Clinical Updates in Infectious Diseases
Supported by an unrestricted educational grant from Glaxo Wellcome Inc
Volume IV, Issue 2 - January 1998
Streptococcus pneumoniae is the most common cause of purulent meningitis, bacteremia, community-acquired pneumonia, and acute otitis media. Mortality and suppurative complications associated with pneumococcal infections dropped dramatically following the advent of penicillin therapy in the 1940s. However, pneumococcal strains with decreased susceptibility to penicillin were identified in Australia and New Guinea in the 1960s and in South Africa in the 1970s. Isolates nonsusceptible (minimal inhibitory concentration [MIC] ≥0.1 �g/mL) or resistant (MIC ≥2.0 �g/mL) to penicillin and other antimicrobial agents became increasingly prevalent in many other countries during the 1980s. Drug-resistant strains were relatively uncommon in the United States (US) throughout the 1980s and penicillin remained the drug of choice for empiric treatment of life-threatening pneumococcal infections. However, a rapid increase in the prevalence of isolates nonsusceptible or resistant to penicillin occurred in the US during the late 1980s and early 1990s (Figure 1). In some parts of the US, over 35% of pneumococcal isolates are now nonsusceptible to penicillin. Concomitant with the emergence of penicillin-resistant strains, pneumococci with decreased susceptibility to other classes of antimicrobial agents also became more prevalent, making selection of therapy difficult. Strains susceptible only to vancomycin have been isolated. The emergence and spread of resistance emphasize the importance of vaccination to prevent infection in persons at increased risk for serious pneumococcal disease and of judicious antibiotic use to prevent development of drug-resistant bacteria strains.
Mechanism of Penicillin Resistance
Penicillin and other b-lactam antibiotics act by binding to penicillin-binding proteins (PBPs) in the bacterial cell wall. PBP-penicillin complexes disrupt cell wall biosynthesis and cause cell death. Resistance to penicillin is mediated through alteration of the PBPs, resulting in reduced affinity for penicillin. Five PBPs have been identified in S. pneumoniae. Strains with the highest levels of resistance (greatest MIC) to penicillin generally have several altered PBPs. Because other b-lactam agents, such as the cephalosporins and the carbapenems (for example, imipenem and meropenem), also act by binding PBPs, strains not susceptible to penicillin also frequently have reduced susceptibility to these agents. MICs to extended-spectrum cephalosporins (ESCs) such as cefotaxime and ceftriaxone and carbapenems tend to be 2- to 8-fold lower than MICs to penicillin. Therefore, resistance to penicillin does not mean these agents will be ineffective. However, strains with high MIC values to all b-lactams and carbapenems are becoming increasingly common and a clone of serotype 23F with MIC values for ESCs higher than that for penicillin has become widely disseminated.
Epidemiology of Drug-resistant Pneumococcal Infections
Early studies of drug-resistant pneumococci in North America indicated nonsusceptible isolates disseminated within communities following introduction of organisms descending from a single clone. More recent studies have found considerable genotypic and phenotypic heterogeneity among resistant isolates, suggesting resistant strains have now evolved from several phylogenetic lineages. Spread of resistance among pneumococcal strains is facilitated by horizontal transfer via transformation of genes coding for altered PBPs from resistant S. pneumoniae and oral a-hemolytic streptococci to susceptible pneumococcal strains. These newly resistant strains, in turn, become increasingly prevalent because of selective antibiotic pressure. Thus, the global spread of penicillin resistance has occurred both by dissemination of genes coding for altered PBPs among streptococcus species (horizontal spread) and by widespread dissemination of resistant organisms (vertical or clonal spread).
Numerous epidemiologic studies have shown therapeutic and prophylactic use of antibiotics is associated with drug-resistant pneumococcal carriage and disease (Table 1). The proportion of pneumococcal isolates resistant to commonly used antibiotics is generally highest among preschool-age children. Because young children are more often colonized with pneumococci and are more frequently given antibiotics that provide selective pressure for drug-resistant strains, it is not surprising to find resistant pneumococcal infections are more common in this age group. Children attending day care are at particularly high risk of drug-resistant pneumococcal infection. Data from active surveillance in metropolitan Atlanta during 1994 showed that, although the incidence of invasive pneumococcal infection was 3-fold higher among African Americans than whites, the proportion of isolates with decreased susceptibility to penicillin was greater among whites. Among African Americans, the rate of disease due to penicillin-nonsusceptible strains was more than doubled among suburban as opposed to urban residents. White race and suburban residence may be surrogates for higher socioeconomic status, easier access to medical care, and more frequent use of antibiotics among more affluent persons.
Treatment of Drug-resistant Pneumococcal Infections
Treatment failures and mortality have been reported among children and adults who had meningitis caused by §-lactam nonsusceptible pneumococci and who received a b-lactam agent as therapy. Because of decreased antibiotic penetration into the cerebrospinal fluid (CSF), b-lactam antibiotic concentrations in the CSF do not consistently achieve adequate levels to treat infections caused by nonsusceptible pneumococci. Studies of adults and children with pneumococcal pneumonia with bacteremia have not demonstrated increased mortality among patients infected with penicillin-nonsusceptible strains-even when treated with penicillin or ampicillin. However, it is important to note that many patients in these studies were infected with pneumococci that were intermediate to penicillin (MIC 0.1 to 1.0 �g/mL). In community-based surveillance for bacteremic pneumococcal pneumonia in Franklin county (Columbus), Ohio during 1991 to 1994, mortality was similar among patients with penicillin-susceptible (19%) and nonsusceptible (21%) isolates but the average duration of hospitalization among survivors was 3.7 days longer for those with nonsusceptible isolates. Additional studies are needed to comprehensively assess the clinical impact and economic costs of drug-resistant pneumococcal infections.
The American Academy of Pediatrics has issued guidelines for treating pneumococcal meningitis and other invasive pneumococcal infections. Vancomycin plus an ESC is recommended to treat suspected bacterial meningitis in children older than 1 month, particularly if the CSF gram stain is suggestive of pneumococcal infection. Because it may be difficult to maintain a bactericidal concentration of vancomycin in the CSF, it is recommended that vancomycin not be used alone to treat meningitis. Moreover, vancomycin plus an ESC produces a synergistic effect against pneumococci nonsusceptible to ESCs. If results of culture and susceptibility testing document meningitis caused by S. pneumoniae susceptible to b-lactam antibiotics, discontinue vancomycin. For patients with immediate hypersensitivity to b-lactam antibiotics, vancomycin plus rifampin is recommended. Experience with agents other than b-lactam antibiotics and vancomycin is limited. Chloramphenicol achieves effective concentration in the CSF but treatment failures with chloramphenicol in meningitis caused by penicillin-nonsusceptible, chloramphenicol-susceptible pneumococci have been reported. The epileptogenic properties of imipenem in patients with central nervous system disease preclude routine use of this agent for meningitis. Meropenem, which has much less epileptogenic potential than imipenem, may provide an alternative for patients who do not tolerate vancomycin and are infected with a strain nonsusceptible to penicillin and ESCs. However, pneumococci resistant to meropenem have also been reported.
For empiric treatment of nonmeningeal invasive pneumococcal infections, the addition of vancomycin should be reserved for patients who are critically ill or immunocompromised. Even in cases where S. pneumoniae are resistant to penicillin and ESCs (and where there is no evidence of meningeal infection), clinical response to therapy is often good. The choice of antibiotic therapy should be guided by the clinical response, susceptibility to other antibiotics, and the results of follow-up blood cultures.
Therapy for upper respiratory infections (URIs) such as otitis media and sinusitis is usually empiric. S. pneumoniae is the leading cause of these syndromes and pneumococcal infections are less likely to resolve in the absence of antimicrobial therapy than are infections caused by other pathogens. Therefore, therapy effective against pneumococcus is paramount for success. Amoxicillin remains first line therapy for otitis media because antibiotic levels in the middle ear fluid generally exceed the MIC of susceptible and intermediately resistant strains and continued clinical effectiveness has been documented. Doubling the dose of amoxicillin to 60 to 80 mg/kg/d may further increase effectiveness against nonsusceptible pneumococcal infections. Several of the new oral cephalosporins widely promoted as therapy for URIs have poor activity against pneumococci and should be avoided if pneumococcal infection is suspected.
Efforts to reduce the impact of drug-resistant pneumococcal infections include judicious use of antibiotics and the prevention of pneumococcal infection by vaccination. The association between antimicrobial use and resistance has been documented. Ecologic studies show an association between amount of antimicrobial use in an area and rates of resistance. Cohort and case-control studies have documented significant associations between recent antimicrobial use and carriage or infection with resistant pneumococci. Longitudinal studies have found increased presence of resistant pathogens following therapeutic or prophylactic antibiotic use. A key strategy, therefore, to stop the spread of resistance is to decrease unnecessary antimicrobial use. Antibiotics are the most commonly prescribed class of drugs in outpatient settings. About 75% of outpatient antibiotic prescriptions are for 5 respiratory diagnoses: otitis media, bronchitis, pharyngitis, sinusitis, and the common cold (nonspecific URI,Figure 2). Although many of these infections are viral and antibiotics provide no benefit, these agents are prescribed because of the physician's diagnostic uncertainty or perceptions regarding patient expectations. Pediatricians and family physicians in Atlanta estimated they could decrease antibiotic use in their own practices by 10% to 50% with no negative impact on patient care.
A beginning step in reducing unnecessary antibiotic use is to consider preventing resistance and its consequences as important factors when making treatment decisions. Avoiding unnecessary antibiotic use decreases the spread of resistance in the community and benefits the patient by avoiding possible medication adverse effects and decreasing the risk of acquiring a resistant organism. A series of principles for judicious antibiotic use in pediatric respiratory infections was developed by the Centers for Disease Control (CDC), American Academy of Pediatrics, and American Academy of Family Physicians. It identified approaches to diagnosis and management consistent with judicious antibiotic use (Table 2). Many of these principles are also relevant for infections in adults.
Because patient expectations also affect physician behavior, educating patients about when antibiotics are or are not needed is important if practices are to change. The CDC developed patient education materials that emphasize antibiotic therapy is not appropriate for all infections and unnecessary use can be harmful. Similar materials may be available from professional societies, managed care organizations, and other sources to aid physician-to-patient communication. In a study of patients with respiratory infections, satisfaction with care was significantly associated with the quality of communication. Patient satisfaction was not associated with whether or not an antibiotic was prescribed.
Increasing pneumococcal vaccine use among persons aged >2 years who are at increased risk for serious pneumococcal infection can prevent a large portion of invasive pneumococcal infections, including those caused by strains with reduced antibiotic susceptibility (Table 3). Nearly 90% of penicillin-nonsusceptible isolates and all penicillin-resistant pneumococci submitted to the CDC through surveillance were serotypes covered by the 23-valent pneumococcal capsular polysaccharide vaccine. The vaccine is approximately 60% effective for preventing invasive pneumococcal infection. Yet, only 35% of persons aged _65 years in the US for whom pneumococcal vaccine is recommended have been vaccinated. The currently available polysaccharide vaccine does not effectively prevent pneumococcal infections in children aged <2 years. Conjugate vaccines, with pneumococcal polysaccharides linked to a protein carrier, elicit T cell-dependent immune responses and appear to be immunogenic in infants and young children. Efficacy trials of pneumococcal conjugate vaccines are underway. Although conjugate pneumococcal vaccines contain a limited number of serotypes, an effective heptavalent vaccine directed against the serotypes most prevalent among children <6 years old (4, 6B, 9V, 14, 18C, 19F, and 23F) would protect against the vast majority of penicillin-nonsusceptible infections. A pneumococcal vaccine that prevents both nasopharyngeal colonization and disease in children may be the most effective method of preventing spread of drug-resistant pneumococcal strains.
S. pneumoniae with decreased susceptibility to ß-lactams and other antibiotics are becoming increasingly widespread in the US and globally. Frequent, prolonged exposure to antibiotics appears to be an important risk factor for carriage and disease with these strains. Empiric treatment of suspected pneumococcal meningitis should include vancomycin until results of susceptibility testing are available. Available data suggest that, for patients with nonmeningeal pneumococcal infection, vancomycin should probably be reserved for those who are critically ill or immunocompromised. Eliminating unnecessary antibiotic use will be crucial to reduce the selective pressure for drug-resistant pneumococcal strains. To prevent invasive pneumococcal infections, increased use of the currently available pneumococcal vaccine and development of an effective vaccine for children <2 years old are urgently needed.
Jay C. Butler, MD
Chief, Respiratory Epidemiology Section
Benjamin Schwartz, MD
Chief, Childhood and Vaccine-Preventable Diseases
Childhood and Respiratory Diseases Branch
Division of Bacterial and Mycotic Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
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