Oral anti-pseudomonal antibiotics for cystic fibrosis.

BACKGROUND: Pseudomonas aeruginosa is the most common bacterial pathogen causing infection in the lungs of people with CF and appropriate antibiotic therapy is vital. Antibiotics for exacerbations are usually given intravenously, and for long-term treatment, via a nebuliser. Oral anti-pseudomonal antibiotics with the same efficacy and safety as intravenous or nebulised antibiotics would benefit the quality of life of people with CF due to ease of treatment and avoidance of hospitalisation. OBJECTIVES: To determine the benefit or harm of oral anti-pseudomonal antibiotic therapy for people with CF, colonised with Pseudomonas aeruginosa, in the: (1) treatment of an exacerbation of respiratory tract infection; and (2) long-term treatment in chronic infection. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We contacted pharmaceutical companies for information on relevant trials and checked reference lists of identified trials. Most recent search: March 2007. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any dose of oral anti-pseudomonal antibiotics, with other combinations of inhaled, oral or intravenous antibiotics, or with placebo or usual treatment for exacerbations and long-term treatment. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials, extracted data and assessed quality. We contacted trialists to obtain missing information. MAIN RESULTS: We included four trials examining exacerbations (197 participants) and two trials examining long-term therapy (85 participants). We regarded the most important outcomes as quality of life and lung function. In our analysis, we were unable to identify any statistically significant difference between oral anti-pseudomonal antibiotics and other treatments for these outcome measures for either exacerbations or long-term treatment. One of the included trials reported significantly better lung function when treating an exacerbation with ciprofloxacin when compared with intravenous treatment; however, our analysis did not confirm this finding. We found no evidence of difference between oral anti-pseudomonal antibiotics and other treatments regarding adverse events or development of antibiotic resistance, but trials were not adequately powered to detect this. AUTHORS' CONCLUSIONS: We found no conclusive evidence that an oral anti-pseudomonal antibiotic regimen is more or less effective than an alternative treatment for either exacerbations or long-term treatment of chronic infection with P. aeruginosa. Until results of adequately-powered future trials are available, treatment needs to be selected on a pragmatic basis, based upon known effectiveness against local strains and upon individual preference.

HIV protease and reverse transcriptase variation and therapy outcome in antiretroviral-naive individuals from a large North American cohort.

OBJECTIVE: To assess the effect of baseline HIV reverse transcriptase (RT) and protease sequence variation on virologic outcomes in a large cohort of antiretroviral-naive patients in British Columbia, Canada. METHODS: Population sequencing of RT and protease was performed on baseline viral RNA of all antiretroviral-naive patients first seeking treatment in British Columbia between June 1997 and August 1998 (n = 479). Relative risks of virological failure associated with genotypic differences from a 'standard' HIV strain (HXB2) were assessed for up to 18 months. RESULTS: The prevalence of key baseline mutations known to confer resistance to RT and protease inhibitors (PI) was 3.4 and 3.8%, respectively. No statistically significant impact on virologic outcomes could be established for these patients. However, the data suggest that some individuals (harboring a M184V mutation in RT or a V82I in protease) may have benefited from pre-therapy resistance tests. 'Secondary' mutations in the protease associated with resistance (e.g. codons 10, 36 or 63) were common, but the presence of these secondary mutations, either alone or in combination, did not appear to result in early loss of therapeutic virological suppression. Preliminary analyses suggest that an amino acid change at codon 35 in the protease may be associated with early treatment failure. CONCLUSIONS: The results suggest that routine genotyping of naive patients about to start antiretroviral therapy would be of benefit to a relatively small proportion of the population. Secondary mutations associated with resistance to PI alone were not found to affect virologic outcomes significantly.

Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens.

OBJECTIVES: To characterize the antiviral response and tolerability of a multi-drug rescue therapy (MDRT) among heavily pretreated patients. METHODS: Observational study conducted in a single, university-based tertiary referral clinic. Patients (n = 106) who failed several prior regimens started MDRT including at least five antiretroviral (ARV) drugs between August 1997 and June 1998. The most common starting regimen included three nucleoside reverse transcriptase inhibitors and two protease inhibitors, which was prescribed to 45 (42.5%) patients. Virologic response was defined as plasma viral load < 400 copies/ml on at least two consecutive visits. RESULTS: Median prior ARV exposure was seven drugs over a median time of 43 months. Fifty-nine percent of the patients were phenotypically (VIRCO Antivirogram) resistant at baseline to seven or more ARV. Median plasma viral load change following initiation of MDRT was -1.04 log10 copies/ml over a median of 15 months. Using intention-to-treat analysis 40% of patients had plasma viral load values < 400 copies/ml between weeks 47 and 57 of follow-up. Twenty-six patients (25%) experienced severe laboratory abnormalities or subjective adverse drug effects and six of these participants discontinued therapy. CONCLUSION: MDRT induced a substantial antiviral response in this heavily pretreated group of patients despite extensive phenotypic resistance at baseline. Adverse effects were frequent but generally manageable. Our data suggest that relying exclusively on historical, clinical and laboratory evidence may not be sufficient to rule out a possible antiviral response when multiple drug regimens are used in this heavily pretreated patient population.

Chemokines, natural killer cells and granulocytes in the early course of Leishmania major infection in mice.

In the present study the early recruitment of leukocytes into the infected skin and into the draining lymph node (LN) was investigated after subcutaneous infection of mice with Leishmania major promastigotes. Flow cytometric analysis of cells recovered from the infected skin revealed that GR-1+ granulocytes were present as early as 10 h after infection, thus representing the first leukocyte population to be recruited to the site of infection. The migration of granulocytes was shown to be associated with a rapid mRNA expression of the neutrophil-attracting chemokine KC in the infected skin. Moreover, L. major promastigotes were found to produce factor(s) that are chemotactic for human neutrophils in vitro. Experiments with human neutrophils revealed that these cells are able to phagocytose the parasites. Natural killer (NK) cells appeared at the site of infection 24 h after infection. The migration of NK cells in resistant mice was found to correlate with the expression of the NK cell-activating chemokine IP-10. Treatment of susceptible BALB/c mice with recombinant mouse IP-10 resulted in a significantly increased NK cell cytotoxic activity in the draining LN. These data suggest that both the early chemokine gene expression and the production of chemotactic factors by the parasites themselves regulate the site-directed migration and activation of cells of the innate immune response, and suggest a role of chemotactic factors in the early defense against the parasites.

Hepatic lesion detection and characterization: value of nonenhanced MR imaging, superparamagnetic iron oxide-enhanced MR imaging, and spiral CT-ROC analysis.

PURPOSE: To determine the accuracy for detection and characterization of focal hepatic lesions of nonenhanced, superparamagnetic iron oxide (SPIO)-enhanced, or a combination of nonenhanced and SPIO-enhanced MR imaging and contrast-enhanced spiral computed tomography (CT). MATERIALS AND METHODS: Spiral CT and T2-weighted SPIO-enhanced (ferucarbotran-enhanced) MR imaging were performed in 35 patients within 2 weeks before surgery for malignant hepatic lesions. Only malignant lesions with histopathologic proof were considered. A total of 875 images with and 800 images without focal lesions were presented to five readers, who were asked to assess the presence and characterization of lesions by using a five-point confidence scale. Receiver operating characteristic analysis was performed. RESULTS: Nonenhanced and SPIO-enhanced images together and SPIO-enhanced images alone yielded the best performance for lesion detection. No differences were found among all imaging techniques with regard to lesion characterization (benign vs malignant). The combined approach resulted in larger area under the ROC curve (A(z) = 0.9062) and accuracy (85.3%) (P < 0.02), as compared with SPIO-enhanced MR imaging (A(z) = 0.8667; accuracy, 73.1%). CONCLUSION: SPIO-enhanced T2-weighted MR imaging was more accurate than nonenhanced T1-weighted and T2-weighted MR imaging and contrast-enhanced spiral CT for the detection of focal hepatic lesions. The combined analysis of nonenhanced and SPIO-enhanced images was more accurate in the characterization of focal hepatic lesions than was review of SPIO-enhanced images alone.

Full suppression of viral load is needed to achieve an optimal CD4 cell count response among patients on triple drug antiretroviral therapy.

OBJECTIVE: To characterize the relationship between plasma viral load (pVL) suppression and triple drug antiretroviral therapy, and the accompanying changes in CD4 cell counts. METHOD: Retrospective study of 465 participants in a HIV/AIDS Treatment Program who initiated triple drug therapy between August 1996 and May 1998. Participants were divided into three groups according to their pVL response: (i) non-responders (NR; n = 112) exhibited pVL persistently > 500 copies/ml over the study period; (ii) partial responders (PR; n = 100) achieved a pVL < 100 copies/ml at least once and subsequently rebounded to > 500 copies/ml; and (iii) full responders (FR; n = 253) achieved a pVL < 500 copies/ml and sustained this level for the remainder of the study period. For each group, the accompanying changes in absolute and fractional CD4 cell counts were evaluated. RESULTS: The median net change in pVL per person from baseline to the end of the observation period was -0.37, -2.27, and -2.56 log10 copies/ml for NR, PR and FR, respectively. During weeks 68-83, the median CD4 cell count (x 10(6) cells/l) was 150 [interquartile range (IQR) 90-370], 380 (IQR 300-480) and 525 (IQR 305-705) for NR, PR and FR, respectively. Median changes in CD4 cells (x 10(6) cells/l) were -20 (IQR -90 to 40), 150 (IQR 30-250) and 240 (IQR 110-365) for NR, PR, and FR, respectively. The net percentage change in CD4 cells per person was 0% (IQR -34-31), 54% (IQR 6-160), and 83% (IQR 39-173) for NR, PR, and FR, respectively. By weeks 68-83, the median fractional CD4 cells was 0.16 (IQR 0.07-0.22), 0.22 (IQR 0.15-0.28), and 0.26 (IQR 0.17-0.34) for NR, PR and FR respectively. CONCLUSIONS: An optimal CD4 cell count response appears to be coupled with continued pVL suppression. Our data indicate that maximal suppression of viral replication should remain the primary goal of therapy.

Antiretroviral effect of two different dose regimens of ritonavir and saquinavir on HIV-infected adults in a population-based setting.

OBJECTIVE: To characterize the antiviral effect and tolerability of higher dose (HD, 600 mg two times daily) and lower dose (LD, 400 mg two times daily) combination regimens of ritonavir and saquinavir in British Columbia (BC), Canada. DESIGN: Intent-to-treat analysis with suppression of plasma viral load to levels below 500 copies/ml as the main outcome measure. PATIENTS: Adult human immunodeficiency virus (HIV)-positive individuals in the province of British Columbia prescribed ritonavir and saquinavir in combination between 1 September 1996 and 30 June 1997, with a minimum of two plasma viral loads, one at baseline and one after the initiation of therapy. RESULTS: A total of 84 participants [27 HD (32%) and 57 LD (68%)] were prescribed ritonavir and saquinavir. There was no difference at baseline in the two groups with respect to age (P=0.466), CD4 cell count (P=0.373) and baseline plasma viral load (P=0.656). However, LD were more likely to have had prior protease experience than HD participants (65 versus 40%, P=0.037). The median follow-up time was 9 months. A total of 44 (52%) subjects demonstrated a decrease in plasma viral load to levels <500 copies/ml. After adjusting for length of follow-up, baseline CD4 cell count and prior AIDS diagnosis, HD participants were as likely to be suppressed to <500 copies/ml as LD individuals (P=0.760). HD participants did report more adverse effects (P=0.042) than LD subjects. CONCLUSION: Our results provide confirmatory evidence that lower doses of ritonavir and saquinavir in combination are better tolerated and as effective as the standard doses of these drugs. This response, however, is seriously compromised by prior exposure to protease inhibitors.

[Current status of the treatment of HIV infection]. / El estado actual del tratamiento de la infección por HIV.

The antiretroviral therapeutic strategy changed in 1996, when the prognostic value of the plasma viral load and the CD4 cell counts were confirmed. Two nucleosides, plus a protease inhibitor or a non-nucleoside, are currently the initial preferred options. Viral resistance, and pharmacokinetic problems, however, have limited the efficacy of these schemes. It should be emphasized that continued use of triple drug therapy regimens have been associated with a decrease of morbidity and mortality associated to AIDS. We have analyzed the different drug combinations used in clinical trials and their results, the definition of therapeutic failure, and its consequences to control the treatment. With the currently available regimens, the virus cannot be totally eradicated from the organism and treatment should be continued for life. The combination of drugs in a single tablet, and the decrease in the number of daily intakes can help the patient with adherence, and allow for supervised treatment programs like the ones already applied with success in the treatment of tuberculosis. The use of virus resistance assays and pharmacokinetic assays will help to select the most appropriate treatment in the near future.

El estado actual del tratamiento de la infección por HIV. / [Current status of the treatment of HIV infection]

The antiretroviral therapeutic strategy changed in 1996, when the prognostic value of the plasma viral load and the CD4 cell counts were confirmed. Two nucleosides, plus a protease inhibitor or a non-nucleoside, are currently the initial preferred options. Viral resistance, and pharmacokinetic problems, however, have limited the efficacy of these schemes. It should be emphasized that continued use of triple drug therapy regimens have been associated with a decrease of morbidity and mortality associated to AIDS. We have analyzed the different drug combinations used in clinical trials and their results, the definition of therapeutic failure, and its consequences to control the treatment. With the currently available regimens, the virus cannot be totally eradicated from the organism and treatment should be continued for life. The combination of drugs in a single tablet, and the decrease in the number of daily intakes can help the patient with adherence, and allow for supervised treatment programs like the ones already applied with success in the treatment of tuberculosis. The use of virus resistance assays and pharmacokinetic assays will help to select the most appropriate treatment in the near future.