Macrolide Resistance Among Invasive S pneumoniae Isolates

Abstract & Commentary

Synopsis: Macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, are the mainstays of empiric outpatient pneumonia therapy. In the setting of increasing macrolide use, pneumococcal resistance has become common. Most resistant strains have MICs in the range in which treatment failures have been reported. Further study and surveillance are critical to understand the clinical implications of this study.

Source: Hyde TB, et al. JAMA. 2001;286:1857-1862.

Macrolides are recommended as first-line therapy for adults in the United States and Canada with community-acquired pneumonia (CAP).1 Newer macrolides (eg, azithromycin, clarithromycin) are popular because of convenient dosing schedules and fewer adverse effects. Unfortunately, resistance to macrolides among Streptococcus pneumoniae, the most common cause of CAP, has been increasing in the United States.

Pneumococcal macrolide resistance is usually expressed as 1 of 2 phenotypes. The first, known as M phenotype, is an efflux pump associated with the mefE gene that results in efflux of macrolides from the cell. M phenotype isolates typically have moderate levels of macrolide resistance and are almost always susceptible to clindamycin. A second phenotype, MLSB, blocks the binding of macrolides, lincosamides (eg, clindamycin), and streptogramin B antibiotics. MLSB phenotype is associated with extremely high macrolide MICs and resistance to clindamycin.

Hyde and associates studied macrolide resistance in 15,481 invasive S pneumoniae isolates from 1995-1999 collected by the Centers for Disease Control and Prevention’s Active Bacterial Core surveillance system in 8 states. Macrolide resistance increased from 10.6% in 1995 to 20.4% in 1999. Increases were significant in all states but were especially high in Georgia (31.5%) and Tennessee (29.1%), and lower in New York (9.0%) and California (8.5%). M phenotype isolates increased from 7.4% to 16.5% (P < 0.001), while the proportion with the MLSB phenotype was stable (3-4%). M phenotype strains were more often from children than persons 5 years or older (25.2% vs 12.6%; P < 0.001) and from whites than blacks (19.3% vs 11.2%; P < 0.001). M phenotype commonly had reduced susceptibility to other antimicrobial agents including penicillin (81.1%), cefotaxime (60.5%), and trimethoprim-sulfamethoxazole (87.8%). Very few of the isolates were resistant to fluoroquinolones (0.3%).

The number of macrolide prescriptions increased significantly (13%) from approximately 17.7 million prescriptions (69 prescriptions/1000 persons) in 1993 to approximately 21.2 million prescriptions (78 prescriptions/1000 persons) in 1999 (P = 0.01). The most dramatic increase was among children younger than 5.

Hyde et al concluded that the prevalence of macrolide resistance among pneumococci doubled from 1995 to 1999 and M phenotype accounted for this increase. Among children younger than 5, factors such as higher incidence of nasopharyngeal carriage of S pneumoniae, day care attendance, and high frequency of antibiotic use may explain higher rates of macrolide-resistant strains. For younger children who are penicillin allergic, however, the management of respiratory tract infections may become problematic because doxycycline and fluoroquinolones are not available as alternatives for this age group. Clinical treatment guidelines for empiric therapy for CAP in adults have recommended using macrolides as first-line agents. The increasing frequency of macrolide resistance among pneumococci and increasing MICs among resistant strains suggest that these treatment recommendations may need re-evaluation. However, it is unclear whether pneumococci with M phenotype are clinically significant, especially since newer macrolides (eg, clarithromycin and azithromycin) achieve higher concentrations intracellularly in tissue and in the epithelial lining fluid of the lung than concentrations achieve in blood.

Comment By David Ost, MD, & Ali Mojaverian, MD

The problem of B-lactam resistance in S pneumoniae has been recently complicated by increasing resistances to macrolides and some older fluoroquinolones (ciprofloxacin and levofloxacin).3 Penicillin susceptibility of S pneumoniae is an important marker for the presence or absence of a multi-drug resistant phenotype. The multi-drug resistant phenotype rarely occurs in penicillin-susceptible isolates, but for a patient infected with penicillin-resistant S pneumoniae, one should assume cross-resistance to oral cephalosporins and a high likelihood (~40%) of additional cross-resistance to macrolides, tetracycline, and trimethoprime-sulfamethoxazole.2

Fogarty and colleagues studied the effectiveness of levofloxacin for adult CAP caused by macrolide-resistant S pneumoniae, and found a clinical success rate of 97.7% in patients infected with erythromycin-resistant isolates. He concluded levofloxacin might be a useful therapeutic option in patients with CAP caused by macrolide-resistant S pneumoniae. However, caution is warranted to prevent overprescription of fluoroquinolones, given the potential for the development of resistance.4 Chen and colleagues demonstrated that isolates with fluoroquinolone resistance in Canadian medical centers increased between 1993 (0.0%) and 1998 (1.7%), which corresponded to Canadian fluoroquinolone prescription increases (0.8-5.5/100 persons per year).5

In conclusion, macrolide-resistant S pneumoniae is becoming a significant problem that is likely secondary to increasing prescriptions for this class of antibiotics, and judicious prescription of antibiotics may be able to slow down the development of further resistant strains.

Dr. Ost, Assistant Professor of Medicine, NYU School of Medicine, Director of Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Northshore University Hospital, Manhasset, NY, is Associate Editor of Internal Medicine Alert. Dr. Mojaverian is a Fellow in Pulmonary and Critical Care Medicine, North Shore University Hospital, Manhasset, NY.


1. Niederman MS, et al. Am Rev Respir Dis. 1993;148: 1418-1426.

2. Zhanel G. Antimicrob Agents Chemother. 1999;43: 2504-2509.

3. Jones RN, Pfaller MA. J Clin Microbiol. 2000;38:4298-4299.

4. Fogarty CM, et al. Clin Ther. 2001;23:425-439.

5. Chen DK, et al. N Engl J Med. 1999;341:233-239.