Department of Medicine, Division of Infectious Diseases, Center for Tuberculosis Research, Johns Hopkins School of Medicine, 424 N. Bond Street, Baltimore, MD 21231-1001, USA
Streptococcus pneumoniae is the most commonly identified cause of community-acquired pneumonia, accounting for 955% of cases among patients requiring hospitalization.1 Although resistance to penicillin and other antimicrobial agents among S. pneumoniae was initially recognized in 1967,2 the prevalence of drug-resistant S. pneumoniae (DRSP) remained low until the early 1990s, when penicillin resistance began to increase at an alarming rate. Current estimates indicate that c. 18% of S. pneumoniae strains from the US have intermediate penicillin resistance (MIC 0.121.0 mg/L) and 33% have high-level resistance (MIC 2 mg/L).3,4 Some estimates have placed the increase in high-level penicillin resistance among S. pneumoniae at 60-fold over the past 57 years.5,6 Outside the US, resistance to penicillin is even higher, with Spain, Hungary and South Africa reporting rates of intermediate and high-level resistance between 40 and 70%.79 Nevertheless, the clinical relevance of antimicrobial resistance in pneumococcal respiratory tract infections remains surprisingly uncertain.
The virulence of pneumococci and the high morbidity and mortality that these organisms exact, even in the face of appropriate therapy, were first chronicled by Austrian & Gold in 1964.10 They reported a mortality rate of 13% in their study of bacteraemic pneumococcal pneumonia from 1952 to 1962, a time when there was no DRSP. Surprisingly, a much more recent analysis by Feikin et al.11 showed a nearly identical case-fatality rate of 12% among persons hospitalized with community-acquired invasive pneumococcal pneumonia from 1995 to 1997 in a population with an 18% prevalence of DRSP. This comparison and other data indicate constancy in pneumococcal pneumonia mortality rates over the past decade, despite the dramatic increase in prevalence of DRSP. Austrian & Gold10 also emphasized an important caveat regarding pneumococcal pneumonia: even with appropriate therapy and no resistance, 1015% of hospitalized patients will fail therapy. This observation is particularly important in considering drug therapies for pneumococcal pneumonia; specifically, they predicted that it will always be possible to identify anecdotal instances of treatment failure with various drugs because of the intrinsic pathogenicity of S. pneumoniae.
Given the stability of mortality rates from invasive pneumococcal pneumonia over the past several decades and the lack of clear-cut evidence for a corresponding increase in treatment failures, it is possible that the impact of DRSP is being overestimated in the arena of respiratory tract infections. Many of the surveillance data used to estimate rates of DRSP in the US are from consortia of academic medical centre laboratories whose annual data are pooled in nationwide tabulations. Such centres frequently serve patients with poorer general health and may not be representative of patients treated in the outpatient setting or in community hospitals. Common risk factors for admission to academic centres, such as extremes of age, recent antibiotic use, recent hospitalizations, residence in a chronic care facility and immunocompromised status, are also known risk factors for drug resistance. Therefore, the inherent reliance on academic medical centre reference laboratories may lead to an overrepresentation of the incidence of pneumococcal antimicrobial resistance. Newer surveillance programmes, such as the Active Bacterial Core (ABC) Surveillance study initiated by the US Centers for Disease Control (CDC) in 1995, may produce microbiological surveillance data more representative of community resistance rates.
Although resistance among pneumococci to drug classes such as ß-lactams, macrolides and fluoroquinolones is increasing, a debate remains as to whether there is a corresponding increase in the rate of treatment failure. The controversy focuses on whether microbiological resistance determinations in vitro are predictive of treatment outcomes in vivo. In the case of pneumococcal meningitis, it is clear that penicillin treatment is contraindicated for isolates with intermediate or high-level resistance. However, in pneumonia and other respiratory tract infections caused by resistant pneumococci, worse outcomes have yet to be demonstrated convincingly. A number of clinical studies of pneumococcal pneumonia have assessed the treatment outcomes following infection by DRSP compared with the course of infection by drug-susceptible S. pneumoniae (DSSP) isolates among the same population.
One important analysis was conducted by Pallares et al.12 in a prospective study in Barcelona of 504 patients with culture-proven pneumococcal pneumonia. Of those patients, 29% had penicillin-resistant strains of S. pneumoniae and 6% had cephalosporin-resistant strains. The overall mortality was 38% in patients with penicillin-resistant strains and 24% in patients with penicillin-susceptible strains. However, after the exclusion of patients with polymicrobial pneumonia and adjustment for other predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strains was 1.0 (95% confidence interval, 0.51.0, P = 0.84). Mortality in patients who had penicillin-resistant S. pneumoniae treated with penicillin G or ampicillin during the first 48 h (discordant therapy) was 25%, whereas mortality in those who had penicillinsusceptible strains treated with the same drugs (concordant therapy) was 19% (P = 0.51). Thus, infection with DRSP and discordant therapy during the first 48 h was not associated with a significant corresponding increase in mortality in this study.
Feikin et al.11 conducted a similar analysis in a 1995 1997 North American surveillance study of 5837 cases of community-acquired invasive pneumococcal pneumonia. They found that case-fatality rates were not significantly higher for patients infected with penicillin-resistant S. pneumoniae than for those infected with penicillinsusceptible strains (14% versus 11%, P > 0.05). Similarly, no statistically significant association was found between mortality and infection with cefotaxime-resistant pneumococci. Echoing the results of previous studies, older age and underlying disease, but not drug resistance in the isolate, were shown to be the most important predictors of mortality from pneumococcal pneumonia.
A prospective outcome study of 101 consecutive patients hospitalized for pneumococcal pneumonia from 1996 to 1998 in Barcelona, conducted by Ewig et al.,13 demonstrated that 47% of the patients had pneumococcal bacteraemia and that resistance rates were 49% for penicillin non-susceptibility, 31% for cephalosporin non-susceptibility and 27% for macrolide non-susceptibility. The overall mortality was 11%. Risk factors for DRSP were increased age, the presence of co-morbid disease and the absence of bacteraemia. Although there was a trend towards higher mortality among patients with penicillin-non-susceptible pneumococci (18%, versus 6% for penicillin-susceptible), these differences were not statistically significant. With macrolide resistance the trend was actually in the opposite direction, with only 7% mortality among patients with macrolide-non-susceptible strains and 14% mortality among those with macrolide-susceptible strains, but without statistical significance. Other measures of morbidity, such as hospital stay, the presence of empyema and ICU admission, also failed to show a statistically significant difference between DRSP and DSSP isolates. When the investigators evaluated whether outcome was affected by the use of antimicrobials inappropriate for a drug-resistant infection (discordant therapy), again there was no statistically significant difference in mortality.
As illustrated in the Table, other studies have reached the same conclusion: lack of a statistically significant association between microbiological resistance in pneumococcal pneumonia and treatment failure.
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Regarding the clinical relevance of highly resistant S. pneumoniae isolates, an interesting observation was made by Ewig et al. from the Barcelona study.13 Although increased mortality was not associated with ß-lactam resistance overall, patients infected with pneumococci which had penicillin MICs of 4.0 mg/L or higher (ultra-high-level resistance) had more than seven times the risk of mortality after the fourth hospital day. The fact that the effect of higher levels of ß-lactam resistance on mortality became significant only after excluding deaths during the first few hospital days is consistent with observations made more than four decades ago by Austrian & Gold, who noted that the effect of penicillin in reducing mortality from pneumococcal pneumonia became evident only after the fifth day of illness.10 Hence, mortality early in the course of pneumococcal pneumonia may reflect factors such as the severity of presenting illness rather than the appropriateness of the therapeutic interventions. These observations indicate that, if there were a true association between drug resistance and increased mortality, it may only become apparent 5 days or more after hospitalization.
Although a majority of studies concluded that resistance does not affect mortality as a measure of clinical failure, antimicrobial resistance may adversely affect other markers of morbidity. However, the significance of these markers of morbidity in the setting of comparable mortality rates in DRSP and DSSP isolates is unclear. Metlay et al. conducted a study involving 192 patients from the Atlanta metropolitan area who were hospitalized with bacteraemic pneumococcal pneumonia in 1994.15 There was a trend toward increased mortality with penicillin-resistant pneumococcal infection, but not a statistically significant one. However, they did find a higher rate of suppurative complications such as empyema, intrapulmonary abscess and osteomyelitis in patients with penicillin-resistant infection. Resistance did not seem to affect other outcomes such as shock, the presence of respiratory failure or admission to the ICU.
Another study looking at 419 episodes of pneumococcal bacteraemia among adult residents in Franklin County, Ohio, between 1991 and 1994, conducted by Plouffe et al.,16 compared mortality rates as well as duration of hospitalization in penicillin-susceptible and penicillin-non-susceptible S. pneumoniae infections. The mortality was similar in both groups, at 19% and 21%, respectively. However, duration of hospitalization among survivors was longer for patients with invasive DRSP infections, at 15.8 days (range 146 days), than for patients with drug-susceptible infections, at 12.1 days (range 157 days, P = 0.05). However, Ewig et al.13 found no statistically significant association between drug resistance and length of hospital stay, severity of pneumonia or complications.
The relationship between treatment outcomes and microbiological resistance profiles for pneumococci remains a paradox. There are several possible reasons for clinical success in the setting of in vitro resistance. During infection, microbes may be in an altered physiological state that may enhance their susceptibility to drugs. In addition, the host metabolism of antibiotics may in some instances potentiate their pharmacological activity. Anti-inflammatory effects of antibiotics may also play a role. Furthermore, susceptibility breakpoints may not adequately reflect clinical data on outcomes.
Currently, there is concern that certain National Committee for Clinical Laboratory Standards (NCCLS) pneumococcal breakpoints are inappropriate for pneumococcal respiratory tract infections. Although the penicillin breakpoints, which were established for pneumococcal meningitis in the 1970s, are highly predictive of pneumococcal meningitis outcomes, data such as those in the Table indicate that they do not predict clinical outcomes of pneumococcal pneumonia. Out of concern for the growing rates of drug resistance among pneumococci, the CDC has convened an expert panel known as the Drug Resistant Streptococcus pneumoniae Therapeutic Working Group (DRSPTWG). This body published its guidelines on the management of community-acquired pneumonia in May 2000, with recommendations for a revised interpretation of penicillin breakpoints and for restriction of fluoroquinolone use in patients with suspected community-acquired pneumonia being managed as outpatients.1 The DRSPTWG recommended that respiratory isolates of S. pneumoniae with intermediate penicillin resistance (MIC 0.121.0 mg/L) need not be of concern for treatment failure, and that only when the penicillin MIC was 4 mg/L or greater should treatment failure with ß-lactam drugs be of signficant concern.
Hence, for respiratory tract infections with S. pneumoniae, there remains a striking in vitroin vivo paradox: high rates of microbiological resistance to ß-lactam drugs and a lack of compelling evidence that treatment failure is associated with resistant strains. Future studies will attempt to identify morbidity markers (which might be more sensitive than mortality) in assessing treatment failure, to look at long-term treatment failure beyond the initial 45 days of hospitalization and to evaluate whether ultra-high-level resistance (MIC 4 mg/L) will show a more clear-cut correlation between resistance and treatment failure. In the meantime, investigators and clinicians should remain cognisant of the observation that current penicillin resistance breakpoints may not adequately predict outcome in pneumococcal respiratory tract infections.
Acknowledgements
The assistance of Annette Kwon in preparing this manuscript is gratefully acknowledged.
Notes
* Tel: +1-410-955-3507; Fax: +1-410-614-8173; E-mail: wbishai{at}jhsph.edu
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