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Drug-Resistant Streptococcus pneumoniae for Community-Acquired Pneumonia: A Moving Target

File, Thomas M. Jr MD

Infectious Diseases in Clinical Practice: November 2008 - Volume 16 - Issue 6 - p 343-344
doi: 10.1097/IPC.0b013e31818db342
Editorial Comment

Infectious Disease Section, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown and Infectious Disease Service, Summa Health System, Akron, OH.

Address correspondence and reprint requests to Thomas M. File Jr, MD, 75 Arch St. Suite 105 Akron, OH 44304. E-mail:

Streptococcus pneumoniae is the most significant bacterial pathogen associated with community-acquired respiratory tract infections. It is particularly an important cause of community-acquired pneumonia (CAP) for which it is the most common cause of mortality. It is therefore, essential that empirical therapy for CAP include antimicrobial agents effective for this pathogen. The decision concerning appropriate empirical therapy has become more complicated over the past 2 decades because of the emergence of strains resistant to penicillin and other antimicrobials. However, the relevance of drug-resistant S. pneumoniae (DRSP) in relation to the clinical outcome of CAP has also been controversial.

Risk factors for DRSP include age younger than 2 years or older than 65 years, recent or repeated β-lactam, macrolide, or fluoroquinolone therapy, alcoholism, medical comorbidities, immunosuppressive illness or therapy, and exposure to a child in a day care center. In this issue of the journal, Aspa et al1 evaluated specific risk factors for multidrug-resistant S. pneumoniae and found that Pneumonia Severity Index score, asthma, human immunodeficiency virus infection, previous hospital admission and nursing home residence are risks in CAP patients. This observation related to multidrug-resistant S. pneumoniae is just a latest in a series of new factors regarding the clinical relevance of DRSP and which have come to light this year. Other factors include: (1) new breakpoint for penicillin; (2) new data concerning macrolide-resistant S. pneumoniae; (3) effect of conjugate pneumococcal vaccine; (4) emergence of resistant "replacement" strains, for example, 19A.

The clinical significance of drug resistant pneumococcal pneumonia appears most relevant to specific minimum inhibitory concentration (MIC) for specific antimicrobials. Current levels of β-lactam resistance generally do not cause treatment failures when appropriate agents (ie, amoxicillin, ceftriaxone, cefotaxime) and doses are used. Treatment failure is more likely for strains with penicillin resistance defined by MICs greater than 4 μg/mL. This factor is reflected by a change in 2008 of the Clinical and Laboratory Standards Institute (formerly National Committee for Clinical Laboratory Standards) breakpoints for parenteral penicillin G of susceptible (≤2 μg/mL), intermediate (4 μg/mL), and resistant (≥8 μg/mL) for nonmeningeal infections such as CAP. This change will hopefully assist clinicians in predicting which patients are at greater risk for clinical failure secondary to a resistant strain. The new more relevant breakpoint for penicillin will reduce the relative % of penicillin-resistant strains.

In addition, recent studies are also causing us to reassess the clinical relevance of macrolide-resistant S. pneumoniae for CAP. Although macrolide-resistant S. pneumoniae rates frequently exceed 25% around the world, macrolides continue to be recommended as empiric agents for CAP, although alternative therapy is recommended when this threshold is exceeded in the community.2 Treatment failures after macrolide therapy for pneumococcal infections are common. Daneman et al3 reported that macrolide failures were significantly more common among patients with pneumococcal bacteremia with isolates exhibiting an erythromycin MIC of 1 μg/mL versus isolates exhibiting MICs of 0.25 μg/mL; the likelihood of macrolide failure was not increased further for MICs greater than 1 μg/mL. Azithromycin and clarithromycin failures were associated with both low-level and high-level resistance. The authors concluded that macrolide resistance contributes to an increased risk of macrolide failure independent of underlying resistance mechanisms, degree of elevation in erythromycin MIC, or the macrolide being used for therapy. These data contradict previous opinion that eradication of mef strains (particularly with MICs <8 μg/mL) with macrolide therapy can often be achieved with sufficiently high tissue levels. In another study, Daneman et al investigated the implications of using the 25% rate of high-level macrolide-resistant S. pneumoniae prevalence as a predictor of risks associated with clinical failure in patients with CAP.4 Their model found that when physicians empirically prescribed macrolides (up to the 25% threshold), therapy-attributable mortality occurred in approximately 1 in 100 patients, and a prolonged course of therapy occurred in 3.3% of patients secondary to infection with a macrolide-resistant strain. This risk was elevated further in older patients and those with underlying comorbidities. These findings question whether empiric macrolide use needs to be curtailed at lower rates of resistance in at-risk individuals.

Finally, availability of the pneumococcal conjugate vaccine has led to a 57% reduction of invasive pneumococcal disease due to drug-resistant strains in young children (<2 years) and the elderly.5 The clinical impact of invasive S. pneumoniae infections due to multidrug-resistant isolates may therefore be waning. However, serotype A19 S. pneumoniae, which is not contained in the conjugate vaccine, has emerged as a cause of clinical infection.6 This strain is resistant to clindamycin and the more potent β-lactams such as ceftriaxone, but does retain susceptibility to the ketolides (eg, telithromycin and cethromycin) and the respiratory fluoroquinolones.

Although our understanding of the clinical relevance of drug resistance is enhanced by these new developments, our approach to therapy must also evolve for the betterment of our patients. It is anticipated that such changes and others to come will be reflected in updates of future guidelines.

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1. Aspa J, Rajas O, de Castro FR, et al. Risk factors for multidrug-resistant pneumococcal pneumonia. Infect Dis Clin Pract. 2008; this issue.
2. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.
3. Daneman N, McGeer A, Green K, et al. Macrolide resistance in bacteremic pneumococcal disease: implications for patient management. Clin Infect Dis. 2006;43:432-438.
4. Daneman N, Low DE, McGreer A, et al. At the threshold: defining clinically meaningful resistance thresholds for antibiotic choice in community-acquired pneumonia. Clin Infect Dis. 2008;46:1131-1138.
5. Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med. 2006;354:1455-1463.
6. Moore MR, Gertz RE Jr, Woodbury RL, et al. Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the US. J Infect Dis. 2008;197:1016-1102.
© 2008 Lippincott Williams & Wilkins, Inc.