Therapeutics

6 weeks of antibiotics was noninferior to 12 weeks for clinical cure in pyogenic vertebral osteomyelitis 多多多多多多夞

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Bernard L, Dinh A, Ghout I, et al; Duration of Treatment for Spondylodiscitis (DTS) study group. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet. 2015;385:875-82.

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Question In patients with pyogenic vertebral osteomyelitis (PVO), is 6 weeks of antibiotic therapy noninferior to 12 weeks of therapy?

Methods Design: Randomized controlled noninferiority trial (Duration of Treatment for Spondylodiscitis [DTS] study). ClinicalTrials.gov NCT00764114, EudraCT 2006-000951-18.

⫺2.5, 95% CI ⫺8.2 to 2.9) analyses. Other outcomes are in the Table.

Conclusion In patients with pyogenic vertebral osteomyelitis, 6 weeks of antibiotic therapy was noninferior to 12 weeks of therapy for clinical cure.

Allocation: Concealed.*

*See Glossary.

Blinding: Blinded* (outcome adjudicators).

Source of funding: French Ministry of Health.

Follow-up period: 1 year.

For correspondence: Prof. L. Bernard, University Hospitals of Tours, Tours, France. E-mail [email protected]. 

Setting: Infectious disease, rheumatology, and internal medicine departments in 71 clinical centers in France.

Commentary

Patients: 359 adults ≥ 18 years of age (mean age 61 y, 69% men) who had microbiologically confirmed PVO with typical radiologic features. Exclusion criteria included presence of vertebral implants; pregnancy or breast-feeding; recurrence of spondylodiscitis; fungal, brucellar, or mycobacterial infection; or life expectancy < 1 year. Intervention: Parenteral and oral antibiotic therapy for 6 weeks (n = 182) or 12 weeks (n = 177). The antibiotic regimen was chosen by the treating physician in accordance with French guidelines. Outcomes: Clinical cure (sustained absence of fever, pain, and the inflammatory syndrome), cured and alive, and cured without further antibiotic therapy at 1 year. Secondary outcomes included adverse events. Noninferiority of 6 weeks of therapy was declared if the lower 95% CI for the between-group difference in the proportion of cured patients was < 10%. Patient follow-up: 81% (intention-to-treat analysis).

Main results The most common causative organisms were Staphylococcus aureus (41%, 2% of patients had methicillin-resistant S. aureus [MRSA]), Streptococcus species (18%), coagulase-negative Staphylococcus (17%), and enterobacterial species (11%). 6 weeks of antibiotic therapy was noninferior to 12 weeks of therapy for clinical cure according to both intention-to-treat (Table) and per protocol (difference in proportion of patients cured

In their multicenter, noninferiority randomized controlled trial (RCT) comparing 6 and 12 weeks of antimicrobial therapy in patients with PVO, Bernard and colleagues used a pragmatic design that allowed physicians to choose antimicrobial regimens for their patients. Concerns arising from the open-label design are partly allayed by the comparable antibiotics used in the 2 groups. The realistic 19% loss to follow-up would not be expected to bias the outcome given the similar distribution of withdrawals across groups and the inclusion of lost patients in the final analysis after blind classification as cures or failures. The representativeness of enrolled patients is a primary consideration in pragmatic trials (1), and the wide inclusion criteria in the RCT helped to achieve representativeness. However, the low prevalence of MRSA should be taken into account in centers with different epidemiology. Time to diagnosis was not reported, which reduces confidence in generalizing the results, particularly because the mean time to diagnosis for PVO is 42 to 59 days after symptom onset (2), and prolonged treatment is sometimes suggested due to delayed diagnosis. Finally, the important consequences of treatment failure coupled with the unclear benefits of a shorter treatment course demand a conservative margin, and the 10% noninferiority margin seems to satisfy this need. Overall, the trial by Bernard and colleagues provides strong evidence for the noninferiority of 6 weeks of antibiotics compared with 12 weeks for PVO. Uncontrolled use of antimicrobial agents has been associated with an increase in antimicrobial resistance. Trials evaluating shorter antimicrobial courses are a crucial step in guiding evidence-based decisions that decrease this antimicrobial pressure (3).

6 vs 12 wk of antibiotic therapy for pyogenic vertebral osteomyelitis† Outcomes

Event rates 6 wk

12 wk

Cured‡

91%

91%

Cured and alive

89%

86%

Cured without further antibiotic therapy

81%

81%

Patients with ≥ 1 adverse event

29%

29%

Fainareti N. Zervou, MD Ioannis M. Zacharioudakis, MD Eleftherios Mylonakis, MD, PhD Brown University Providence, Rhode Island, USA

At 1 y RBI (95% CI)

NNT

0.06% (⫺7 to 7)§ Not significant 3% (⫺5 to 13)

Not significant

0.1% (⫺10 to 11) Not significant

RRI (CI)

NNH

1% (⫺27 to 41)

Not significant

†Abbreviations defined in Glossary. RBI, RRI, and CI calculated from event rates in article.

References 1. Caro JJ, Ishak KJ. Optimizing the design of pragmatic trials: key issues remain. J Comp Eff Res. 2012;1:319-27. 2. Landman GW. Vertebral osteomyelitis [Letter]. N Engl J Med. 2010;362: 2335; author reply 2335-6. 3. Rice LB. The Maxwell Finland Lecture: for the duration—rational antibiotic administration in an era of antimicrobial resistance and Clostridium difficile. Clin Infect Dis. 2008;46:491-6.

‡Sustained absence of fever, pain, and the inflammatory syndrome. §Criterion for noninferiority was met because the lower CI of the difference in proportion of patients cured (0.05%, CI ⫺6.2 to 6.3) was < 10%.

19 May 2015

Annals of Internal Medicine

ACP Journal Club

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姝 2015 American College of Physicians

ACP Journal Club. 6 weeks of antibiotics was noninferior to 12 weeks for clinical cure in pyogenic vertebral osteomyelitis.

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