Searching for the Optimal Treatment of Ceftriaxone-Resistant Streptococcus pneumoniae in Community-Acquired Pneumonia

Abstract

Ceftriaxone-resistant Streptococcus pneumoniae (CRSP) (minimal inhibitory concentration > 1 mcg/mL) is a growing major concern in the optimal selection of empirical antimicrobial treatment of community-acquired pneumonia (CAP). It has been estimated that up to 37.9% of S. pneumoniae are resistant to ceftriaxone in the United States in 2012,1 with a mean of 19.2% in Europe including greater than 25% in Eastern Europe (Bulgaria, Romania, and Turkey) in 20112 and 18.5% in China in 2011.3 This high rate of CRSP has been in part correlated with the introduction of the PCV7 in 2001 and of PCV13 in 2010 and the selection of serotypes 19A, 6C, and 22F.4,5 The increasing use of antimicrobials in humans and in food-producing animals among others is expected to contribute to the rising rate of CRSP.6 Mutation of cell wall penicillin-binding protein (PBP), particularly PBP1a, PBP2x, and PBP2b, was associated with CRSP.7 Because S. pneumoniae is the most common etiologic agent of CAP, physicians should optimize the empirical therapy of CAP in areas with a high rate of CRSP. Wenzler et al8 examined in this issue the clinical outcomes of patients with CRSP (minimal inhibitory concentration > 1 mcg/mL) versus ceftriaxone-susceptible S. pneumoniae in adult patients with pneumonia and respiratory culture positive for S. pneumoniae. Regardless of the sample size limitation, this study has striking findings. None of the patients with CRSP infection had 90 days of previous exposure of ceftriaxone. Time to clinical cure was longer in patients with CRSP (4 [1–5] vs 8 [3–12] days, P = 0.51), and length of stay was longer for patients with CRSP (17 [9–23] vs 9 [7–13] days, P = 0.46). The empirical treatment was changed in 50% of the patients with CRSP infection versus 0% in those with ceftriaxone-susceptible pneumoniae infection. A 50% of patients with CRSP infection were treated with fluoroquinolones, and 70% were treated with either vancomycin or linezolid. Among other findings, 70% of the patients with CRSP infection had pneumonia severity index of IV or greater. Overall, both groups had similar clinical outcomes although these outcomes may not have been similar if patients with CRSP infection were treated with ceftriaxone according to CAP treatment guidelines. Large prospective studies are needed to validate the optimal treatment of CRSP CAP. Current options for the treatment of CRSP CAP are fluoroquinolones, vancomycin, linezolid, and ceftaroline. Ceftaroline is the first of the growing group of active cephalosporins against methicillin-resistant Staphylococcus aureus and it also has activity against CRSP. Ceftaroline showed sustained bactericidal activity against CRSP in a pharmacokinetics and pharmakodynamics model study.9 This ceftaroline activity was validated in a rabbit model at a simulated human dose of 20 mg/kg by reducing 6 log units of CRSP in the lungs.10 Furthermore, a second analysis of studies focus 1 and 2 revealed that patients with S. pneumoniae CAP treated with ceftaroline had more favorable outcome than patients treated with ceftriaxone (odds ratio, 2.6; 95% confidence interval, 1.11–6.17; P = 0.0286).11 An approach in the empirical therapy of CRSP CAP could be a similar strategy used for bacterial meningitis by adding vancomycin to ceftriaxone treatment. Current Infectious Diseases Society of America guidelines do not recommend the use of vancomycin in cases with severe CAP nor CRSP. Vancomycin has a limited bactericidal activity when compared with β-lactams. Although levofloxacin and moxifloxacin have effective activity against CRSP, fluoroquinolones use has been reported to trigger higher rates of multiple drug resistance Pseudomonas, methicillin-resistant Staphylococcus aureus, and Clostridium difficile infections.12 In contrast to linezolid, ceftaroline has a spectrum similar to ceftriaxone covering gram-negative rods, including those etiologic organisms of CAP such as Klebsiella spp., Haemophilus spp., and Moraxella. In summary, physicians should consider antimicrobials with activity against CRSP in patients with CAP residing in areas with substantial prevalence of CRSP, in particular, those from the US southern states, having history of previous antibiotic therapy, and being immunocompromised.1,6 This concern is critical in patients with advanced comorbidities and increased risk for poor outcomes. Current data support more the use of ceftaroline treatment in cases with suspected CRSP pneumonia. Physicians should be cautious to use fluoroquinolones treatment of CRSP infection given the risk for antimicrobial resistance. Other treatment options include vancomycin although it has limited bactericidal activity compared with β-lactams and linezolid, which has the advantage of 100% of intestinal absorption that makes it a candidate for oral therapy.