Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia

Lodise, Thomas P.; Kwa, Andrea Lay-Hoon; Cosler, Leon E.; Gupta, Rishu; Smith, Raymond P.

doi:10.1128/aac.00006-07

Cited by 104 publications

(76 citation statements)

References 48 publications

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“…Two non-randomized trials reported different conclusions; one favoured levofloxacin and one favoured a combination of β-lactam and macrolide. 46,47 A possible explanation for the higher treatment success in the fluoroquinolone groups may be because there was zero baseline resistance of the isolated pathogens to fluoroquinolones compared to the higher levels of resistance found for β-lactams and especially macrolides. However, the trials included in our analysis mainly examined S. pneumoniae isolates.…”

Section: Odds Ratio (95% Ci)mentioning

confidence: 99%

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials

Vardakas¹,

Siempos²,

Grammatikos³

et al. 2008

Canadian Medical Association Journal

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CMAJ ResearchBackground: We investigated whether the use of respiratory fluoroquinolones was associated with better clinical outcomes compared with the use of macrolides and β-lactams among adults with pneumonia. Methods:We searched PubMed, Current Contents, Scopus, EMBASE, ClinicalTrials.gov and Cochrane with no language restrictions. Two reviewers independently extracted data from published trials that compared fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) with macrolides or β-lactams or both. A meta-analysis was performed with the clinical outcomes of mortality, treatment success and adverse outcomes. Results:We included 23 trials in our meta-analysis. There was no difference in mortality among patients who received fluoroquinolones or the comparator antibiotics (OR 0.85, 95% CI 0.65-1.12). Pneumonia resolved in more patients who received fluoroquinolones compared with the comparator antibiotics for the included outcomes in the intention-to-treat population (OR 1.17, 95% CI 1.00-1.36), clinically evaluable population (OR 1.26, 95% CI 1.06-1.50) and the microbiologically assessed population (OR 1.67, 95% CI 1.28-2.20). Fluoroquinolones were more effective than a combination of β-lactam and macrolide (OR 1.39, 95% CI 1.02-1.90). They were also more effective for patients with severe pneumonia (OR 1.84, 95% CI 1.02-3.29), those who required admission to hospital (OR = 1.30, 95% CI 1.04-1.61) and those who required intravenous therapy (OR = 1.44, 15% CI 1.13-1.85). Fluoroquinolones were more effective than β-lactam and macrolide in open-label trials (OR = 1.35, 95% CI 1.08-1.69) but not in blinded randomized controlled trials (OR = 1.13, 95% CI 0.85-1.50).Interpretation: Fluoroquinolones were associated with higher success of treatment for severe forms of pneumonia; however, a benefit in mortality was not evident. A randomized controlled trial that includes patients with severe pneumonia with or without bacteremia is needed.

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Section: Odds Ratio (95% Ci)mentioning

confidence: 99%

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials

Vardakas¹,

Siempos²,

Grammatikos³

et al. 2008

Canadian Medical Association Journal

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“…The previous clinical data demonstrated that macrolide combination effects were more prominent in more severe cases of pneumonia (38,39). Accordingly, the question of how macrolides affect and modulate sepsis and sepsis-related host responses reflects another important issue for investigation.…”

Section: Cd11cmentioning

confidence: 99%

Efficacy of β-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia

Yoshioka

Kajiwara

Ishii

et al. 2016

Antimicrob Agents Chemother

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b Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although ␤-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of ␤-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo. We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone-treated group. Notably, the analysis of cell surface markers in the ceftriaxone-plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b ؉ CD11c ؉ ) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxoneplus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research.

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“…Data from retrospective analyses of patients with bacteremic pneumococcal pneumonia suggest that combination antibiotic therapy is associated with reduced mortality compared to that seen in those who receive monotherapy only (9). Combinations of antibiotics are usually adopted with the double aim of widening coverage and increasing antibacterial activity, which limits the occurrence and spread of resistant strains (10). A highly bactericidal antibiotic combination with excellent tissue penetration that does not lead to the emergence of resistance would be a major advantage in the treatment of pneumococcal diseases, particularly for the most severe forms.…”

mentioning

confidence: 99%

Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

Majhi

Adhikary

Bhattacharyya

et al. 2014

Antimicrob Agents Chemother

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In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10 6 CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates.

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Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia

Cited by 104 publications

References 48 publications

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials

Efficacy of β-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia

Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

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