Treating CAP caused by penicillin-resistant S pneumoniae – community-acquired pneumonia
Thomas M. File Jr
ABSTRACT: Over the last decade, the incidence of penicillin resistance among Streptococcus pneumoniae isolates has markedly increased. This trend is unsettling because infections caused by S pneumoniae are among the leading causes of morbidity and mortality in young children, the elderly, and persons with debilitating medical conditions. There is evidence that drug-resistant S pneumoniae affects clinical outcome in patients with meningitis and otitis media, but the clinical relevance of drug resistance in managing community-acquired pneumonia has been less clear. Furthermore, penicillin-resistant strains may also be resistant to other antimicrobials, including cephalosporins, macrolides, tetracyclines, trimethoprim-sulfamethoxazole, and chloramphenicol. Newer antimicrobials that have enhanced activity against S pneumoniae (including resistant strains) are available, and other agents are being investigated. However, to minimize antimicrobial resistance, the CDC recommends improving vaccination rates and using antibiotics judiciously (J Respir Dis. 1999; 20(12):833-842)
During the 1980s and 1990s, Streptococcus pneumoniae has been the most common bacterial pathogen associated with community-acquired respiratory tract infections (RTIs). The most significant development in the last decade has been the rapid increase in drug-resistant S pneumoniae isolates. As noted in the October 1999 issue of this journal, the Editorial Board members of The Journal of Respiratory Diseases consider this to be one of the most significant developments affecting respiratory diseases in the past decade.
However, the clinical relevance of drug resistance in managing lower RTIs is unclean While there is adequate evidence that penicillin-resistant S pneumoniae affects the treatment of meningitis or otitis media, its significance in treating lower RTIs, especially pneumonia, is unsettled.
In this article, I will review the history and clinical significance of community-acquired pneumonia (CAP) caused by penicillin-resistant S pneumoniae isolates. I will also discuss strategies for responding to this problem.
EMERGENCE OF RESISTANCE
Before the early 1990s, S pneumoniae was nearly uniformly susceptible to penicillin.  Rare strains had been documented to be intermediately resistant to penicillin, defined as a minimum inhibitory concentration (MIC) of 0.1 to 1 [micro]g/mL. However, most clinical isolates were susceptible to penicillin (MIC below 0.1 [micro]g/mL.). For patients who had pneumococcal infections and were not allergic to penicillin, it was clearly the drug of choice.
The appearance of drug-resistant S pneumoniae was identified in New Guinea as early as 1967. Medical experts at the time concluded that the microorganisms were not likely to spread and thus posed little threat to the general population. This prediction proved false.
Pneumococcal infections caused by strains that have increasing MICs became prevalent in South Africa in the 1970s and in Europe in the 1980s. These strains have become increasingly prevalent in the United States during the 1990s.
By 1998, several surveillance studies indicated that the overall rate of penicillin resistance among S pneumoniae isolates is approximately 30% to 40% (Figure); about 50% of the isolates expressed high-level resistance to penicillin, defined as an MIC of 2 [micro]g/mL or higher. [2-4] This is of major concern because S pneumoniae infections are among the leading causes of illness and death in young children, the elderly, and persons with debilitating medical conditions. Identified risk factors associated with drug-resistant S pneumoniae include recent use of antimicrobials and recent hospitalization (Table 1). Although a discussion of the mechanism of resistance and specific epidemiology of transmission is beyond the scope of this article, there are some excellent review articles available. [5,6]
Multicenter surveillance studies document that emerging penicillin-resistant isolates are also resistant to other drugs, including cephalosporins, macrolides, tetracyclines, trimethoprim-sulfamethoxazole, and chloramphenicol. [2-4] Resistance to macrolides is a significant concern because these agents are commonly used for empiric therapy for respiratory infections, including those caused by S pneumoniae.
A close correlation is found between [beta]-lactam and macrolide resistance. This is not because the genes encoding resistance are linked but because resistant determinants are selected in the same environment, and additive selective determinants confer selective advantage to those strains each time they are exposed to antibiotics. 
Studies indicate that approximately 20% of respiratory isolates are resistant to the macrolides–including the newer agents, such as azithromycin and clarithromycin.
However, many isolates that are not susceptible to penicillin (MIC of 0.1 [micro]g/mL or greater) are resistant to the macrolides. Of most recent concern is the occasional resistance to fluoroquinolones noted in some studies. [8,9]
As indicated by Bryan and coworkers,  “therapy of pneumococcal pneumonia is at a crossroads.” While penicillin G has been the drug of choice for CAP in the past, there is widespread impression that it is seldom used for CAP. Because of the number of possible causative organisms, broader-spectrum antibiotics are favored.
Rising concerns about penicillin resistance may prompt therapy with newer cephalosporins, newer fluoroquinolones, or even vancomycin for suspected or proven pneumococcal disease. Moreover, invasive pneumococcal disease that is resistant to third-generation cephalosporins as well as other classes of drugs, such as macrolides, is now being reported.
When pathogens become increasingly resistant, therapeutic choices are limited. Also, the emergence of resistant pathogens often exerts additional selective pressure on any antimicrobial that remains effective. Since S pneumoniae infections are so common, the awareness of drug resistance has led to increased use of agents such as vancomycin; this may result in resistance to this agent as well.
In this scenario, recommendations for managing pneumococcal pneumonia have become increasingly problematic. At present, there is no consensus on the appropriate therapy for infection with drug-resistant S pneumoniae.
While there is compelling information that drug-resistant S pneumoniae affects clinical outcome for patients who have meningitis or otitis media, the clinical relevance of drug resistance in managing nonmeningeal pneumonia has been controversial. [7,11-13] Much of the controversy relates to the interpretation of the break point classification for susceptibility and resistance.
The National Committee on Clinical Laboratory Standards currently defines the susceptibility of pneumococcal isolates to penicillin as follows: susceptible, MIC of 0.06 [micro]g/mL or less; intermediate, MIC of 0.1 to 1 [micro]g/mL; and resistant, MIC of 2 [micro]g/mL or more.  However, studies comparing the response of CAP caused by penicillin-susceptible S pneumoniae with that caused by intermediately resistant strains suggest there is no difference in clinical outcomes. Thus, treatment with a [beta]-lactam is clinically effective for pneumococcal pneumonia caused by strains with MICs less than 2 [micro]g/mL. [11-13, 15-18]
Limited data suggest that increased complications or mortality is associated with pneumonia caused by penicillin-resistant isolates. Feikin and colleagues’9 compared the mortality of patients who had bacteremic pneumococcal pneumonia caused by penicillin-susceptible strains with the mortality of patients who had intermediately resistant or penicillin-resistant strains. They controlled for conditions strongly associated with mortality (age, geographic area, and underlying illness) and observed a significantly higher mortality rate among the 57 patients who had resistant strains (adjusted odds ratio [OR], 4.2; 95% confidence interval [CI], 1.7 to 10) compared with patients who had susceptible strains. Patients who had infection caused by intermediately resistant strains had no difference in mortality (OR, 1.2; CI, 0.56 to 2.6) compared with patients who had susceptible strains. The increase in mortality was confined to deaths occurring after the fourth day following hospital admission, which is consistent with previous observations that early hospital mortality is not influenced by antibiotic therapy.
In another study of S pneumoniae bacteremia managed at a large hospital in New York City, Turett and associates  found that highlevel penicillin resistance (MIC higher than 1 [micro]g/mL was an independent predictor of mortality (42% for high-level resistance compared with 16% for the others). Other investigators have reported clinical failure in patients with CAP due to S pneumoniae with an MIC greater than 2 [micro]g/mL. [21-23]
For many of these studies, a number of confounding variables, other than specific MIC of the pathogen, may influence outcome. Such variables include age, underlying disease, and duration and extent of illness at the start of therapy In addition, several of the reports do not specify the drug regimens, which limits interpretation of the results.
Pharmacokinetic and pharmacodynamic data suggest that penicillin should be effective against pneumococcal strains with MICs up to 2 [micro]g/mL. Assuming that high-dose penicillin therapy can achieve levels higher than the MIC for greater than 50% of the dosing interval, intravenous penicillin may be effective for pneumonia caused by pneumococcal isolates with MICs up to approximately 2 to 4 [micro]g/mL. [10,24]
In 1998, a CDC working group convened to discuss the management of pneumonia in the era of drug resistance. While a consensus statement has yet to be published, panel discussions suggested that most S pneumoniae isolates defined as intermediately resistant to penicillin by current break points should respond well to standard treatment with a [beta]-lactam. However, treatment failures may occur at higher levels of resistance. On this basis, the group recommended that break points for pneumonia be changed for non-meningitis-associated pneumonia.
Presented data suggest that drug-resistant S pneumoniae affects the clinical outcome of patients with CAP when isolates have an MIC of 2 [micro]g/mL or higher. In two recent surveillance studies, the incidence of S pneumoniae isolates with MICs of 4 [micro]g/mL or higher was 3.5% and 7%. [2,25] It is anticipated that as a higher percentage of pneumococcal isolates associated with CAP show MICs of 4 [micro]g/mL or higher, significant alteration of therapy–away from [beta]-lactams–will be required.
Thus, the evidence suggests that patients who have CAP caused by intermediately penicillin-resistant S pneumoniae isolates should respond well to treatment with a 13,[beta]-lactam used in appropriate doses. Therapeutic failures are more likely to occur at higher levels of antimicrobial resistance.
Based on expected pharmacologic properties, the following oral [beta]-lactams have good activity against S pneumoniae: cefuroxime axetil, amoxicillin, amoxicillinclavulanate, cefprozil, and cefpodoxime. Parenteral [beta]-lactams with good activity are cefuroxime, cefotaxime, ceftriaxone, cefepime, ampicillin (with or without sulbactam), and piperacillin (with or without tazobactam). However, one disadvantage of [beta]-lactam antibiotics is the lack of activity against atypical pathogens (Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila), which are also common causes of CAP.
Current recommendations for empiric therapy for outpatients include a macrolide, a fluoroquinolone with enhanced activity against S pneumoniae, or doxycycline.  Both the macrolides and doxycycline have activity against pneumococci that are susceptible to penicillin but are often less active against penicillin-resistant strains.
Although recent surveillance studies show increasing resistance of S pneumoniae to the macrolides, there are a few reports of clinical failure in patients without significant risk factors for drug-resistant S pneumoniae. Thus, for most patients, macrolides remain effective for empiric therapy. The new fluoroquinolones are currently active against more than 98% of S pneumoniae (including drug-resistant isolates) and are appropriate choices when there are strong risk factors for these strains or they have been documented by culture.
The spread of penicillin-resistant S pneumoniae presents a challenge to health care providers. In 1996, the CDC published recommendations to address this concern which, if implemented, should benefit all our patients.  Strategies include the adherence to current guidelines for the use of available vaccines (influenza and pneumococcal) as well as promotion of judicious antimicrobial use (Table 2).
Certainly, increased use of vaccines to prevent pneumonia will be beneficial, and recent information suggests they are being used with greater frequency in high-risk patients. A greater challenge to all of us as health care providers will be to practice better prescribing habits. Numerous studies suggest that inappropriate use of antimicrobials for nonbacterial (usually viral) respiratory infections is the most significant factor associated with drug-resistant S pneumoniae. Data from the National Center for Health Statistics indicate that approximately three fourths of all outpatient antimicrobial use is for respiratory infections. 
Although many respiratory infections require antimicrobial therapy for optimal management, most “outpatient” respiratory infections (such as acute bronchitis, nasopharyngitis or the common cold, and nonspecific upper RTI) are caused by viruses for which antibiotic use is not warranted (Table 3). In many of these conditions, cough is a common manifestation.
The differential diagnosis of cough includes both infectious and noninfectious etiologies. Examples of noninfectious causes are smoking, asthma, gastroesophageal reflux, postnasal drip syndrome, and pollutants. Infectious causes of cough include a spectrum of conditions, such as nasopharyngeal infection (common cold), acute bronchitis, chronic bronchitis, sinusitis, and pneumonia.
Cough, even if it is prolonged or productive, may not necessarily indicate bacterial infection. Cough often occurs with uncomplicated viral upper RTI, including the common cold. This understanding should help practitioners and patients avoid unnecessary antimicrobial use. [28,29]
Approximately 40% of patients who have experimental rhinovirus colds (volunteers inoculated with rhinovirus and observed in isolation rooms) experience cough as a prominent symptom, and the cough persists longer than other symptoms, such as fever, myalgia, and sneezing. In fact, 14 days after inoculation, about 20% of patients still had a cough.  Ausculatatory findings are nonspecific and often normal; but variable findings, such as scattered crackles, wheezing, and prolonged expiratory phase, may be present, especially in patients with reactive airways disease.
DIFFERENTIATING ACUTE BRONCHITIS FROM CAP
Acute bronchitis is one of the most common disorders confused with CAP because it may present with similar manifestations (such as acute onset of cough); distinguishing between these conditions is paramount to optimizing therapy. In general, acute bronchitis does not warrant antibiotic therapy while pneumonia does. The term “acute bronchitis” is generally used to describe a transient (less than 15 days) respiratory illness in patients without chronic lung inflammatory conditions and characterized by cough (with or without sputum), fever, and/or substernal discomfort, and no radiographic findings of pneumonia (Table 4).
Distinguishing acute bronchitis from nonserious pneumonia has important therapeutic and prognostic implications. A review of published studies indicates that no combination of clinical findings can reliably define the presence of pneumonia.  While the absence of any vital sign abnormality or any abnormalities on chest auscultation substantially reduces the likelihood of pneumonia, the only definitive method to differentiate acute bronchitis from pneumonia is chest radiography.
In a time of limited resources, it may be attractive to treat patients for CAP based on the presenting manifestations without radiographic confirmation. However, this approach should be discouraged because of the cost and potential dangers (side effects and increased resistance, for example) of unnecessary antimicrobial use for acute bronchitis.
Accordingly, recent guidelines recommend that a chest radiograph be obtained for the routine evaluation of patients who are likely to have CAP.  The rationale is to appropriately establish the diagnosis of pneumonia for which antimicrobials are justified and differentiate respiratory illnesses, such as acute bronchitis.
Acute bronchitis is most often associated with respiratory viruses for which antibacterial therapy is unwarranted. [32,33] A small proportion of cases are caused by bacteria; M pneumoniae, C pneumoniae, and Bordetella pertussis have been linked to acute bronchitis. 
There is little evidence for an important role of S pneumoniae or Haemophilus influenzae in the etiology of acute bronchitis in adults in the absence of airway violation (such as tracheostomy), immunosuppression (such as AIDS), or serious associated disease (such as cystic fibrosis). A sputum culture may yield these organisms, but the presence of these pathogens is just as likely to represent upper airway colonization as lower RTI. 
Nonvalue of antibiotics for acute bronchitis
The value of antimicrobials in the treatment of immunocompetent patients with acute bronchitis has not been confirmed, and the use of these agents is not recommended. Several controlled trials suggest that for most patients with a cough resulting from acute bronchitis, antibiotics are of no measurable or clinically significiant benefit. [28,35-37]
Conflicting results of clinical trials may be explained by variation in methodology and patient type (including patients with an acute exacerbation of chronic bronchitis). Some studies have demonstrated benefit of bronchodilators (such as [beta]-agonists), which would more effectively relieve symptoms than would antibiotics. 
Despite information that antibiotics are generally not indicated for acute bronchitis, studies show that primary care providers use these agents in most cases. [38,39] In one survey of primary care physicians, antibiotics were considered the primary treatment for acute bronchitis in otherwise healthy adults.
The overuse of antibiotics increases pressure for antimicrobial resistance. Several reasons are given to justify the use of antibiotics in acute bronchitis:
* Patient expectations.
* Preventing secondary bacterial infection.
* Managing treatable causes (such as infection with M pneumoniae or C pneumoniae).
However, one recent study found that patient satisfaction did not depend on receipt of an antibiotic prescription as long as physicians explained the rationale for management.  In addition, a metaanalysis of nine trials concluded that antibiotics did not prevent or decrease the severity of bacterial complications in children with upper RTIs. 
All health care providers are encouraged to decrease unnecessary antimicrobial therapy for acute bronchitis by improving their clinical approach or explaining to their patients the lack of benefit, possible side effects, and development of antimicrobial resistance.  Increased education of patients and family members must be emphasized if they are to accept a rational approach to management.
Several of my primary care colleagues have told me that the simple practice of hanging posters on examining room walls explaining the potential harm of “overusing antibiotics” has helped reduce patient “requests” for these agents. The practice of not prescribing antibiotics for most patients who present with a cough is supported by the literature.
The cost of follow-up visits for patients who do not improve over a few days should be balanced against the high likelihood of spontaneous resolution and the risk to the patient and the community of unnecessary antibiotic use.  One recent study demonstrated a meaningful reduction in antibiotic use for acute RTIs, such as acute bronchitis, by combining patient education and clinician interventions (Table 5). 
Despite substantial advances in our knowledge of the pathogenesis, epidemiology, and molecular biology of S pneumoniae, disease caused by this organism remains a worldwide threat to health. The emergence of drug resistance has complicated the management of infections, including CAP.
The newer fluoroquinolones that have enhanced activity against pneumoniae appear to be an appropriate alternative for treating S pneumoniae infections that are associated with high MICs of the [beta]-lactams (including cephalosporins) and macrolides.
The challenge is to use these medications judiciously. Other agents being investigated that show promise for the treatment of penicillin-resistant S pneumoniae infections include the oxazolidinones, streptogramins, glycopeptides, glyglycycline, and the everninomicin class of antimicrobials.
The increased frequency of drug resistance among S pneumoniae isolates mandates routine surveillance of pneumococcal resistance in most laboratories. At present, the best recommendations for avoiding the spread of antimicrobial resistance is the optimal use of vaccines and more judicious use of antibiotics to treat infections.
Dr File is professor of internal medicine, Northeastern Ohio Universities, College of Medicine, Rootstown, Ohio, and chief of the infectious disease service at Summa Health System, Akron. He also is a member of the Editorial Board of The Journal of Respiratory Diseases.
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Years Intermediate resistance High resistance
1988-1989 3.8% 0.2%
1992-1993 15.2% 2.6%
1994-1995 14.1% 9.5%
1996-1997 19.9% 13.6%
1997-1998 22% 14%
Feb-June 1997 27.8% 16%
Resistance of Streptococcus pneumoniae to penicillin has
increased dramatically in the last 10 years. High-level
resistance is defined as a minimum inhibitory concentration
of 2 [micro]g/mL or higher. (Data from references 1, 2, and 4.)
Risk factors for drug-resistant Streptococcus pneumoniae infection
Extremes of age ([greater than] 65 y or [less than] 6 y)
Recent antimicrobial therapy
Coexisting illness or underlying disease
Immunodeficiency, including HIV infection
Attending a day-care center
Contact with a child attending a day-care center
Recent or current hospitalization
Institutionalization (such as nursing home or prison)
Adapted from campbell GO Jr, Silberman R. Clin Infect Dis. 1998. 
Strategies for stopping the spread of drug-resisant Streptococcus pneumoniae
Promote judicious use of antimicrobials
Avoid inappropriate use of antimicrobials (such as prescribing antibiotics for viral infections or using the improper dosage)
Establish rational treatment guidelines
Publish national and regional resistance trends
Adapted from Jernigan DB et al. MMWR. 1996. 
Deciding when to prescribe antimicrobials
Warranted Not warranted
Pneumonia Viral rhinosinusitis/common cold
Acute exacerbation of chronic Chronic bronchitis without exacerbation
bronchitis [*] Acute bronchitis
Bacterial sinusitis Asthma
Cough caused by pollutants or smoking
(*.)Patients with increased dyspnea, sputum production, and sputum
Characteristics of acute bronchitis
Transient ([less than] 15 days) respiratory illness among patients without chronic inflammatory lung conditions
Characterized by cough, with or without sputum; fever; or substernel discomfort Absence of radiographic findings suggestive of pneumonia
More than 90% caused by viruses
Most studies indicate antimicrobials of no significant benefit [beta]-Agonists shown to be effective in controlled trials
Decreasing antibiotic use in ambulatory patients
Patient education Clinician intervention
Mailing of educational material Description of materials sent to
(Such as brochres [*] and refrigerator patients
magnets [+]) to the home Listing of site-specific antibiotic
Physician letter, which explains the prescription rates for acute
campaign to combat antibiotic (to discourage antibiotic use)
resistance by reducing unnecessary Evidence-based data from literature,
antibiotic use which support not using antibiotics to
treat acute bronchitis
Learning to explain to patients why
antibiotic therapy is unnecessary
(*.)Your Child and Antibiotics: Unnecessary Antibiotics CAN Be Harmful. Produced by the American Academy of Pediatrics, CDC, and American Society for Microbiology. Examples of these educational materials are available on the internet at http ://www. uchsc edu/uh/gim/educate/bronchitis.html.
(+.)Outlining issues related to prevention self care when to seek care, and what to expect from the office visit for colds, flu and bronchitis.
From Gonzales R et al JAMA 1999. 
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