methicillin-sensitive Staphylococcus aureus (HCA-MSSA); (II) to thoroughly assess the role of recent antibiotic use qualitatively and quantitatively. METHODS: The time-period for our study was from October 1997 through September 2001. Through applying strict criteria, we identified two groups of inpatients, one with a new HCA-MRSA infection and one with a new HCA-MSSA infection. We recorded demographic, clinical and antibiotic use-related data up to 30 days before the positive culture date. RESULTS: We identified 127 and 70 patients for each group, respectively. Two logistic regression models were carried out to assess the role of antimicrobial use (qualitatively and quantitatively). In model I, duration of hospital stay, presence of chronic wounds, aminoglycoside and fluoroquinolone use retained statistical significance. In model II, duration of hospital stay and history of intubation during the last month stood out as the only significant predictors of a subsequent HCA-MRSA infection. No significant differences in outcome were noted. CONCLUSIONS: The length of exposure to the hospital environment may be the best predictor of a new HCA-MRSA infection. Use of aminoglycosides and fluoroquinolones may also stand independently along with presence of chronic ulcers and surgical procedures. No independent association between quantitative antibiotic use and subsequent HCA-MRSA infection was documented.

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OBJECTIVE: One hundred thirty-one cases of postsurgical infections were reported in Southern Region of Brazil between August 2007 and January 2008. Thirty-nine (29.8%) cases were studied; this report describes epidemiological findings, species identification, antimicrobial susceptibility and clonal diversity of rapidly growing mycobacteria isolated in this outbreak. METHODS: All 39 isolates were analyzed by Ziehl-Nielsen stained smear, bacterial culture and submitted to rpoB partial gene sequencing for identification. The isolates were also evaluated for their susceptibility to amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, tobramycin and sulfamethoxazole. RESULTS: Thirty-six isolates out of the confirmed cases were identified as Mycobacterium massilienseand the remaining three were identified as Mycobacterium abscessus, Mycobacterium chelonae and Mycobacterium fortuitum. All M. massiliense isolates were susceptible to amikacin (MIC90 = 8 µg/mL) and clarithromycin (MIC90 = 0.25 µg/mL) but resistant to cefoxitin, ciprofloxacin, doxycycline, tobramycin and sulfamethoxazole. Molecular analysis by pulsed-field gel electrophoresis clustered all 36 M. massiliense isolates and showed the same pattern (BRA 100) observed in three other outbreaks previously reported in Brazil. CONCLUSIONS: These findings suggest a common source of infection for all patients and reinforce the hypotheses of spread of M. massiliense BRA100 in Brazilian hospital surgical environment in recent years.

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OBJECTIVES: Apoptosis is the process of programmed cell death (PCD) that occurs in both animal and plant cells. Protozoan parasites possess metacaspase and these caspase-related proteases could be involved in the PCD pathways in these organisms. Therefore we analyzed the activities of metacaspase and PARP genes in Leishmania infantum (MCAN/IR/96/LON49) treated with miltefosine. MATERIALS AND METHODS: Anti-leishmania activity of miltefosine was studied by treatment of cultured promastigotes with various concentration of miltefosine. MTT assay and Annexin-V FLUOS staining by using FACS flow cytometry methods were used. Cytotoxic potential of HePC on the amastigots of L.infantum was evaluated in J774 cell line. In addition, metacaspase and PARP genes expression of treated L. infantum were studied. RESULTS: Miltefosine led to dose-dependent death of L. infantumwith features compatible with apoptosis. Over expression of metacaspase and PARP was seen 6 hr after treatment. CONCLUSIONS: Our study showed that miltefosine exerts cytotoxic effect on L. infantum via an apoptotic-related mechanism.

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OBJECTIVE: The treatment of the chronic hepatitis C (HCV) with α-interferon is associated with thyroid dysfunction (TD). The aim of this study was to evaluate thyroid function outcome among patients with chronic HCV under treatment with conventional interferon (IFN) or peguilated interferon (PEG-IFN) in association with ribavirin. PATIENTS AND METHODS: We studied 293 patients with chronic HCV, submitted to drug therapy for 24 or 48 weeks. Initially, we evaluated FT4, TSH, TPOAb, TgAb, and continued to monitor FT4 and TSH every three months during therapy and six months thereafter. RESULTS: At baseline, TD prevalence was 6.82% (n = 20); 6.14% hypothyroidism; 0.68% hyperthyroidism. TPOAb was present in 5.46% of euthyroid patients. Out of 273 euthyroid patients at baseline, 19% developed TD: 17.2% hypothyroidism; 1.8% hyperthyroidism; 5.1% destructive thyroiditis (DT). 90% of TPOAb-positive patients at baseline developed hypothyroidism vs 14.5% of TPOAb-negative patients (p < 0.001). On average, TD occurred after 25.8 ± 15.5 weeks of treatment. 87.2% of patients who developed hypothyroidism did so during the first therapeutic cycle (p = 0.004; OR = 3.52; 95% CI = 1.36-9.65). Patients infected with genotype 1 virus were 2.13 times more likely to develop hypothyroidism (p = 0.036; 95% CI = 1.04-4.38). Hypothyroid and DT patients presented higher TSH levels before-treatment than patients who had remained euthyroid (p < 0.001; p = 0.002, respectively). DT patients presented lower qALT (p = 0.012) than euthyroid patients. CONCLUSION: Hypothyroidism was the most frequent TD, especially during the first cycle of α-interferon. Genotype 1 virus was associated with a risk two times higher for developing the illness. There was no need to interrupt or to change HCV treatment. Therefore, approximately 34% of TD was transient.

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OBJECTIVE: The pandemic of new influenza A (H1N1) has spread rapidly throughout the world, characterized by high transmissibility, but low pathogenicity and virulence. The aim of this study was to understand the pandemic event and available technologies for disease surveillance, prevention, control and management. METHODS: In this retrospective study, we used data from patients in the State of Paraná who had been diagnosed with the disease during the 2009 pandemic. Data were collected from the disease notification form and the study only included patients with confirmed laboratory diagnosis by RT-PCR. RESULTS: We present the epidemiological profile of 4,740 patients that met the inclusion criteria. The variables age, level of schooling and gestational age were shown to be associated with mortality due to the infection. Gender and race/ethnicity were not associated with the outcome of the infection. CONCLUSION: These results underscore the importance of knowing the variables associated with unfavorable outcomes of pandemic influenza infection in order to minimize the health related consequences. Attention should be given to its forms of transmission and to the frailty of certain age groups that have no cross-immunity.

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OBJECTIVES: To examine the spatial distribution of Streptococcus pneumoniae and its clonal patterns collected between 2002 and 2006 in São Paulo, Brazil. METHODS: As part of an observational study in São Paulo city, Brazil, S. pneumoniae isolates routinely cultured from blood, respiratory specimens, or cerebrospinal and other profound fluids were selected. Additionally, only isolates with either penicillin (PEN) intermediate (I) or resistant (R) status on routine antibiogram were included, in order to obtain a higher probability of clonal isolates. A single I/R S. pneumoniae isolate per patient was included and submitted to genotypic determination by pulsed field gel electrophoresis (PFGE). Minimum inhibitory concentrations (MICs) were determined for the isolates by Etest® to PEN and other antimicrobials. Each isolate was geocoded in a digital map. The Kernel function and ratio methods between total isolates vs. clones were used in order to explore possible cluster formations. RESULTS: Seventy-eight (78) S. pneumoniae community isolates from two major outpatient centers in São Paulo, Brazil, were selected from the databank according to their penicillin susceptibility profile, i.e. R or I to penicillin assessed by oxacillin disc diffusion. Of these, 69 were submitted to PFGE, 65 to MIC determination, and 48 to spatial analytical procedures. Preliminary spatial analysis method showed two possible cluster formation located in southwest and southeast regions of the city. CONCLUSION: Further analyses are required for precisely determining the existence of S. pneumoniae clusters and their related risk factors. Apparently there is a specific transmission pattern of S. pneumoniae clones within certain regions and populations. GIS and spatial methods can be applied to better understand epidemiological patterns and to identify target areas for public health interventions.

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BACKGROUND: It is clinically important to detect and type human papillomavirus (HPV) in a sensitive and specific manner. OBJECTIVES: Development of a nested-polymerase chain reaction-restriction fragment length polymorphism (nested-PCR-RFLP) assay to detect and type HPV based on the analysis of L1 gene. METHODS: Analysis of published DNA sequence of mucosal HPV types to select sequences of new primers. Design of an original nested-PCR assay using the new primers pair selected and classical MY09/11 primers. HPV detection and typing in cervical samples using the nested-PCR-RFLP assay. RESULTS: The nested-PCR-RFLP assay detected and typed HPV in cervical samples. Of the total of 128 clinical samples submitted to simple PCR and nested-PCR for detection of HPV, 37 (28.9%) were positive for the virus by both methods and 25 samples were positive only by nested-PCR (67.5% increase in detection rate compared with single PCR). All HPV positive samples were effectively typed by RFLP assay. CONCLUSION: The method of nested-PCR proved to be an effective diagnostic tool for HPV detection and typing.

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In the last years, the prevalence of HPV infection in the anal region has increased, especially in some groups like homosexual and HIV-positive people. Since this infection can be associated with the development of squamous anal cancer due to its progression from HPV infection to anal intraepithelial neoplasia (AIN) and finally to cancer, the screening and evaluation of these conditions are important. Anal cytology and high resolution anoscopy are good methods that are available and can be used. Although useful, these methods should be performed correctly and not indiscriminately in all patients. Patients for whom anal cytology screening is recommended are: HIV-infected patients, homosexuals, women who present with high-grade vulvar squamous intraepithelial neoplasia, vulvar cancer or cervical cancer. An abnormal anal cytology should be further evaluated with high resolution anoscopy.

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Phenotypic and genotypic SPM and IMP metallo-β-lactamases (MBL) detection and also the determination of minimal inhibitory concentrations (MIC) to imipenem, meropenem and ceftazidime were evaluated in 47 multidrug-resistant Pseudomonas aeruginosa isolates from clinical specimens. Polymerase chain reaction detected 14 positive samples to either blaSPM or blaIMP genes, while the best phenotypic assay (ceftazidime substrate and mercaptopropionic acid inhibitor) detected 13 of these samples. Imipenem, meropenem and ceftazidime MICs were higher for MBL positive compared to MBL negative isolates. We describe here the SPM and IMP MBL findings in clinical specimens of P. aeruginosa from the University Hospital of Botucatu Medical School, São Paulo, Brazil, that reinforce local studies showing the high spreading of blaSPM and blaIMP genes among brazilian clinical isolates.

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Reye's syndrome is an infrequently diagnosed medical condition affecting mainly children. The etiology, epidemiology and natural history of Reye's syndrome have been cloudily written in footnotes of medical books and exotic papers since the initial description in early 1950s. We report here a case of adult Reye's syndrome associated with serologic evidence of parvovirus B19 infection.

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Cytomegalovirus (CMV) infection is a common opportunistic systemic infection in immunocompromised patients, but skin involvement is rare. Herein, we report a 10 year-old girl from consanguineous parents who was referred to our center because of disseminated maculopapular rash. She had history of upper and lower respiratory tract infections. In immunological studies, increased serum IgE level and decreased responses to tetanus and diphtheria were detected. Polymerase chain reaction (PCR) examination of bronchoalveolar lavage and serum sample revealed the presence of CMV. Early diagnosis of cutaneous CMV and appropriate treatment are the key actions in management of patients with underlying immunodeficiencies to avoid further complications.

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Nocardia infection is rare but potentially fatal. Therapy of Nocardia infection remains difficult. Linezolid, a novel oxazolidinone antibiotic, has proven to be effective, but clinical data are limited. Here we describe a case of a 45-year-old man with pulmonary N. farcinica infection following a liver transplantation. The initial therapy was trimethoprim-sulfamethoxazole, which showed no effect. According to susceptibility test, linezolid was administered with clearly improving the patient's condition. The treatment was stopped for anemia as drug related adverse event, and the therapy lasted for as long as 5 months. At the end of treatment clinical cure was confirmed and anemia reversed after discontinuation of linezolid. We also analyzed the clinical data of previously published reports by literature review, focusing on the efficacy and safety of linezolid treatment for Nocardia infection.

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Acute pancreatitis is an atypical complication of dengue fever and is rarely described. We are reporting a case of dengue hemorrhagic fever complicated by acute pancreatitis in a patient with history of diabetes mellitus type 1 and end stage renal disease on hemodialysis.

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Leptospirosis is a spirochetal bacterial infection of great public health importance. It has a broad spectrum of clinical manifestations which goes from subclinical infection and self-limited anicteric febrile illness (80-90% of all cases) to icteric leptospiropirosis known as Weil's disease. This is a severe disease characterized by hemorrhage, acute renal failure and jaundice. It is uncommon for leptospirosis to present itself as a primary neurological disease. Additionally, acute pancreatitis is an unusual gastrointestinal manifestation. We report a case of leptospirosis presenting as ascending progressive leg weakness and complicating with acute pancreatitis in an adult patient treated at Hospital Universitário, Universidade Federal de Santa Catarina. The diagnosis was confirmed through ELISA-IgM antibody testing positive for leptospirosis. After antibiotic therapy and support treatment for a few weeks, total resolution of severe manifestations was achieved. Rare and unusual presentations of leptospirosis should be kept in mind in relevant epidemiological scenario.

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Darunavir (DRV) is an HIV-1 protease inhibitor that is used together with a low boosting dose of ritonavir as part of an antiretroviral therapy (ART) regimen in treatment-experienced and naïve HIVpositive patients. In naïve and experienced patients with no DRV-mutations, DRV is licensed at the dose of 800 mg plus 100 mg of ritonavir once daily. We report our results in seven ART-experienced HIV-infected patients, in whom a reduced dose of darunavir/ritonavir (600/100 mg once daily) successfully controlled viral replication