Correspondence
Emergence of Macrolide Resistance during Treatment of Pneumococcal Pneumonia
N Engl J Med 2002; 346:630-631February 21, 2002
- Article
To the Editor:
The emergence of antibiotic resistance during treatment for pneumococcal infection is exceedingly rare.1 To our knowledge, there is no previous report of a genetically characterized, antibiotic-resistant pneumococcal mutant emerging during therapy and serving as the cause of treatment failure.
A previously healthy 28-year-old man presented with a five-day history of cough and dyspnea. He had hypotension, hypothermia, and rales in the right upper lung. His white-cell count was 14,000 per cubic millimeter (28 percent bands). Chest roentgenography showed infiltrates in the right middle and upper lobe. The sputum contained abundant gram-positive diplococci, and culture yielded Streptococcus pneumoniae; blood cultures were negative.
Empirical therapy with 500 mg of azithromycin per day intravenously was begun at admission, and the patient's condition improved rapidly. On the fourth day of treatment, his condition suddenly deteriorated, and hypotension and hypothermia again appeared. Roentgenography revealed extensive right-sided infiltrates and pleural effusion. Cultures of bronchoalveolar-lavage and pleural fluids yielded pneumococcus; blood cultures were negative. Ceftriaxone and vancomycin were administered, but multiorgan failure developed, and the patient died. His relatives declined to give permission for an autopsy.
The isolates of S. pneumoniae from the initial sputum sample and from pleural fluid obtained at the time of relapse were serotype 3 and were identical on BOX polymerase chain reaction (BOX elements are interspersed repetitive DNA sequences in S. pneumoniae) and ribotype analysis.2 The initial isolate was fully susceptible to all antibiotics tested, including penicillin (minimal inhibitory concentration [MIC], <0.016 μg per milliliter), clindamycin (MIC, 0.008 μg per milliliter), erythromycin (MIC, 0.015 μg per milliliter), azithromycin (MIC, 0.008 μg per milliliter), and quinupristin–dalfopristin (MIC, 0.12 μg per milliliter). In contrast, the later isolate, although still susceptible to penicillin and clindamycin, was resistant to erythromycin, azithromycin, and quinupristin–dalfopristin (MIC, 2 to 4 μg per milliliter). Neither isolate contained erm(B) or mef(A),3 two determinants of erythromycin resistance.
Genes encoding 23s ribosomal RNA and ribosomal proteins involved in macrolide binding were sequenced. The gene for ribosomal protein L22 in the macrolide-resistant mutant contained an 18-bp tandem repeat that was not present in the original isolate. This insertion resulted in the duplication of six amino acids — 102KRTAHITRTAHITVA116 — adjacent to the macrolide-binding site on the 23s RNA (Figure 1Figure 1
The Macrolide-Binding Site of the Resistant Mutant.). No other mutations were identified.Macrolides inhibit bacterial-protein translation by inserting themselves into a pocket of the 23S ribosomal subunit at the site of protein assembly. Most macrolide-resistant pneumococci alter the macrolide-binding site by erm(B)-encoded methylation of A2058 or exclude macrolides by a mef(A)-encoded efflux pump.5 Mutations that alter protein sequences in this pocket may, however, cause macrolide resistance, as has been demonstrated for ribosomal proteins L4 and L22.6,7 We hypothesize that, in the mutant strain from this patient, the six-amino-acid repeat in L22 disrupts the binding cavity by altering the tertiary structure of the hairpin (Figure 1). The mutation occurred during therapy, causing a relapse that was fatal.
7 ReferencesDaniel M. Musher, M.D.
Veterans Affairs Medical Center, Houston, TX 77030
daniel.musher@med. va. gov Mark E. Dowell, M.D.
Wyoming Medical Center, Casper, WY 82601Virginia D. Shortridge, Ph.D.
Robert K. Flamm, Ph.D.
Abbott Laboratories, Abbott Park, IL 60024James H. Jorgensen, Ph.D.
University of Texas Health Science Center, San Antonio, TX 78284Pierre Le Magueres, Ph.D.
Kurt L. Krause, Ph.D., M.D.
University of Houston, Houston, TX 772041
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