ATLANTA--Increasing rates of pneumococcal resistance pose a challenge for physicians who treat patients with community-acquired pneumonia (CAP). When should Streptococcus pneumoniae be considered susceptible to penicillin and other antimicrobial agents? How is resistance defined in patients with CAP? Should pneumococcal resistance to ß-lactams influence CAP therapy? What are the best empiric antimicrobial regimens for the treatment of outpatients and hospitalized patients with CAP?

To address these questions, the Centers for Disease Control and Prevention (CDC) convened the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. That panel has issued new recommendations for the management of CAP.[1]

"In this era of pneumococcal drug resistance, it is difficult for clinicians to select judicious drug regimens for CAP," Cynthia G. Whitney, MD, MPH, said in an interview with PULMONARY REVIEWS. "There is a tendency among some clinicians to treat aggressively with some of the newer broad-spectrum agents, even in patients in whom the standard narrow-spectrum agents would be more appropriate," added Dr. Whitney, a Medical Epidemiologist in the Respiratory Diseases Branch of the National Center for Infectious Diseases at the CDC in Atlanta.

DEFINING SUSCEPTIBILITY

The current categories for classifying pneumococcal isolates as penicillin-susceptible are not appropriate for guiding the treatment of pneumonia, the CDC panel concluded. "The National Committee for Clinical Laboratory Standards categories are more applicable to meningitis than to pneumococcal pneumonia," Dr. Whitney suggested. "It's much harder to treat meningitis because you have to get [the drug] into the spinal fluid," she added.

"With a bloodstream or lung infection, you can get a much higher concentration of antibiotic to the site of the infection. Because of that, you can use a standard agent, such as penicillin, even when there is some resistance," according to Dr. Whitney.

A key recommendation of the CDC panel, therefore, is to alter the interpretation of minimum inhibitory concentrations (MICs), because MICs have been shown to influence which antimicrobial agents clinicians choose for the treatment of pneumococcal pneumonia. The current definition of S pneumoniae susceptibility--0.06 µg/mL or below--is too low in patients with pneumonia, the working group decided. In addition, this low break point may actually contribute to the overprescribing of broad-spectrum antibiotics, which are known to cause pneumococcal resistance.

This is especially true given that clinicians' choice of antibiotic is frequently influenced more by the MIC interpretation than by the status of the patient.[2] Thus, modifying the MIC break points for CAP so that more pneumococcal pneumonia isolates are reported appropriately as susceptible may lead to a decrease in the overuse of broad-spectrum antibiotics.

Therefore, the panel recommended adjusting the penicillin susceptibility categories for pneumonia-causing pneumococcal isolates so that all isolates with MIC no greater than 1 µg/mL would be defined as susceptible, isolates with MIC of 2 µg/mL would be considered intermediate, and isolates with MIC of no less than 4 µg/mL would be classified as resistant. Studies have demonstrated that even when the penicillin MIC is as high as 1 µg/mL, treatment with a ß-lactam antibiotic is effective against CAP.

OUTPATIENT THERAPY

According to the CDC panel, suitable empirical antimicrobial regimens for outpatients age 5 years or older with CAP should include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children age 8 years or older, or an oral ß-lactam with good antipneumococcal activity (eg, cefuroxime, amoxicillin, amoxicillin-clavulanate).

An oral fluoroquinolone with activity against S pneumoniae (eg, grepafloxacin or levofloxacin) can be used in adults who are allergic to alternative agents or who have a documented infection with highly drug-resistant pneumococci; it can also be administered when one of the other regimens has failed.

Nevertheless, the newer fluoroquinolones, such as levofloxacin or sparfloxacin, should be administered judiciously, Scott F. Dowell, MD, MPH, suggested in a recent interview with PULMONARY REVIEWS. "Overprescribing will speed the emergence of fluoroquinolone-resistant strains and limit the usefulness of these agents," explained Dr. Dowell, Acting Associate Director for Global Health, National Center for Infectious Diseases at the CDC in Atlanta. For children younger than age 5 years, in whom doxycycline and fluoroquinolones should be avoided, the panel recommends ß-lactams.

INPATIENT THERAPY

For moderately ill hospitalized patients with pneumonia, the CDC panel recommends a parenteral ß-lactam (eg, cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam) combined with a macrolide (eg, erythromycin, azithromycin, or clarithromycin). A fluoroquinolone is an alternative that can be used in selected adult patients.

Critically ill patients with CAP should initially receive an empiric antimicrobial regimen. One option is to combine an intravenous ß-lactam, such as cefotaxime or ceftriaxone, and an intravenous macrolide, such as erythromycin or azithromycin. Alternatively, intravenous ceftriaxone or cefotaxime plus a fluoroquinolone may be used for critically ill adults.

Monotherapy with a fluoroquinolone is not recommended, however, given that the efficacy of the new fluoroquinolones for critically ill patients with pneumococcal pneumonia has not been established. Furthermore, no single empirical regimen can cover all potential pathogens.

However, the CDC panel recommends that for moderately ill hospitalized patients--defined as those not admitted to the ICU--initial antimicrobial treatment should target the suspected etiologic agents and omit coverage of rare pathogens. The panel also noted that critically ill patients in the ICU should receive more comprehensive antimicrobial coverage.

USE OF VANCOMYCIN

Vancomycin should not be routinely utilized for the treatment of pneumococcal pneumonia, according to the panel. However, vancomycin should be included in the initial antimicrobial regimen for patients with suspected bacterial meningitis. The drug may also be appropriate for selected critically ill children with CAP. If included in an empirical antimicrobial regimen, vancomycin should be promptly discontinued if culture results indicate that the infecting strain does not require treatment with the drug.

Dr. Dowell stressed that while vancomycin is uniformly effective against pneumococci, indiscriminate use of the drug has been associated with resistance among other pathogens. "In general, vancomycin should be a last resort for patients with pneumococcal pneumonia," he added.

LABORATORY TESTING

The final recommendations issued by the CDC panel focused on laboratory testing and surveillance. The panel acknowledged that its suggestion to move the penicillin break points upward will require changes in the way laboratories report and clinicians interpret susceptibility results; susceptibility break points will differ according to the clinical syndrome being treated.

"Laboratories should report MICs for penicillin and extended-spectrum cephalosporins for all pneumococcal isolates from appropriately collected [specimens]," the report states. The panel recommended that all local laboratories should include the following antimicrobials in surveillance for antipneumococcal activity: penicillin, cefotaxime (or ceftriaxone), erythromycin, doxycycline (or tetracycline), clindamycin, and fluoroquinolones. Reference laboratories should also survey amoxicillin, cefuroxime, cefpodoxime (or cefprozil), clindamycin, vancomycin, trimethoprim-sulfamethoxazole, and meropenem.

--Stanley Nelson

References
1. Heffelfinger JD, Dowell SF, Jorgensen JH, et al. Management of community-acquired pneumonia in the era of pneumococcal drug resistance. Arch Intern Med. 2000;160:1399-1408.
2. Jernigen DB, Dowell SF, Liedtke LA, Strasbaugh LJ, for the Infectious Diseases Society of America Emerging Infections Network. Factors influencing antibiotic selection for community-acquired pneumonia (CAP). In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998, Denver, CO. Washington, DC. Infectious Diseases Society of America; 1998. Abstract 683.

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