The clinical impact of macrolide resistance in pneumococcal respiratory infections

International Journal of Antimicrobial Agents 18 (2001) S33– S38 www.ischemo.org

The clinical impact of macrolide resistance in pneumococcal respiratory infections J. Garau * Department of Medicina Interna, Hospital Mutua de Terrassa, Uni6ersity of Barcelona, C/san Antonio 8 -14, 08221 -Tarrasa, Barcelona, Spain

Abstract By the 1960s, several reports of bacteria with reduced susceptibility to antibiotics were published. In recent years, the problem of antibiotic resistance has magnified. In the treatment of respiratory tract infections, the development of resistance is of particular concern; 67% of antibiotic use in adults and 87% in children is for the treatment of such infections. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and is a frequently isolated bacterial species in patients with other respiratory tract infections. Increasing levels of resistance may have important implications in the clinical setting. Physicians need to consider local susceptibility data, in addition to the pharmacokinetic and pharmacodynamic features of compounds, when selecting appropriate antibiotics for the treatment of bacterial infections. © 2001 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Penicillin; Macrolide; Community-acquired pneumonia; Streptococcus pneumoniae; Resistance

1. Introduction In the 20 years following the introduction of penicillin, a wide range of antimicrobial agents had become available and they were proven to be clinically effective. As a consequence, infectious disease was no longer viewed as a public-health threat. At about the same time, however, isolated reports of bacteria developing resistance to antibiotics first appeared. In 1952, Haight and Finland reported strains of Streptococcus pneumoniae with increasing levels of resistance to erythromycin [1]. Occasional articles subsequently appeared, including the identification of six erythromycin-resistant pneumococcal strains in a study of 470 patients with bronchitis in 1964 and the isolation of an erythromycinresistant strain from empyema fluid of a male patient with cancer [2,3]. A study published in 1988 found that 25/379 of invasive pneumococcal isolates were resistant to erythromycin. This publication also reported an increase in erythromycin resistance from 1.1% in 1983 to 13% in 1988 [4]. Accounts of erythromycin resistance accelerated in the 1990s. Sanchez and coworkers de-

* Tel.: +349-3-735-5050; fax: +349-3-736-5059. E-mail address: [email protected] (J. Garau).

scribed two pneumonia patients who failed to respond to treatment and found to be infected with erythromycin-resistant S. pneumoniae [5]. In 1993, 5% of pneumococcal blood isolates studied by Lonks and Medeiros were resistant to erythromycin [6]. Other instances of macrolide resistance were described by Moreno et al. [7]. 2. Prevalence of pneumococcal infections In the treatment of respiratory tract infections, the development of resistance is of particular concern, as 67% of antibiotic use in adults and 87% in children is for the treatment of such indications [8]. S. pneumoniae is implicated in nearly 500 000 cases of communityacquired pneumonia each year in the USA alone [9–12]. In addition, this pathogen is commonly found in samples obtained from patients with acute otitis media, acute exacerbations of chronic bronchitis and sinusitis [13]. A meta-analysis of 122 reports of community-acquired pneumonia published between 1966 and 1995 found that S. pneumoniae was responsible for 66% of more than 7000 cases in which the aetiology was established [14]. Most patients recover from a pneumococcal infection, but fatality rates for bacteraemic

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pneumonia due to penicillin-resistant S. pneumoniae are substantial, ranging from 5 to 30% [15– 17].

Table 2 Prevalence of penicillin-intermediate and resistant S. pneumoniae strains [23]

3. Definitions of resistance

Location

Intermediate in %

Resistant in %

Cleveland, USA Hong Kong Johannesburg, South Africa Mexico City, Mexico New York, USA Riyadh, Saudi Arabia Sao Paulo, Brazil San Francisco, USA

15 6 26 13 13 42 14 17

19 56 5 37 27 6 0 11

The National Committee for Clinical Laboratory Standards (NCCLS) publishes guidelines for the interpretation of susceptibility testing of S. pneumoniae using defined methods and conditions [18]. Breakpoints for resistance to macrolides are based on pharmacokinetic/ pharmacodynamic parameters and use standard dosing regimens and criteria appropriate to each agent. For clarithromycin and erythromycin, drug concentrations in serum present for 50– 60% of the dosing interval are considered, whereas for azithromycin, a value of greater than 25 for the 24-h area under the concentration– time curve to minimum inhibition concentration (MIC) ratio is utilized [19,20]. 4. Importance of susceptibility surveillance Surveillance data have become increasingly meaningful with the emergence of resistance, and the importance of culture of sputum samples for susceptibility testing is acknowledged in certain guidelines for the management of community-acquired pneumonia. Historically, penicillins were highly active against S. pneumoniae, but with the decline in the susceptibility to penicillins no longer can one assume that the first-line therapeutic choice will be capable of bacteriological eradication (Table 1). Although the clinical relevance of penicillin resistance among isolates of S. pneumoniae can be debated, there is no question that this resistance can be documented in vitro [8,21–25]. 5. Penicillin resistance in S. pneumoniae The prevalence of penicillin-resistant strains varies geographically. The distribution of pneumococcal penicillin resistance worldwide, based on the findings of a multinational study, is shown in Table 2 [23]. The total prevalence of high-level penicillin resistance was 10.4%, with particularly high levels in Hong Kong (56%) and Mexico City (37%). Geographical differences in penicillin resistance between, and within countries, have been detected in a number of studies. Other studies have Table 1 Definition of penicillin susceptibilities in S. pneumoniae [18] Susceptibility determination

MIC (mg/l)

Susceptible Intermediate resistant Resistant

50.06 0.1–1.0 ]2

shown that rates of penicillin-resistant S. pneumoniae are very high in certain areas (e.g. Spain, Eastern Europe, France, Israel, South Africa and some Asian countries), ranging from 25 to 86% [26,27]. By contrast, penicillin-resistant strains remain uncommon (B 5%) in Northern European countries, such as Sweden [23], Finland [23] and the Netherlands [23], and a number of other countries [21]. Recent studies established that the majority of penicillin-resistant strains in Europe [28,29], the USA [22], South America [22] and Asia [23] are derived from three dominant clones (serotypes 23F, 6B, 14), believed to have been introduced from Spain and France. Once resistant strains are present in a geographic locale, subsequent spread may escalate rapidly by selection pressure. The dramatic rise in resistance in certain areas, such as Korea, eastern Europe and Spain, may be attributed to the inappropriate or uncontrolled use of antibiotics [30,31]. Penicillin-resistant S. pneumoniae are often resistant to non-b-lactam antibiotics, mainly macrolides and tetracyclines [21,23]. Resistance to three or more classes of antibiotics (e.g. penicillins, macrolides and tetracyclines) is defined as multi-drug resistance [32], and such isolates are now prevalent in many countries [13,33,34]. Inevitably, this has important implications for the selection of antibiotics. Risk factors for multi-drug-resistant S. pneumoniae include prior antibiotic use, extremes of age and hospitalization of the patient [35].

6. Erythromycin resistance in S. pneumoniae Since Dixon’s description of the development of erythromycin resistance in an isolate obtained from the pleural fluid of a 63-year-old man with lung cancer, reports of erythromycin-resistant pneumococci continued to appear in the literature [5–7]. Erythromycin-resistant strains are predictably resistant to clarithromycin, azithromycin and roxithromycin [7,36], and are usually resistant to penicillin and several other antibiotics [37]. A surveillance survey conducted in the USA in 1997 evaluated the susceptibilities of S. pneumoniae isolated

J. Garau / International Journal of Antimicrobial Agents 18 (2001) S33–S38

from specimens obtained from outpatients in six geographical regions [21]. In total, 1476 isolates were examined. Table 3 shows the percentage of S. pneumoniae susceptible to macrolides using NCCLS and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints [38]. Overall, 69.8% of the isolates were sensitive to azithromycin and clarithromycin. Jacobs et al. also found significant cross-resistance between penicillin and macrolides among S. pneumoniae isolates [38], with 5% of the penicillin-susceptible strains being macrolide-resistant, compared with 37% of the intermediate isolates and 66% of the resistant isolates. In a multicentre surveillance study conducted during the 1997– 1998 respiratory illness season in the USA, 13% of 4148 pneumococcal isolates were resistant to penicillin and 21– 22% were resistant to macrolides [39]. Another study conducted in Taiwan, where the incidence of macrolide resistance is among the highest in the world, 82% of pneumococcal isolates obtained from patients in the National Taiwan University Hospital between January and December were resistant to erythromycin [40]. Of the penicillin-non-susceptible isolates, 96.7% were resistant to erythromycin [40]. Non-penicillin-susceptible isolates were also found to be resistant, in varying degrees, to other antibiotics including cefotaxime and trimethoprim/sulphamethoxazole, but not rifampicin. Pneumococci resistant to macrolides and trimethorprim/sulphamethoxazole are frequently associated with penicillin or multi-drug resistance, and may have evolved in response to different antibiotic pressures in the various communities. Data from the multinational Alexander Project demonstrated national variations in macrolide resistance according to penicillin susceptibility [23]. 7. Clinical significance of in vitro resistance to macrolides Resistance to erythromycin in S. pneumoniae is due to two main mechanisms: one involves the target site Table 3 Percentage of S. pneumoniae isolates susceptible to macrolides using NCCLS and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints [38] Susceptibility breakpoint All isolates (n= 1476) (mg/l) NCCLS

PK/PD

NCCLS

PK/PD

Clarithromycin 0.25

0.25

69.8

69.2

Azithromycin Penicillin

0.12 NA

69.8 49.6, 67.5a

69.8

0.5 0.06, 1a

a Penicillin susceptibility and intermediate penicillin susceptibility breakpoints.

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Table 4 Macrolide concentrations and pharmacokinetic parameters in erythromycin-resistant S. pneumoniae [42] Erythromycin ermAM (n = 100) MIC90 (mg/l) \32 Range 0.25–\32 mefE (n = 101) MIC90 (mg/l) Range

Clarithromycin Azithromycin

\128 0.25–\128

\32 1–\32

8 0.5–\32

4 0.06–8

8 0.5–\32

Pharmacokinetic parameters Cmax (mg/l) 0.7 ELFmax (mg/l) 0.8 AMmax (mg/g) 0.8

2.0 34.5 480.0

0.09 2.18 57.2

Cmax, maximum plasma antibiotic concentration; ELFmax, maximum antibiotic concentration in epithelial lining fluid; AMmax, maximum antibiotic concentration in alveolar macrophages.

modification by an enzyme that methylates 23S rRNA, the erythromycin resistance methylase (erm) and the second, is the presence of a macrolide efflux pump (mef) [41]. In general, isolates carrying efflux pumps are microbiologically less resistant than isolates that carry the erm gene. Efflux mutants account for approximately 60–75% of macrolide-resistant strains of S. pneumoniae in North America. The strains that express the MLSB phenotype exhibit cross-resistance to macrolides, lincosamides and streptogramin B-type antibiotics and are the most prevalent of the erythromycin-resistant pneumococci, accounting for \ 90% of strains in Spain and Italy. Recently, presented data suggest that clarithromycin and azithromycin could be effective against S. pneumoniae carrying the mefE gene [42]. Table 4 illustrates the MIC values and pharmacokinetic parameters of erythromycin, clarithromycin and azithromycin. Maximum concentrations of both clarithromycin and azithromycin in alveolar macrophages were several-fold greater than the MIC of mefE-bearing strains, but it will be necessary to document clinical efficacy before assuming that these strains are suitable for treatment with macrolides. In fact, azithromycin and clarithromycin fail against mefA-bearing strains in murine models of S. pneumoniae peritonitis and pneumonia. An increasing number of reports of macrolide treatment failure have been reported in the recent past [5,7]. Development and progression of pneumococcal infections (bacteraemia/meningitis) in four young children occurred while receiving either clarithromycin or azithromycin [43,44]. Fogarty described three cases of bacteraemic treatment failure with azithromycin in adults [45]. The three patients, who were previously healthy, non-smoking adults, were infected with erythromycin-resistant and penicillin-/cephalosporin-non-

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susceptible strains. Breakthrough pneumococcal bacteraemia in four patients that had previously taken either azithromycin or clarithromycin for 3– 5 days has been recently published [46]. All four had pneumococcal strains that exhibited low-level resistance to macrolide antibiotics. A case of fatal pneumococcal pneumonia attributed to macrolide resistance (erythromycin MIC, 18 mg/l) and azithromycin monotherapy has also been reported [47]. Another recent study investigated the clinical relevance of macrolide antibiotic therapy in bacteraemic patients infected with a macrolide-resistant S. pneumoniae [48]. Data on susceptibility to macrolide antibiotics were available on blood isolates of S. pneumoniae from The Miriam Hospital, Rhode Island, from 1986 to 1999, the Rhode Island Hospital, for several months during 1997 and from Hospital Mutua de Terrassa, Barcelona, from 1988 to 1999. The investigators reviewed the medical records of bacteraemic patients with a macrolide-resistant S. pneumoniae. Among the blood isolates from Barcelona 42 were resistant to erythromycin, as were 15 from the Rhode Island hospitals. Nine patients from Barcelona and three from Rhode Island developed bacteraemia with a macrolide-resistant S. pneumoniae while receiving macrolide therapy. The primary diagnosis was pneumonia in all but one of these patients. All the isolates from Barcelona carried the ermB gene, but one isolate from Providence had the mef gene. Two isolates had high-level penicillin resistance, intermediate penicillin resistance was present in six, and three were fully susceptible to penicillin. All patients were treated successfully with a b-lactam antibiotic. These data show that in vitro resistance to macrolides may be clinically important. Evidence that clinical failure is associated with increasing MICs also comes from a recently published study performed by Dagan et al. [49]. They demonstrated a clear correlation between the persistence of the pathogen and increased MICs of azithromycin or cefaclor for S. pneumoniae. Fig. 1 summarizes the bacteriological failure rates among 41 children with acute otitis media treated with either antibiotic according to the respective drug’s MICs. The findings of this study provide further confirmation of the need to take into account susceptibility and pharmacokinetic data when selecting an antibiotic for the treatment of infection.

different microorganisms developing resistance to virtually every known antibiotic. The consequences have been very important in clinical practice, as patients infected with a multi-resistant organism suffer increased morbidity and mortality, and often require the use of expensive and potentially toxic antibiotic regimens in order to achieve effective treatment. Macrolide antibiotics have been traditionally used for the treatment of community-acquired pneumonia because of their spectrum of activity against the major pathogens. The development of in vitro resistance as reported in a number of surveillance studies and an increasing number of reports of clinical failures has brought their empiric use into question. The incidence of macrolide-resistant S. pneumoniae is increasing worldwide and is often associated with penicillin resistance. Two resistance mechanisms have been identified in S. pneumoniae— ribosomal methylase, ermAM (MLSB phenotype) and macrolide efflux pump, mefE (M phenotype). The M phenotype is more prevalent in the USA [35], whereas the MLSB phenotype represents over 90% of all erythromycin-resistant S. pneumoniae in some, but not all European countries [23]. The prevalence and type of resistance may require review of the current recommendations for the treatment of community-acquired pneumonia. At present, the occasional reports of treatment failure do not justify any modification in respect to the use of macrolides in the empiric treatment of respiratory tract infections, but in cases of suspected pneumococcal infection in areas with a high prevalence of macrolide-resistant pneumococci, macrolides should not be used empirically for the treatment of these infections.

8. Conclusions The introduction of antibiotics heralded a new era in the chemotherapy of infectious diseases, but over the ensuing years bacterial evolutionary responses to the selective pressure of antibiotics have resulted in

Fig. 1. Bacteriological failure rate according to MICs for S. pneumoniae in patients with acute otitis media treated with azithromycin or cefaclor.

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