IMPORTANCEThe clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial.OBJECTIVE To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS Open-label, multicenter, noninferiority, randomized trial conducted from in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONSPatients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm.MAIN OUTCOMES AND MEASURES Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCEWe did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.2. Nie W, Li B, Xiu Q. β-Lactam/macrolide dual therapy versus β-lactam monotherapy for the treatment of community-acquired pneumonia in adults: a systematic review and meta-analysis.

HCV infection has a severe course of disease in HIV/HCV co-infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV-specific T-cell responses in 86 HCV mono-infected patients, 48 HIV/HCV co-infected patients and 42 liver transplant recipients. IFN-c and IL-2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCVderived peptides. We observed that HCV-specific T-cell responses were polyfunctional in HCV mono-infected patients, with presence of proliferating single IL-2-, dual IL-2/IFN-c and single IFN-c-producing CD4 1 and dual IL-2/IFN-c and single IFN-c-producing CD8 1 cells. In contrast, HCV-specific T-cell responses had an effector profile in HIV/HCV coinfected individuals and liver transplant recipients with absence of single IL-2-producing HCV-specific CD4 1 and dual IL-2/IFN-c-producing CD8 1 T cells. In addition, HCV-specific proliferation of CD4 1 and CD8 1 T cells was severely impaired in HIV/HCV co-infected patients and liver transplant recipients. Importantly, ''only effector'' T-cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores.Ã These two authors contributed equally to this work. Therefore, the present results suggest that immune-based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV-1 co-infection and liver transplantation.

We compared the efficacy of a long-duration (3-week) therapy of vancomycin, fleroxacin, fleroxacin plus rifampin, and vancomycin plus fleroxacin and rifampin, in a. recently developed rat model of chronic staphylococcal foreign-body infection. Subcutaneous tissue cages containing polymethylmethacrylate coverslips were infected with 1 x 105 to 5 x 105 CFU of methicillin-resistant Staphylococcus aureus. Three weeks later, a quantitative culturing of the fluid that had accumulated in the cages was done (mean, 6.72 log1o CFU/ml; n -110) and treatment was initiated after randomization. The CFUs in the cage fluid were counted on days 11 and 22 and 1 week after the termination of treatment; in addition, a final culture of coverslips (surface-bound microorganisms) was performed. The three-drug therapy was significantly superior to the other treatments on day 11 (a 5.16 log1o decrease of bacterial counts versus a 2.12 log1o to 2.94 logl0 decrease for vancomycin, fleroxacin, and fleroxacin plus rifampin; P < 0.01). On day 22, count decreases were 4.16 loglo for vancomycin, 4.91 log1o for fleroxacin (vancomycin versus fleroxacin, not significant), 6.14 loglo for two-drug therapy, and 6.34 log1o for three-drug therapy (vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin, not significant; fleroxacin-rifampin versus monotherapies, P < 0.01); the numbers of CFU in most cage fluids were under the detection limit (20 CFU/ml) in combination groups. One week after the end of treatment, 92% of fluids and coverslips (detection limit, 1 CFU) were culture negative with tritherapy, 88% of fluids and 41% of coverslips were negative with bitherapy, and less than 12% of fluids and coverslips were negative with single drugs (for coverslips, P was <0.01 for vancomycin-fleroxacin-rifamhpin versus fleroxacin-rifampin and P was <0.001 for fleroxacin-rifampin versus the monotherapies). No mutants resistant to rifampin or fleroxacin were detected. In conclusion, antimicrobial combinations were highly effective and superior to single drugs in treating a chronic staphylococcal foreign-body infection for 3 weeks. The three-drug therapy decreased bacterial counts more rapidly than the two-drug therapy under study and appeared to be curative in most cases.Infection of implanted prosthetic devices is a major concern in modern medicine and surgery. Staphylococcus aureus is a frequent pathogen of such infections (18,25), and methicillin-resistant strains, encountered with increasing frequency (1, 27), raise important therapeutic problems. Standard antibiotic regimens, such as vancomycin alone or in combination with rifampin (11,13), are rarely able to cure patients without removal of the foreign implant (3, 5, 21), and rifampin-resistant mutants may emerge even under combination therapy (2,8,10,17,34).In a rat model of chronic staphylococcal subcutaneous foreign-body infection, we recently showed that a combined regimen of fleroxacin and rifampin administered for 6 days had the same efficacy as vancomycin plus rifampin and did not lead to the emer...

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