Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections.

Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC(24))/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC(24)s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P = 0.013) relationship between microbiological response and the free-drug AUC(24)/MIC ratio was detected. At a free-drug AUC(24)/MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC(24)/MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC(24)/MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC(24)/MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.

Epstein-Barr virus-induced infectious mononucleosis complicated by acute renal failure: case report and review.

Infectious mononucleosis, most commonly caused by Epstein-Barr virus (EBV), is generally a benign, self-limited illness. Occasionally, however, more severe complications may arise such as acute renal insufficiency. While subclinical renal involvement appears to be relatively common in patients with infectious mononucleosis, patients with significant renal parenchymal dysfunction have rarely been described in the English-language literature. In this report, we review 27 previous cases ad present a case of oliguric renal failure complicating heterophil-positive infectious mononucleosis. The patient required hemodialysis but recovered promptly with treatment with the combination of corticosteroids plus acyclovir. Renal biopsy revealed interstitial nephritis, and immunoperoxidase studies demonstrated a predominance of suppressor/cytotoxic T cells, which has been described in only one previous case report. In situ hybridization done on renal biopsy tissue failed to reveal evidence of EBV-encoded RNA-1. Acute renal failure in infectious mononucleosis is rare, often self-limited, and usually caused by interstitial nephritis that is likely the result of immunopathologic injury precipitated by EBV infection.

HIV-1 Tat modulates invasion by a bacterial enteric pathogen into a human intestinal cell line.

OBJECTIVE: To explore the possibility that an HIV-1 gene product may modulate entry of an invasive enteric pathogen into a terminally differentiated human intestinal cell line. HIV-1 Tat was selected for investigation because of its unique ability to cross cell membranes. METHODS: After transient transfection of HT29-C1 cells with plasmids containing HIV-1 long terminal repeat (LTR)-lacZ plus a Tat expression cassette, or with a pSR-lacZ control plasmid, bacterial invasion assays were performed on both groups of cells utilizing a clinical Salmonella isolate. Assays were performed concurrently on a control group of non-transfected cells. A second series of experiments compared bacterial invasion into cells transfected with the Tat expression vector alone versus cells transfected with either an isogenic expression vector that did not make Tat, or with pSR-lacZ. Finally, the ability of exogenous Tat protein to transactivate an HIV-1 LTR-chloramphenicol acetyltransferase (CAT) plasmid which had been transfected into HT29-C1 cells and to modulate Salmonella invasion was also assessed. RESULTS: HT29-C1 cells transfected with a Tat expression vector, either alone or in combination with another plasmid, were significantly less susceptible to bacterial invasion than cells that either did not undergo transfection, were transfected with an otherwise isogenic expression vector without Tat, or transfected with an unrelated plasmid. Duplicate experiments also demonstrated that exogenous purified Tat protein transactivated an HIV-1 LTR-CAT plasmid which had been transfected into HT29-C1 cells and inhibited Salmonella invasion compared with unexposed cells. CONCLUSION: HIV-1 Tat inhibits Salmonella invasion of a human enterocyte cell line whether the protein is expressed intracellularly or provided exogenously.

Diagnostic strategies in HIV-infected patients with diarrhea.

PIP: Infectious disease specialists have proposed guidelines on diagnostic evaluation of HIV infected patients with diarrhea. They are based on using clues from a careful history, physical examination, and evaluation of known laboratory data. Early on, clinicians must differentiate between small and large bowel diarrhea to properly evaluate any patient with diarrhea. If available, they should use the patient's absolute CD4 count, duration of diarrhea, frequency and characteristics of stools, degree of weight loss, and exposure history (e.g., residence and water supply). When conducting the patient history, clinicians should ask about recent antibiotic or antiretroviral use, previous opportunistic infections, and other illnesses or hospitalizations. The physical exam should include height and weight, orthostatic blood pressure, and degree of wasting. Abnormalities of skin and mucous membrane may indicate nutrient deficiencies (e.g., vitamin B deficiency = stomatitis). The disease specialists provide us with an algorithm to the diagnostic evaluation of HIV infected patients with diarrhea using the CD4 cell count and the type of diarrhea (small or large bowel) as the defining factors. For example, clinicians should request stool cultures for Salmonella, Campylobacter, and Yersinia and examination with saline and iodine for the presence of ova and parasites for patients with CD4 counts greater than 200 cells x 1 million/l and small bowel diarrhea. If the patient also has a fever, blood cultures should be done to test for Salmonella. If all these tests are negative and the patient still has symptoms, modified acid-fast staining should be done to look for cryptosporidium oocysts. If this test is negative and symptoms continue, upper endoscopy with biopsy is warranted. This strategy should result in a less time-consuming and more directed diagnostic strategy that may improve quality of life.^ieng