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Antibiotic resistant pneumococci



Streptococcus pneumoniae causes more cases of community-acquired pneumonia than any other pathogen. The pneumococcus is responsible for more than half of all community-acquired pneumonia deaths. Particular populations are very vulnerable to pneumococcal pneumonia, including the elderly, patients with chronic obstructive lung disease and congestive heart failure, and patients with asplenia, sickle cell anemia, and multiple myeloma. It is estimated that 500,000 cases of pneumococcal pneumonia occur annually in the United States.
Within the past several years, some strains of pneumococci have developed resistance to penicillin and other antibiotics. Although penicillin was always recommended as the antibiotic of choice for pneumococcal infection, this recommendation is now not always appropriate, and the management of pneumococcal infection is much more complex. The problem is exacerbated by the common practice of using empiric antibiotic therapy for the treatment of community-acquired pneumonia without efforts to determine a particular etiologic agent. This type of empiric therapy is much more difficult in areas where resistant pneumococci have emerged.
The development of resistance to penicillin has been well recognized in Australia and New Guinea for 20 years. Resistance in South Africa has also been well appreciated, with early efforts for vaccine development sparked by concerns about antibiotic resistance. The resistance of the pneumococcus to penicillin and erythromycin was carefully tracked in the 1980s with increasing concern in Spain and other European countries. In 1994, a multicenter surveillance study in the United States showed that 24% of pneumococcal isolates had reduced sensitivity to penicillin, and 10% had high-level resistance. These percentages have been found to vary dramatically from one region of the country to another, and they can change rapidly in any one region.
The majority of penicillin-resistant pneumococci are of a few specific serotypes, and these serotypes are included in the 23-valent pneumococcal vaccine. Penicillin resistance has developed through chromosomally mediated genetic mutations that have caused changes in penicillin-binding proteins. The affinity of penicillin for these binding proteins is weakened, resulting in less antibiotic activity.
Classification of penicillin activity in regard to pneumococci can be confusing, as different authors have set up somewhat different categories. S. pneumoniae with minimal inhibitory concentrations (MIC) of less than 0.06 µg/mL are always considered penicillin-susceptible. Penicillin resistance is defined as intermediate when the MIC falls between 0.1 and 1 µg/mL. High-level resistance is usually defined as greater than 1 µm/mL, but sometimes as greater than 2 µm/mL. These breakpoints are most useful in understanding the treatment of meningitis, in that the breakpoints were determined based on antibiotic levels in cerebrospinal fluid.
Because alterations in penicillin-binding proteins will influence the binding of other b-lactam antibiotics, some pneumococci have developed multiple drug resistance. Resistance to cephalosporins generally develops in association with penicillin resistance, particularly when penicillin-binding proteins 2x and 1a are affected. However, different b-lactams bind to different proteins, and some antibiotics may retain their activity even when penicillin-binding protein changes have occurred. Hence, some b-lactams, such as ceftriaxone and cefotaxime, may be active against penicillin-intermediate and even penicillin-resistant strains.
With the development of resistance to penicillin, there has been a parallel rise in the incidence of resistance to other antibiotics, particularly the macrolides. In a recent drug susceptibility study sponsored by the Centers for Disease Control, most penicillin-resistant isolates were also resistant to at least one additional group of antibiotics, suggesting that penicillin resistance serves as a marker for other types of antibiotic resistance.
Resistance to erythromycin is an issue of particular importance because the most popular empiric regimen for community-acquired pneumonia continues to be the macrolide group. The resistance to erythromycin of pneumococci in the United States has been reported to be as high as 19%, too high to justify empiric treatment of community-acquired pneumonia with this antibiotic group. Erythromycin resistance is more likely to occur with penicillin-resistant organisms, although, of course, the mechanism of resistance is different. Erythromycin resistance usually emerges through changes in the ribosome or development of a macrolide efflux system.
Fluoroquinolones continue to show activity to both penicillin-sensitive and penicillin-resistant pneumococci. However, the older quinolones have not been recommended for pneumococcal disease because of well-documented cases of treatment failures. Newer quinolones, such as sparfloxacin and levofloxacin, exhibit good in vitro activity against most pneumococcal isolates, including penicillin-resistant strains; they have good penetration into pulmonary tissue and a good safety profile in adults.
Antibiotic susceptibility studies should be performed on all isolates of pneumococci that have been obtained from patients who are suspected of having pneumococcal disease. For patients at high risk for penicillin-resistant organisms, these studies must be carried out as quickly as possible. High-risk patients include those who are at the extremes of age, have previously received antibiotic therapy, have been recently hospitalized or institutionalized, or are attending day care or respite care centers.
The 1-µg oxacillin disk is used for screening of nonsusceptible strains. The disk will detect more than 99% of nonsusceptible strains with 80% specificity. These nonsusceptible strains should then be tested for susceptibility to vancomycin, ceftriaxone, fluoroquinolones, and other agents, depending perhaps on local susceptibility data.
The E test is a new, simpler method for MIC determination. A calibrated, antibiotic-impregnated strip is applied to the surface of an inoculated plate. An antibiotic gradient is produced that results in an elliptic zone of inhibition. The test correlates well with microdilution methods for determining MICs to the pneumococcus.
Even if adequate sputum samples and blood cultures are obtained from all patients with pneumococcal pneumonia, culture results will not be available for several days, and initial antibiotic regimens must be chosen without the benefit of this information. In addition, clinical studies are not yet available to settle fully controversy about the importance of in vitro sensitivity testing in treating penicillin-resistant pneumococci. At least one study could not show any difference in mortality among patients with sensitive versus resistant pneumococci as long as meningitis was not present and corrections were made for other predictors of mortality. Another study found that success of treatment was no different for penicillin-sensitive and penicillin-intermediate strains. Nevertheless, the Infectious Disease Society of America, in its guidelines for the management of community-acquired pneumonia, has made the following recommendations for the treatment of pneumococcal pneumonia:

For penicillin-susceptible strains of pneumococci: Penicillin or ampicillin is recommended (as always in the past before the emergence of resistant pneumococci).

For isolates that are intermediately resistant to penicillin (MICs between 0.1 and 1 µg/mL): Parenteral penicillin, ceftriaxone or cefotaxime, amoxicillin, or fluoroquinolones are recommended.

For highly resistant strains of pneumococci (MIC >2 µg/mL): Fluoroquinolones or vancomycin is recommended. Other agents can then be chosen based on results of susceptibility tests.

For empiric therapy: Fluoroquinolones are recommended. Penicillin can be used when the rate of penicillin resistance in the community is low and the patient is low risk for penicillin-resistant pneumococci.
Although these recommendations have been reviewed by many infectious disease experts, some will be concerned about the lack of data regarding clinical success with high-dose penicillin for intermediately resistant strains. There are also only preliminary data regarding the success of fluoroquinolones for highly resistant pneumococci. Whether the pneumococcus will develop resistance to fluoroquinolones as they become drugs of choice for this organism is also not known.
Slightly different recommendations have been published by others. Some have recommended ceftriaxone for intermediately resistant pneumococci if the MIC of ceftriaxone is less than 2 µg/mL. This would be the recommendation for a patient with pneumococcal pneumonia and possible or documented meningitis. Others have suggested that vancomycin and not fluoroquinolones be considered the initial drug of choice for highly resistant pneumococci in debilitated patients.
Immunization also becomes of increasing importance in the era of higher mortality from pneumococcal infection. The currently available pneumococcal vaccine includes the major serotypes in which resistance has developed. Newer, more immunogenic vaccines will be used in children. These vaccines may decrease the colonization rate in day care centers and decrease the spread of resistant organisms from children to adults.
Reynolds and others have recommended that the use of performed specific antibody be reevaluated for life-threatening pneumococcal infection in preparation for the possibility of increasing antibiotic resistance. (S.L.B.)
Aubier M, et al. Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults. Clin Infect Dis 1998;26:1312.
Sparfloxacin treatment was successful in patients with pneumococcal pneumonia, including 20 of 24 patients with bacteremia.
Austrian R. The enduring pneumococcus: unfinished business and opportunities for the future. Microb Drug Resist 1997;3:111.
Essay puts penicillin resistance in historical perspective and emphasizes the value of the pneumococcal vaccine.
Bartlett JG, et al. Community-acquired pneumonia in adults: guidelines for management. Clin Infect Dis 1998;26:811.
Practice guidelines for pneumonia developed by the Infectious Disease Society of America. The article emphasizes the importance of specific diagnosis and provides antibiotic recommendations for pneumococcal pneumonia based on whether organism is susceptible to penicillin, intermediately resistant, or completely resistant. The use of fluoroquinolones is recommended for penicillin-resistant pneumococci.
Breiman RF, et al. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271:1831.
Surveillance study found that 6.6% of all pneumococcal isolates from 13 hospitals in 12 states were penicillin-resistant. Most of the resistant isolates were serotypes present in the 23-valent pneumococcal vaccine.
Campbell GD, Silberman R. Drug-resistant Streptococcus pneumoniae. Clin Infect Dis 1998;26:1188.
Includes discussion of risk factors for antibiotic-resistant pneumococci. These include extremes of age, recent antimicrobial therapy, coexisting illness, HIV infection, attendance at day care centers, and recent hospitalization or institutionalization.
Guillemot D, et al. Low-dosage and long-term treatment duration of b-lactam. Risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998; 279:365.
Low-dose and long-duration therapy with b-lactam antibiotics promotes pharyngeal carriage of penicillin-resistant pneumococci.
Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990;3:171.
Detailed review of the prevalence and mechanism of resistance of pneumococci to penicillin, erythromycin, tetracycline, chloramphenicol, and other agents.
Musher DM. Infections caused by Streptococcus pneumoniae: clinical spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis 1992;14:801.
Summarizes data on the clinical features of pneumococcal pneumonia and approach to diagnosis. Predicted the increasing use of quinolones in the treatment of penicillin-resistant pneumococci.
Nuorti JP, et al. An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents. N Engl J Med 1998;338:1861.
A multidrug-resistant (type 23F) pneumococcus caused an outbreak of pneumonia in a nursing home. None of the patients had received the pneumococcal vaccine. After vaccination, there were no additional cases and the colonization rate decreased.
Pallares R, et al. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987; 317:18.
Patients with penicillin-resistant pneumococci had a higher mortality rate than patients with penicillin-sensitive organisms. Sixty-five percent of patients with resistant pneumococci had previously received b-lactam antibiotics.
Reynolds HY. Respiratory infections: community-acquired pneumonia and newer microbes. Lung 1996;174:207.
Detailed review of newer pathogens in community-acquired pneumonia provides recommendations for management of pneumococcal pneumonia, including long-term strategies of immunotherapy.


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