Summa Health System, Akron, Ohio and North-eastern Ohio Universities College of Medicine, Rootstown, Ohio, USA

REVIEW Clinical implications and treatment of multiresistant Streptococcus pneumoniae pneumonia T. M. File Jr Summa Health System, Akron, Ohio and North-eastern Ohio Universities College of Medicine, Rootstown, Ohio, USA ABSTRACT Streptococcus pneumoniae is the leading bacterial cause of community-acquired respiratory tract infections. Prior to the 1970s this pathogen was uniformly susceptible to penicillin and most other antimicrobials. However, since the 1990s there has been a significant increase in drug-resistant Streptococcus pneumoniae (DRSP) due, in large part, to increased use of antimicrobials. The clinical significance of this resistance is not definitely established, but appears to be most relevant to specific MICs for specific antimicrobials. Certain b-lactams (amoxicillin, cefotaxime, ceftriaxone), the respiratory fluoroquinolones, and telithromycin are among several agents that remain effective against DRSP. Continued surveillance studies, appropriate antimicrobial usage campaigns, stratification of patients based on known risk factors for resistance, and vaccination programmes are needed to appropriately manage DRSP and limit its spread. Keywords implication, multiresistant, pneumonia, review, Streptococcus pneumoniae Clin Microbiol Infect 2006; 12 (Suppl. 3): 31 41 INTRODUCTION Streptococcus pneumoniae is the most significant bacterial pathogen associated with communityacquired respiratory tract infections (RTI). It is particularly an important cause of communityacquired pneumonia (CAP) for which it is the most common cause of mortality. It is therefore, essential that empirical therapy of CAP include antimicrobial agents effective for this pathogen. The decision concerning appropriate empirical therapy has become more complicated because of the emergence of strains resistant to penicillin and other antimicrobials. However, the relevance of drug-resistant S. pneumoniae (DRSP) in relation to the clinical outcome of CAP is controversial. This article reviews the clinical significance of DRSP, with a focus on CAP, and its effect on the approach to management. Corresponding author and reprint requests: T. M. File Jr, 75 Arch St. suite 105, Akron, Ohio 44304, USA E-mail: filet@summa-health.org S. PNEUMONIAE: MOST COMMON CAUSE OF CAP Despite the emergence of newly identified pathogens as a cause of CAP, S. pneumoniae remains the most commonly identified cause. A metaanalysis of 122 reports of CAP showed that S. pneumoniae accounted for two-thirds of cases in which etiological diagnosis was made, as well as for two-thirds of the deaths [1]. The majority of studies that have evaluated the aetiology of CAP have involved hospitalised patients, where laboratory processes are more likely to be available for diagnosis. However, when patients were stratified by disease severity [ambulatory, hospitalised (nonsevere) and intensive care unit (ICU) (severe])], S pneumoniae was the most common cause of CAP among patients in all settings [2]. PNEUMOCOCCAL RESISTANCE Historically, clinicians prescribed b-lactams or other antimicrobials for empirical treatment of community RTIs with little concern about the susceptibility of the pneumococcus to the chosen Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

32 Clinical Microbiology and Infection, Volume 12 Supplement 3, 2006 antimicrobial. However, during the past decade there has been an increase in antimicrobial resistance of S. pneumoniae [3,4]. The first reports of clinical resistance of S. pneumoniae to penicillin appeared in the 1960s, nearly 20 years after the introduction of penicillin G [5]. In the 1970s, pneumococcal resistance to penicillin and other antimicrobials was documented in South Africa, and in the 1980s, pneumococcal resistance was reported in many European, African, and Asian countries [5]. In the United States, few strains of pencillin-resistant S. pneumoniae (PRSP) were recovered in a surveillance programme conducted by the Centers for Disease Control and Prevention (CDC) in the 1980s [6]. However, a sharp increase in the prevalence of PRSP occurred in the United States in the early 1990s. The results of antimicrobial surveillance studies demonstrate that the prevalence of penicillin-nonsusceptible S. pneumoniae (PNSP) in the United States was approximately 18% in 1990 91 and almost 35% by 2002 [7]. Similar trends of increasing S. pneumoniae resistance to penicillin have been observed worldwide (Table 1) [8]. High-level penicillin resistance (i.e., penicillin MIC 2.0 mg L) among S. pneumoniae has increased to a greater degree during the past 10 years than has intermediate resistance (MIC between 0.12 and 1.0 mg L) (Fig. 1) (Doern, personal communication, 2002). Resistance of S. pneumoniae to the macrolides has also increased over the past decade (Table 1). In the United States, the prevalence of resistance to newer macrolides (e.g., azithromycin, clarithromycin) among S. pneumoniae isolates is similar to that of erythromycin (approximately 24%) [8]. Table 1. Comparative prevalences of penicillin and erythromycin resistance in Streptococcus pneumoniae (MICs 2.0 and 0.5 mg L, respectively). Modified from Jacobs et al., 2003 [8] Location Penicillin resistance (%) Erythromcyin resistant (%) Brazil 1.1 3.3 The Netherlands 1.1 3.8 Russia 1.2 6.2 Germany 1.9 6.9 Italy 4.3 35.2 UK 10.9 13.0 South Africa 17.9 19.8 Saudi Arabia 21.7 13.2 Mexico 22.2 25.0 Singapore 24.8 36.8 USA 25.0 28.8 Spain 26.4 27.5 Japan 28.5 71.0 France 40.5 53.2 Hong Kong 69.9 80.3 Fig. 1. Trends in penicillin resistance among Streptococcus pneumoniae in the United States (Doern 2002, personal communication). *Number of centres contributing isolates. The most common mechanisms of resistance include erm-mediated methylation of the ribosomal target and efflux of the macrolides by a cell membrane protein transporter, encoded by mef S. pneumoniae strains which contain mef are resistant at a lower level (most with MICs generally 1 32 mg L) than erm-encoded strains. The mef-encoded strains are usually susceptible to clindamycin. Most erm-encoded isolates have an MIC > 64 mg L to erythromycin and are considered highly resistant to all macrolides and clindamycin. Currently mef-associated resistance predominates in North America. Erm-associated resistance predominates in Europe and is common in Japan [9]. Although the worldwide prevalence of pneumococcal resistance to the newer fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin) remains low (less than 2%), in some countries resistance has increased significantly [10 13] The prevalence of pneumococcal isolates in Canada with reduced susceptibility to fluoroquinolones increased from 0% in 1993 to 1.7% in 1997 98 [12]. The overall prevalence of fluoroquinolone resistance (levofloxacin > 4mg L) in Hong Kong in 2000 had increased to 13.3% due to the dissemination of a fluoroquinolone-resistant clone [10]. Risk factors for levofloxacin resistance were identified as: prior exposure to a fluoroquinolone, nursing home residence, nosocomial infection, and COPD [13]. Telithromycin has been introduced into numerous countries over the past few years. To date, there is very little evidence of increasing resistance [14 16]. In one recent surveillance study of 31 000 isolates of S. pneumoniae collected from patients with community RTIs from 2000 to 2003, 99% were susceptible to telithromycin [16].

File Implications of multiresistant S. pneumoniae 33 Of particular concern when selecting an appropriate antimicrobial for empirical treatment of CAP is the increasing prevalence of multidrug resistance that has been documented with S. pneumoniae. Multidrug resistance and cross-resistance to other antimicrobials are common with S. pneumoniae. Among S. pneumoniae respiratory isolates evaluated in a recent worldwide surveillance programme the prevalence of strains multidrugresistant to at least three among erythromycin, doxycycline, choramphenicol, cotrimoxazole, or ofloxacin was 17.5% overall, ranging from 0% in centres in The Netherlands to 76% in Hong Kong centres [8]. From this study, and of the strains from the US that were intermediately or fully resistant to penicillin, 49.8% and 72.4%, respectively, also were resistant to macrolides azalides [8]. In the recent study by Doern et al. 22.2% of isolates were found to be multidrug resistant (defined in this study as nonsusceptible to penicillin plus nonsusceptible to at lest two of the following four agents: erythromycin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline) [7]. DRIVERS OF RESISTANCE Factors that may drive resistance include antimicrobial consumption, particularly antimicrobial use in the past 3 months, inappropriate use of antimicrobials (i.e., use when not indicated such as for viral RTIs and suboptimal dosages), clonal spread of multidrug-resistant strains, and presence of comorbidities. A study from Spain demonstrated that an increase in the use of penicillin was associated with an increase in penicillinnonsusceptible isolates [17]. Hyde and colleagues (2001) demonstrated that the use of macrolides in children was associated with an increase in macrolide resistance [18]. Similarly, Chen and colleagues (1999) showed that an increase in the use of ciprofloxacin in Canada correlated with emergence of ciprofloxacin resistance among pneumococci. Recent and inappropriate use of antimicrobials is also independent to risk factors for development of resistance [19,20]. In a study by Guillemot and colleagues (1998), b-lactam use within the past 30 days [odds ratio (OR), 3.0; confidence interval (CI), 1.1 8.3], doses lower than clinically recommended (OR, 5.9; CI, 2.1 16.7), and treatment for more than 5 days (OR, 3.5; CI, 1.3 9.8) were identified as risk factors for penicillinresistant pneumococcal nasopharyngeal carriage [19]. A recent study by Yu and colleagues (2003) evaluated the clinical relevance of bacteraemic pneumococcal pneumonia and the underlying factors associated with the development of resistance [21]. The two factors that were shown to be independently associated with resistance on multivariate analysis were underlying disease (i.e., heart, liver, renal, or lung disease, or diabetes mellitus) (OR, 2.1; p < 0.0001) and prior antimicrobial therapy (OR, 1.9; p < 0.0091). Other risk factors for DRSP include alcoholism, immunosuppressive illness or therapy, medical comorbidities (i.e., congestive heart disease, diabetes, liver or kidney disease, chronic lung disease, cancer), and exposure to others at high risk for carriage of DRSP (e.g., children who attend a day care centre). The relative predictive value of all these factors is unclear. Treatment with recent antimicrobials is likely to be the most significant factor predictive of DRSP. When strains of bacteria develop resistance, the resistance can spread, especially in the presence of extensive use of antimicrobials. Most of the DRSP strains in the United States are of five different serotypes, and the dominant factor of emergence of PRSP in the United States has been the result of human-to-human spread of a few clonal groups [22]. ECONOMIC IMPACT OF CAP DUE TO DRSP Several studies have shown that resistant pneumococcal infection in patients who require hospitalisation is associated with increased length of stay [23,24], mortality [23,25], and cost of care [23,26]. A case-control study in Iceland from 1988 to 1994 demonstrated increased costs from pneumonia caused by penicillin-resistant S. pneumoniae (PRSP) based on prolonged hospitalisations and use of expensive antimicrobial agents [23]. Results from a more recent study from ten New York hospitals conducted between 1998 and 2000 demonstrated that PRSP is associated with a longer stay (9.7 days vs. 7.9 days) and greater total direct inpatient costs ($6262 vs. $4011) [26]. Although the clinical relevance of DRSP is controversial, there are economic consequences associated with the management of patients who are infected with strains of S. pneumoniae that are resistant to commonly used antimicrobials.

34 Clinical Microbiology and Infection, Volume 12 Supplement 3, 2006 RELEVANCE OF DRSP TO CLINICAL OUTCOME B-lactams The clinical relevance of DRSP in meningitis is well understood. We know that adequate antimicrobial concentrations in the cerebrospinal fluid (CSF) must be attained to kill bacteria at that site, and that high concentrations can overcome low and intermediate levels of resistance. Penicillin breakpoints have been defined according to CSF concentrations in which an MIC of 0.06 mg Lor less is considered susceptible, an MIC of 0.12 1.0 mg L is intermediate, and an MIC of 2 mg L or more is resistant (NCCLS, 2000). In CAP, the clinical relevance of resistance has been less well understood. Data on mortality rates from penicillin-susceptible and b-lactam-resistant S. pneumoniae are conflicting. Several studies controlling for potential confounding factors (i.e., age, underlying disease, severity of illness) have not shown a difference in mortality between patients with penicillin-susceptible pneumococci and those with PRSP [21]. However, many studies included S. pneumoniae isolates with intermediate susceptibility to penicillin, which may not be as clinically relevant with regard to patient outcomes in CAP as infection with highly resistant (MIC 4mg L) isolates [3]. In a prospective, 10-year study in Spain, mortality was not correlated with resistance even though resistance to penicillin, cephalosporins, and erythromycin increased during the study period [27]. In contrast, several studies have shown a significant association between mortality and high-level penicillin resistance (MIC 4 mg L) in S. pneumoniae [25,28,29]. In a study from the CDC, investigators found that after hospital day 4, the risk of death was seven times greater in patients infected with high-level PRSP (MIC 4.0 mg L; 19 1151 patients) than in patients infected with intermediate isolates (MIC 0.012 1.0 mg L; 81 1151) [25]. However, treatment and severity of disease were not recorded. In a trial of 192 patients, medical outcomes (in-hospital mortality, medical complication rates, and time to clinical stability) in patients with bacteraemic pneumococcal pneumonia caused by penicillin-susceptible strains of S. pneumoniae were compared with those in patients infected with PNSP [28]. Compared with patients infected with penicillin-susceptible strains, patients infected with PNSP (MIC 0.12 lg L) had a greater risk of in-hospital death due to pneumonia [relative risk (RR), 2.1; 95% CI, 1 4.3]. In addition, the risk of suppurative complications of infection was increased in patients infected with PNSP (RR, 4.5; 95% CI, 1.0 19.3). However, after adjustment for baseline differences in severity of illness, only the risk of suppurative complications of infection remained statistically significant (adjusted RR, 4.8; 95% CI, 1.2 18.8). In an international, prospective, observational study of 844 patients, an association was identified among age, severity of illness, and co morbidity, but not with whether the isolates were PRSP [21]. Similar results were found in the follow-up, case-control study of patients with bacteraemic pneumococcal pneumonia, which addressed the limitations of the trial by Feikin and colleagues and controlled for risk factors, severity, and treatment [30]. The findings from this multivariate analysis showed no contribution of antimicrobial resistance to mortality or requirement for ICU, but determined that more important predictors of outcome included severity of illness and whether there was a do not resuscitate order on the patient s chart. Thus, based on present data, it appears that current levels of penicillin resistance do not adversely affect outcomes for CAP in immunocompetent patients as long as the MIC is < 4.0 mg L (the majority of nonsusceptible isolates) [31 34]. In part, because of these data, the National Committee for Clinical Laboratory Standards (NCCLS; now renamed the Clinical Laboratory Standards Institute, CLSI) recently increased the MIC breakpoints for cefotaxime, ceftriaxone and amoxicillin for nonmeningeal infections, recognising that infections such as pneumonia due to strains formerly considered nonsusceptible can be treated successfully with the usual doses of these b-lactam drugs. Macrolides Until recently reports of failure in cases of CAP treated with macrolides has been rare, particularly for patients at low risk for drug-resistant strains. However, since 2000, anecdotal reports and a controlled study have documented failures due to macrolide-resistance in patients treated with an oral macrolide who have subsequently required admission to the hospital with S. pneumoniae bacteraemia [35 38]. The clinical relevance

File Implications of multiresistant S. pneumoniae 35 of macrolide-resistant S. pneumoniae may be dependent on the type of resistance expressed by a particular strain. In-vitro resistance may not result in treatment failures for levels of resistance that can be exceeded by tissue levels of certain macrolides [39]. Notably, of the two major mechanisms of macrolide resistance, the efflux pump that confers the mef phenotype is associated with levels of resistance that may be exceeded in vivo (particularly if the MIC is < 8 and one of the newer macrolides azalides that achieve higher levels in the tissue is used) while the ribosomal target modification that confers the MLS B phenotype is associated with levels of drug resistance that almost certainly exceed the levels of drug achievable in vivo (however, mef strains may also exhibit high MICs which would affect the efficacy of the newer agents). Thus, the interpretation of studies examining the impact of macrolide resistance on bacteriological and clinical outcomes must be conducted in light of the dominant mechanisms of resistance (and their MICs) involved in the study population. Fluoroquinolones Several cases of treatment failure due to fluoroquinolone resistant pneumococcal infections in adults with CAP have also been reported [40 42]. These reports include cases in which resistance was present at the start of therapy or emerged during therapy and both types of patients experienced delayed clinical improvement. Fluoroquinolone resistance has manifested clinically as levofloxacin treatment failure in patients with levofloxacin-resistant S. pneumoniae infection. Many of the patients described in these recent reports had been previously treated with fluoroquinolones. TREATMENT CONSIDERATIONS FOR ANTIMICROBIAL-RESISTANT PNEUMOCOCCAL CAP Decisions concerning antimicrobial therapy are guided by several considerations such as spectrum of activity, pharmacokinetics, efficacy, safety profile, cost and concern for resistance. Despite the controversies concerning the clinical relevance of DRSP (at least for some antimicrobials), there is enough concern on the part of most clinicians that the decision for initial empirical management of CAP has become more complicated. In this context, the approach to appropriate therapy for community RTIs entails several principles. These include: appropriate use of antimicrobials, choice of the most appropriate agent when antimicrobials are indicated, and prevention of DRSP. Appropriate use of antimicrobials In the face of growing antibacterial resistance, we must recognise that overuse of antimicrobials is the prime driver of this resistance; therefore, judicious antibiotic usage is paramount. Principles of optimised therapy should be promoted and utilised by prescribing clinicians in order to achieve the best outcomes for our patients and reduce the emergence of antibiotic resistance. Many appropriate antibiotic-use initiatives have been published or implemented over the past several years and they appear to be having a positive effect in reducing the overuse of antimicrobials for community RTIs as well as resulting in reduced resistance [43 45]. Ball et al. have published a list of principles for appropriate antimicrobial prescribing which were developed by an independent, multinational, interdisciplinary group [43]. The goal of these principles is to maximise beneficial patient outcomes and counter bacterial resistance. The Group listed several core principles of antibiotic therapy that should provide optimal benefit for patients as well as minimise resistance; among these are: 1 Use antibacterial therapy only in those patients with bacterial infection. 2 Utilise diagnostic and other measures to reduce prescribing. 3 Therapy should maximally reduce or eradicate the bacterial load. 4 Use antimicrobial agents with optimal pharmacodynamics to achieve eradication. 5 Use locally relevant resistance data in the decision process. 6 Understand that antimicrobial acquisition cost may be insignificant compared with therapeutic failure. Optimal Drug Selection for DRSP If antibiotic therapy is warranted, it is important to select the right drug, dose and duration of

36 Clinical Microbiology and Infection, Volume 12 Supplement 3, 2006 therapy. Appropriate empirical therapy for infections for which S. pneumoniae is a consideration requires awareness of local susceptibility pattern. The in-vitro activity against S. pneumoniae of several antimicrobials collected worldwide and collected separately in the USA is presented in Table 2. Those agents for which greater than 95% of isolates are susceptible include: the respiratory fluoroquinolones, telithromycin, ceftotaxime, ceftriaxone, amoxicillin (with or without clavulanate), linezolid, rifampin, and vancomycin. Since community-acquired RTIs may also be caused by pathogens other than S. pneumoniae (i.e., Haemophilus spp., atypical organisms), and since the initial clinical manifestations of illness do not reliably predict the aetiology, agents which are also effective for these other possible pathogens may be preferable for empirical therapy when risk for DRSP is present. Single agents effective against DRSP, Haemophilus spp., and the atypical pathogens include: the respiratory fluoroquinolones and telithromycin. In addition to in-vitro activity, appropriate antibiotic therapy should be guided by pharmacodynamics (PD). Integration of MIC values with pharmacokinetic (PK) parameters provides PK PD indices, which are valuable tools to Table 2. In-vitro susceptibility of Streptococcus pneumoniae Antimicrobial Study Jacobs et al. a PK/PD3 (% Susceptible) Doern et al. b NCCLS (% Resistant) % Resistant Penicillin NA 18.2 18.5 Amoxicillin 95.1 2.1 5.3 Amoxicillin Clav 95.7 2.1 4.6 Amoxicillin Clav (2000 125) 97.9 NA NA Cefuroxime 78.6 19.7 21.6 Ceftriaxone d 95.1 0.6 1.6 Erythromycin 75.3 24.6 28.6 Azithromycin 75.5 24.1 27.4 Clarithromycin 74.3 24.4 26.9 Clindamycin NA 13.9 9.3 Tetracycline NA NA 15.6 Doxycycline 71.3 NA NA Chloramphenicol 88.1 11.9 4.7 Co-trimoxazole 63.3 24.8 25.4 Rifampin NA NA 0.2 Levofloxacin 98.9 1.1 0.7 Gatifloxacin 98.5 1.5 0.7 Moxifloxacin 98.9 1.1 0.2 Gemifloxacin 99.9 NA 0.2 Vancomycin NA NA 0 Linezolid NA NA 0 Qiunuprisitin-dalfopristin NA NA 0.025 a Worldwide surveillance (1998 2000), modified from Jacobs et al., 2003 [8]; b From 44 US Medical Centres (2002 03), modified from Doern et al., 2005 [7]; Based on pharmacokinetic pharmacodynamic breakpoints; d Non-meningeal breakpoints (resistance 4mg L). predict antibacterial effects and guide optimal drug dosage [46]. Based on present PK PD principles, high-dose amoxicillin (amoxicillin 1 g three times a day or amoxicillin clavulanate 2 g 125 mg twice a day) should be effective for > 95% of S. pneumoniae infections and is the preferred oral b-lactam for community RTIs when DRSP is a consideration [8]. Similarly, the third generation cephalosporins, cefotaxime and ceftriaxone, are active against the majority of DRSP and can be used confidently for infections of the respiratory tract. On the contrary, the use of cefuroxime, which has a lesser PK PD index than cefotaxime or ceftriaxone, has been associated with clinical failure in the context of DRSP [21]. Of the respiratory fluoroquinolones, based on PK PD indices, gemifloxacin and moxifloxacin are more potent than gatifloxacin and levofloxacin against S. pneumoniae, although, the clinical relevance of this is not definitively established [47]. Numerous clinical trials have documented the efficacy of the respiratory fluoroquinolones, telithromycin, and high dose amoxicillin in the treatment of DRSP [47 49]. In a pooled analysis of several prospective randomised trials using a pharmacokinetically enhanced formulation of amoxicillin clavulanate (2000 125 every 12 h) in RTIs, the success rate for infections due to PRSP (penicillin MICs of 2 16 mg L) was 98.2% (55 56) [48]. A recent pooled analysis by Low et al. determined the activity of telithromycin by invitro susceptibility testing of key respiratory tract pathogens isolated from subjects with CAP, AECB, and ABS who were enrolled in telithromycin trials, in order to correlate this data with the observed clinical outcomes [49]. In the pooled bacteriologic modified intent-to-treat population, telithromycin treatment for 5 or 7 10 days resulted in an overall clinical cure rate of 88.1% (1593 1808) and a rate of satisfactory bacteriological outcome of 89.0% (1593 1789). In cases involving infection with key respiratory pathogens, the following clinical cure and bacterial eradication rates were achieved with telithromycin: S. pneumoniae, 92.7% and 94.3%; H. influenzae, 87.0% and 85.6%; and M. catarrhalis, 89.7% and 89.7%, respectively. Use of fluoroquinolones for CAP The development of the respiratory fluoroquinolones has had a major impact on the management

File Implications of multiresistant S. pneumoniae 37 of CAP. Since the introduction of levofloxacin in 1997, and the subsequent availability of gatifloxacin, moxifloxacin, and gemifloxacin, these agents have been increasingly used in North America and other parts of the world. At the same time several compounds have been withdrawn because of serious safety concerns. These agents have made excellent choices for treatment of CAP because of their intrinsic activity against the key pathogens-including DRSP and the atypical organisms, and they penetrate well into pulmonary sites of infection. The emergence of DRSP and increased awareness of the atypical pathogens influenced the use of the fluoroquinolones. Additional advantages include once daily dosing and high bioavailability. This latter property has enhanced approaches to treatment of CAP by: (1) providing potent oral therapy for patients who otherwise may have required hospitalisation; (2) allowing more rapid IV-to-oral switch; and (3) allowing oral therapy for selected patients who require hospitalisation. In addition, several randomised clinical trials have compared monotherapy using a respiratory fluoroquinolone with standard therapy and found an advantage in favour of the fluoroquinolone. However, with the widespread use, and the possible misuse, of these agents, there is concern about the emergence of resistance including S. pneumoniae, Enterobacteriaciae, and Pseudomonas aeruginosa. Appropriate use of these agents is of paramount concern. Stratification of patient risk factors for correct use and application of PK KD parameters may lead to better clinical outcomes and decrease the emergence of resistance. Recommendations for treatment of DRSP within guidelines The selection of the right drug may be facilitated by guidelines, which can be an effective tool to promote appropriate antibiotic use as they discourage the use of antibiotics to treat viral RTI infections and can promote specific use of antimicrobials according to patient risk factors for DRSP [50]. As indicated earlier in this section there are several available agents effective against DRSP. The pertinent question becomes: do we need to treat all patients empirically as if they have DRSP? The answer must take into consideration the relative rate of DRSP within a community and, to a lesser extent, the mechanism of resistance (e.g., mef vs. erm for macrolide resistance). In locations where the rate of DRSP is relatively low it seems reasonable to reserve agents such as the fluoroquinolones and telithromycin. An important principle in many of the guidelines for community RTIs is to reserve the fluoroquinolones and telithromycin for patients with mild infection who are more likely to be infected with such strains in an attempt to avoid over use of these agents. The general North American approach is to choose among macrolides, doxycycline, a respiratory fluoroquinolone (e.g., gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin), or the combination of a b-lactam plus macrolide as treatment options for patients who are mildly ill and can be treated as outpatients (Table 3) [51 53]. More recently telithromycin has also been included as an option since its introduction into the market in 2004 [54]. The specific selection is related to the relative likelihood of DRSP based on the known risk factors as listed previously. Usually, the North American guidelines recommend a macrolide as first-line treatment for outpatients with no comorbidity or risk factors for DRSP. The rationale is that the macrolides provide effective therapy for the most common bacterial pathogens, primarily S. pneumoniae (which have been, up until the present, mostly macrolide-responsive in North America) as well as the atypical organisms (especially M. pneumoniae and Chlamydophila pneumoniae which are common in outpatients). The positioning of the macrolides as prominent first line agents in these guidelines is partially based on the presumption that resistance is less likely in patients who do not have any of the know risk factors for DRSP. In addition, the newer macrolides (azithromycin and clarithromycin) may be effective against MRSP strains in which lower-level resistance results from increased drug efflux with MIC values often < 8 mg L. However, because recent data indicate that mef-mediated resistance is becoming associated with higher MICs (from a median of 4 8 mg L), it is reasonable to consider alternative therapy (i.e., respiratory fluoroquinolone, or high dose amoxicillin ( 3g day for and adult) + macrolide) if risk factors for DRSP are present. Despite the reports of clinical failures in patients with pneumococcal pneumonia treated with macrolides as outpatients, the numbers are relat-

38 Clinical Microbiology and Infection, Volume 12 Supplement 3, 2006 Table 3. Comparison of recommendations of recently published guidelines for empirical antimicrobial treatment of community-acquired pneumonia in adults (from North America and United Kingdom) Guideline Outpatient a General Ward a ICU Severe a North American Guidelines (synthesis from Canadian, 2000; ATS, 2001, IDSA, 2003) [50 52] British Thoracic Society (2001) [53] If no significant risks for DRSP b : Macrolide c or doxycycline If risks for DRSP b : Antipneumococcal fluoroquinolone d OR High-dose amoxicillin (3 g day) or amoxicillin clavulanate + macrolide (if amoxicillin is used and there is a concern for H. influenzae, use agent active for b-lactamase producing strains c ) OR Telithromycin e Amoxicillin 500 1000 mg, three times a day (Alternative: erythromycin or clarithromycin) b-lactam (ceftriaxone, cefotaxime, ampicillin sulbactam) + macrolide c (can use doxycycline if macrolide not tolerated) OR Antipneumococcal fluoroquinolone d alone If admitted for nonclinical reasons or previously untreated in the community: amoxicillin (macrolide as alternative). If admitted for pneumonia and oral therapy appropriate: amoxicillin + [erythromycin or clarithromycin]; (Alternative: antipneumococcal fluoroquinolone) If Parenteral appropriate: [ampicillin or benzylpenicillin] + [erythromycin or clarithromycin] (Alternative: IV levofloxacin) b-lactam (ceftriaxone, cefotaxime, ampicillin sulbactam) + macrolide c or fluoroquinolone d (if b-lactam allergy, use fluoroquinolone d + clindamycin) Modifying factors Structural lung disease: antipseudomonal agent (piperacillin tazobactam, carbapenem, or cefepime) + antipseudomonal fluoroquinolone (high dose ciprofloxacin or levofloxacin) (Defined as severe) Co-amoxiclav or 2nd 3rd gene ceph plus [IV erythromycin or clarithromycin + rifampin] (Fluoroquinolone with enhanced pneumococcal activity + benzylpenicillin as alternative) a Site of care; ICU, intensive care unit; DRSP, drug resistant Streptococcus pneumoniae; b b-lactam therapy within the past 3 months, hospitalisation within the past month, alcoholism, immune-suppressive illness (including therapy with corticosteroids), multiple medical comorbidities, exposure to a child in a day care centre; c If COPD, use a macrolide active against b-lactamase producing H. influenzae (i.e., azithromycin, clarithromycin); d Gatifloxacin, Levofloxacin, Moxifloxacin; e Telithromycin is not listed in the published North American guidelines since it was not approved until after the most recently published statement, however, it is recommended as an option in a more recent recommendation [53] and is included here for completeness. ively small in light of the large number of patients treated [50]. In addition, when such patients were hospitalised and treated with a b-lactam and a macrolide they generally survived. Most of these patients had risk factors for which monotherapy with a macrolide is not recommended in the present guidelines. Thus, for patients without significant risks for DRSP or Gram-negative bacilli, monotherapy with macrolide can at present still be considered appropriate. The use of fluoroquinolones in ambulatory CAP without comorbid conditions or recent antimicrobial use in locations without a high percentage of high level macrolide-resistant pnemococcus is discouraged for fear that widespread use may lead to the development of fluoroquinolone resistance among the respiratory pathogens (as well as other pathogens colonising the treated patients). In contrast, the presence of risk factors for DRSP (i.e., recent use of antibiotics, multiple comorbities, etc.) increases the likelihood for DRSP and enteric gram-negative bacteria. For such outpatients, empirical therapeutic options in the North American statements include: a respiratory fluoroquinolone (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin); a ketolide alone (i.e., telithromycin), if enteric Gram-negatives are not a concern or combination therapy with a b-lactam effective for S. pneumoniae plus a macrolide (doxycycline as alternative) [53]. These regimens can also be appropriate for patients without comorbidities or recent antimicrobial use in locations where the prevalence of high-level macrolide-resistant S. pneumoniae is high (which includes most countries outside of North America). In comparison with the North American approach, the primary agents recommended in the recently published British Thoracic Society guidelines for outpatients are b-lactams, basically penicillins, and not macrolides [55]. The rationale is that these agents are effective against S. pneumoniae, and when given in high doses are even effective for most strains with decreased sensitivity to penicillin. Since most of the macrolide resistance in Europe is erm-mediated high-level resistance, the macrolides are not regarded as optimal first-line empirical agents to treat infections if they are considered likely to be due to S. pneumoniae. In addition the British statement places less significance on the need to treat the atypical pathogens empirically in ambulatory patients (mild disease). Rather, the statement suggests that since M. pneumoniae exhibits epidemic periodicity every 4 5 years and largely affects younger persons, a policy for initial empirical therapy that aims always to cover this pathogen was unnecessary. For patients requiring admission to a general ward in the hospital, North American and Euro-

File Implications of multiresistant S. pneumoniae 39 pean recommendations begin to converge. The view here is that these patients require broader coverage, and that recommended agents should cover both S. pneumoniae (including consideration for DRSP) and Legionella spp. (as well as more unusual pathogens). In North America, the first-line recommendation for these patients is a b-lactam macrolide combination or one of the new fluoroquinolones. In Europe, a b-lactam (e.g., benzylpenicillin) macrolide combination is the widely recommended first-line treatment for patients requiring parenteral therapy. New fluoroquinolones are beginning to be recommended more frequently throughout Europe in the hospital setting. Preventing DRSP through vaccination The introduction of the conjugate pneumococcal vaccine for children appears to be reducing the amount of DRSP in those locations where it is being utilised. The heptavalent vaccine includes two serotypes that most commonly cause antimicrobial-resistant disease in children. One study has shown that 2 years after the use of the vaccine in the US, the incidence of infection due to DRSP diminished by 35% [56]. In addition, the use of the conjugate vaccine may reduce antimicrobial resistance indirectly through its impact on decreasing antimicrobial use. Another study in California found a reduction in the number of antimicrobial prescriptions among children who received the conjugate vaccine [57]. There is concern, however, that non-vaccine serotypes may begin to emerge as causes of serious infection as the vaccine serotypes are diminished; as this occurs it is possible that drug resistance may emerge among these other serotypes as a result of the selective pressure of antimicrobial usage. Nevertheless, the initial impact of this vaccine has been very positive in reducing the burden of pneumoccocal disease specifically, but also in reducing the amount of resistance. CONCLUSION Clinicians need to be cognisant of the aetiological agents of community RTIs, local antimicrobial sensitivity patterns, and pharmacological options for appropriate empirical therapy. S. pneumoniae is the most significant bacterial cause and empirical therapy should target this pathogen, taking into consideration the possibility of drug-resistant isolates. The judicious prescribing of antimicrobial therapy is warranted, not only because it is good clinical practice, but also because it is necessary to curtail current patterns of increasing bacterial resistance to commonly used antimicrobials. Patient risk factors can be helpful in stratifying patients for appropriate antibiotic treatment. As new specimen-sampling techniques and microbiological detection methods become available, a shift from empirical therapy toward pathogendirected therapy may result in improved outcomes and curb antimicrobial resistance. REFERENCES 1. Fine MJ, Smith MA, Carson CA et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996; 275: 134 141. 2. File TM Jr. Community-acquired pneumonia. Lancet 2003; 362: 1991 2001. 3. File TM Jr. Appropriate use of antimicrobials for drugresistant pneumonia: focus on the significance of b-lactamresistant Streptococcus pneumoniae. Clin Infect Dis 2002; 34 (Suppl. 1): S17 S26. 4. Felmingham D. Comparative antimicrobial susceptibility of respiratory pathogens. Chemotherapy 2004; 50 (Suppl. 1): 3 10. 5. Appelbaum PC. Antimicrobial resistance in Streptococcus pneumoniae: an overview. Clin Infect Dis 1992; 15: 77 83. 6. Doern GV, Brueggemann A, Holley HP Jr, Rauch AM. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 95: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996; 40: 1208 1213. 7. Doern GV, Richter SS, Miller A et al. Antimicrobial resistance among Streptococcus pneumonaie in the United States: Have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis 2005; 41: 139 148. 8. Jacobs MR, Felmingham D, Appelbaum PC, Grüneberg RN and the Alexander Project Group. The Alexander Project 1998 2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 2003; 52: 229 246. 9. Nishijima T, Saito Y, Aoki A. Distribution of mefe and ermb genes in macrolide-resistant strains of Streptococcus pneumoniae and their variable susceptibiity to various antibiotcs. J Antimicrob Chemother 1999; 43: 637 643. 10. Ho PI, Yung RWH, Tsang DNC et al. Increasing resistance of Streptococcus pneumoinae to fluoroquinolones: results of a Hong Knog multicenter study in 2000. J Antimciob Chemther 2001; 48: 659 665. 11. McGee L, Goldsmith CE, Klugman KP. Fluoroquinolone resistance among clinical isolates of Streptococcus pneumoniae belonging to international muliresistant clones. J Antimicrob Chemother 2002; 49: 173 176.

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