Correspondence
Drug-Resistant Streptococcus pneumoniae
N Engl J Med 1996; 334:53-55January 4, 1996
- Article
To the Editor:
Since the first description of infection caused by β-lactam–resistant Streptococcus pneumoniae, the optimal empirical antibiotic therapy for patients with suspected meningitis caused by this microorganism has remained unknown. Hofmann et al. (Aug. 24 issue)1 reported a 25 percent prevalence of penicillin-resistant S. pneumoniae isolates and a 9 percent prevalence of cephalosporin-resistant isolates among 431 patients with invasive pneumococcal infections in Atlanta. The authors recommended adding vancomycin to the initial therapeutic regimen of patients with suspected pneumococcal meningitis. Their suggestion appears questionable because they did not present the susceptibility patterns of the meningeal strains or discuss morbidity and mortality, there are insufficient published data to support their recommendation, and the adjunctive use of dexamethasone may reduce the penetration of vancomycin into the cerebrospinal fluid. In addition, there have been reports in the literature on the failure of vancomycin monotherapy for S. pneumoniae meningitis.2 Finally, it has recently been shown that the clinical outcome of patients with meningitis due to S. pneumoniae that is relatively resistant to broad-spectrum cephalosporins (minimal inhibitory concentration [MIC] of cefotaxime, <2 μg per milliliter) is similar to that of patients infected with susceptible strains and that treatment with high doses of cefotaxime could be appropriate in this setting.3,4
Before recommending the routine addition of vancomycin to the regimen used to treat suspected cases of S. pneumoniae meningitis, one should first demonstrate that its use is associated with a significant survival benefit. Another approach would be to reserve the use of vancomycin for infections that do not respond to β-lactam antibiotics, which would help delay the emergence of vancomycin-resistant strains of S. pneumoniae, such as we are now seeing with the strains resistant to broad-spectrum cephalosporins.
4 ReferencesEnrique Redondo, M.D.
Hospital Ramón y Cajal, 28034 Madrid, Spain1
Hofmann J ,Cetron MS ,Farley MM , et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995;333:481-486
Full Text | Web of Science | Medline2
Viladrich PF ,Gudiol F ,Linares J , et al. Evaluation of vancomycin for therapy of adult pneumococcal meningitis. Antimicrob Agents Chemother 1991;35:2467-2472
Web of Science | Medline3
Tan TQ ,Schutze GE ,Mason EO Jr ,Kaplan SL . Antibiotic therapy and acute outcome of meningitis due to Streptococcus pneumoniae considered intermediately susceptible to broad-spectrum cephalosporins. Antimicrob Agents Chemother 1994;38:918-923
Web of Science | Medline4
Almirante B, Cortés E, Pigrau C, et al. Clinical significance and outcome of meningitis caused by Streptococcus pneumoniae relatively resistant to broad-spectrum cephalosporins. In: Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 17–20, 1995. Washington, D.C.: American Society for Microbiology, 1995:289. abstract.
To the Editor:
In the study by Pallares et al. (Aug. 24 issue)1 the mortality rate in patients with pneumonia caused by penicillin- or cephalosporin-resistant S. pneumoniae who were treated with penicillin, cefotaxime, or ceftriaxone was similar to that in patients infected with pneumococcal strains that were sensitive to these drugs. In the accompanying study by Hofmann et al., the prevalence of penicillin-resistant strains was 25 percent and of cefotaxime-resistant strains 9 percent among 431 patients in the Atlanta area.2 Neither report specifically mentioned ceftazidime. The data show that ceftazidime is much less active against penicillin-resistant strains than is cefotaxime.3
The mortality rate for severe community-acquired pneumonia is high (20 to 50 percent), and the most common etiologic agent is S. pneumoniae (followed closely by Legionella pneumophila). The 1993 recommendations of the American Thoracic Society for empirical treatment include the use of a macrolide antibiotic plus an antipseudomonal third-generation cephalosporin.4 But the use of an agent such as ceftazidime, which is approximately 16 times less active than cefotaxime against penicillin-resistant strains, may not in fact yield results such as those reported by Pallares et al.1 The addition of erythromycin to a regimen including ceftazidime may be of only limited benefit in patients with penicillin- or cephalosporin-resistant pneumococcal disease, given the rate of resistance to erythromycin of approximately 45 percent among these isolates.2
Do Pallares et al. have any data on patients with penicillin- or cephalosporin-resistant pneumococcal strains who were treated with ceftazidime alone or on patients with erythromycin-resistant strains who were treated with erythromycin alone? If Hofmann et al. tested the pneumococcal strains against ceftazidime, what was the overall resistance rate? What percentage of strains had an even higher level of resistance (i.e., MIC, >8 or 16 μg per milliliter)? It is in patients infected with such strains that ceftazidime may fail as a therapeutic agent.
Most patients with pneumonia are treated without a definite etiologic agent ever being identified. Many of these patients will have pneumococcal disease, and the efficacy of ceftazidime in patients infected with resistant pneumococcal strains remains uncertain.
4 ReferencesNeville Clynes, M.D.
Columbia–Presbyterian Medical Center, New York, NY 100321
Pallares R ,Linares J ,Vadillo M , et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474-480
Full Text | Web of Science | Medline2
Hofmann J ,Cetron MS ,Farley MM , et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995;333:481-486
Full Text | Web of Science | Medline3
Friedland IR ,McCracken GH Jr . Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994;331:377-382
Full Text | Web of Science | Medline4
Niederman MS ,Bass JB Jr ,Campbell GD , et al. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy. Am Rev Respir Dis 1993;148:1418-1426
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Redondo that the optimal therapy for drug-resistant S. pneumoniae infections has not been defined, especially for strains with intermediate levels of drug resistance. Our comments were focused on the treatment of meningitis due to S. pneumoniae that is resistant (MIC, >2.0 μg per milliliter) to extended-spectrum cephalosporins (i.e., cefotaxime and ceftriaxone). There are adequate data to suggest that this condition should not be treated with an extended-spectrum cephalosporin alone. Clinical failures have been reported,1 and cerebrospinal fluid levels of drug2 are frequently far less than that needed to achieve bactericidal activity against resistant strains. A synergistic effect occurs when vancomycin is added to an extended-spectrum cephalosporin to treat strains resistant to extended-spectrum cephalosporins,2 and recent data suggest that dexamethasone therapy does not diminish levels of the drug achievable in cerebrospinal fluid in children with meningitis.2
In our study, 1 of 18 cerebrospinal isolates (6 percent) was resistant to cefotaxime (MIC, 4.0 μg per milliliter). Although this number of isolates is too small to estimate the prevalence of resistance, our data on 431 pneumococcal isolates from normally sterile sites provide precise estimates of drug resistance among pneumococci circulating in Atlanta during the study period. Bacterial meningitis is a life-threatening infection with high mortality and the potential for severe neurologic sequelae if optimal therapy is delayed. In communities such as Atlanta, with four percent of isolates resistant to cefotaxime (MIC, >2.0 μg per milliliter), it would be unreasonable to await more clinical data before recommending that vancomycin be added empirically to regimens including extended-spectrum cephalosporins for the treatment of pneumococcal meningitis. Vancomycin should be discontinued immediately if the strain is susceptible to extended-spectrum cephalosporins. For nonmeningeal infections, appropriate recommendations are not as clear. Additional outcome data and interim consensus recommendations for treatment are critically needed. We agree that routine use of vancomycin is not warranted for the vast majority of pneumococcal infections and may promote the emergence of a vancomycin-resistant strain.3 Our recommendations were focused on meningitis in Atlanta, where the prevalence of strains resistant to extended-spectrum cephalosporins is high; however, even if our recommendations were applied nationally, limited use of vancomycin for meningitis as we described would exert minimal selective pressure, given that only 3000 cases of pneumococcal meningitis occur in the United States annually and most patients (with strains susceptible to extended-spectrum cephalosporins) would be treated for only one to two days.
The patterns and prevalence of drug-resistant S. pneumoniae vary geographically and temporally.3 Few communities in the United States currently have access to timely surveillance data like those available for Atlanta. Surveillance for drug-resistant S. pneumoniae will soon be conducted nationwide and will provide clinicians with timely, community-specific information for making rational choices for the empirical treatment of pneumococcal infections.3
We did not test pneumococcal isolates for resistance to ceftazidime because it has poor activity against penicillin-resistant strains of S. pneumoniae. 4
4 ReferencesJo Hofmann, M.D.
Martin S. Cetron, M.D.
Robert F. Breiman, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333Monica M. Farley, M.D.
Emory University School of Medicine, Atlanta, GA 303031
Paris MM ,Ramilo O ,McCracken GH . Management of meningitis caused by penicillin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 1995;39:2171-2175
Web of Science | Medline2
Klugman KP ,Friedland IR ,Bradley JS . Bactericidal activity against cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis. Antimicrob Agents Chemother 1995;39:1988-1992
Web of Science | Medline3
Cetron MS, Jernigan DJ, Breiman RF, DRSP Working Group
CrossRef | Web of Science | Medline4
Linares J ,Alonso T ,Perez JL , et al. Decreased susceptibility of penicillin-resistant pneumococci to twenty-four β-lactam antibiotics. J Antimicrob Chemother 1992;30:279-288
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Clynes that ceftazidime is much less active against penicillin-resistant pneumococci than is cefotaxime or ceftriaxone. We and others1,2 have previously reported that ceftazidime belongs to the group of β-lactam antibiotics with the poorest activity against pneumococci with intermediate and high levels of resistance to penicillin. For penicillin-resistant pneumococci, the MICs of ceftazidime ranged from 1 to 64 μg per milliliter, whereas the MICs of cefotaxime or ceftriaxone ranged from 0.03 to 2 μg per milliliter.1 Among the 35 pneumococcal strains isolated from our patients with pneumonia that showed resistance to cefotaxime or ceftriaxone (MIC, 1.0 to 4.0 μg per milliliter), the MICs of ceftazidime ranged from 16 to 64 μg per milliliter.
We have no experience with patients with penicillin-resistant pneumococcal pneumonia treated with ceftazidime alone. The three patients infected with penicillin-resistant pneumococci who were treated with ceftazidime also received either erythromycin or vancomycin, and the strains isolated were susceptible to these drugs. However, pneumococcal pneumonia developed in four patients during or shortly after a course of ceftazidime therapy, and in these four cases the MICs of ceftazidime ranged from 8 to 32 μg per milliliter. Therefore, we believe that ceftazidime should not be used for the treatment of penicillin-resistant pneumococcal pneumonia. We also agree with Clynes that the addition of erythromycin to ceftazidime therapy may be of only limited benefit because of the high frequency of erythromycin-resistant pneumococci that is being reported worldwide.
Among our 34 patients with pneumococcal pneumonia who were treated with erythromycin alone, there were no cases of resistance to this agent (for all these strains the MIC of erythromycin was <0.25 μg per milliliter). In a recent study3 therapy with erythromycin failed in two of six patients with pneumococcal pneumonia because the strains were resistant to erythromycin.
We believe that patients with pneumonia caused by pneumococci with high-level resistance to erythromycin (MIC, >4.0 μg per milliliter) should not be treated with this drug and that clinicians should be cautious in prescribing erythromycin for the empirical treatment of pneumonia, particularly in areas with a high prevalence of resistant pneumococci.
On the basis of the current levels of resistance, we think that most patients with severe pneumonia can be treated empirically with ceftriaxone or cefotaxime plus erythromycin. However, in selected patients with serious underlying conditions (e.g., neutropenia), a regimen including erythromycin and an antipseudomonal agent such as imipenem should be given.
3 ReferencesRoman Pallares, M.D.
Josefina Liñares, M.D.
Francesc Gudiol, M.D.
Hospital de Bellvitge, Barcelona, Spain1
Linares J ,Alonso T ,Perez JL , et al. Decreased susceptibility of penicillin-resistant pneumococci to twenty-four β-lactam antibiotics. J Antimicrob Chemother 1992;30:279-288
CrossRef | Web of Science | Medline2
Spangler SK ,Jacobs MR ,Appelbaum PC . Susceptibilities of 177 penicillin-susceptible and -resistant pneumococci to FK 037, cefpirome, cefepime, ceftriaxone, cefotaxime, ceftazidime, imipenem, biapenem, meropenem, and vancomycin. Antimicrob Agents Chemother 1994;38:898-900
Web of Science | Medline3
Moreno S ,Garcia-Leoni ME ,Cercenado E ,Diaz MD ,Bernaldo de Quiros JC ,Bouza E . Infections caused by erythromycin-resistant Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study. Clin Infect Dis 1995;20:1195-1200
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
T.J Shaar, R Al-Hajjar. (2000) Antimicrobial susceptibility patterns of bacteria at the Makassed General Hospital in Lebanon. International Journal of Antimicrobial Agents 14:2, 161-164
CrossRef
