This report was reviewed for medical and scientific accuracy by Gary V. Doern, PhD, Professor, Section Director, Clinical Microbiology, University of Iowa, Iowa City

Introduction

Streptococcus pneumoniae (S. pneumoniae) is among the leading causes of infection and death worldwide for young children, persons who have underlying chronic diseases, and the elderly. This important respiratory tract pathogen is the leading cause of community-acquired pneumonia (CAP) and acute otitis media in the United States (US).¹ The pneumococcus is now also recognized as the most common bacterial cause of meningitis in the US.¹

Until recently in the US, S. pneumoniae was nearly uniformly susceptible to penicillin and other Я-lactam antimicrobial agents. This allowed clinicians to treat patients, even those with severe pneumococcal infections, with Я-lactam agents alone. In vitro susceptibility testing was largely unnecessary. Since the early 1990's, however, the prevalence of Я-lactam resistance in S. pneumoniae has risen steadily each year.

Results from a multicenter US national surveillance study² conducted between November 1999 and April 2000 indicate that ~35% of pneumococci are now non-susceptible to penicillin (minimum inhibitory concentration (MIC) ≥ 0.12 µg/mL) with circa 60% of these isolates expressing high-level penicillin resistance (MIC ≥ 2 µg/mL). Overall, antimicrobial resistance was highest among middle ear fluid and sinus isolates of S. pneumoniae; lowest resistance rates were noted with isolates from cerebrospinal fluid and blood. Resistant isolates were most often recovered from children 0 to 5 years of age.²

Mechanism of Resistance

The principal mechanism of resistance to penicillin and other Я-lactam antibiotics with S. pneumoniae is alterations in penicillin-binding proteins (PBPs) as a consequence of a mosaic of genetic changes at the level of the bacterium's chromosome.³ Я-lactam resistant pneumococci are characterized by PBPs with diminished antibiotic affinity, leading in turn to decreased antibiotic effect (i.e. increased Я-lactam MICs). Resistance to numerous other non-Я-lactam antibiotic classes (e.g. macrolides, clindamycin, tetracyclines, chloramphenicol, trimethoprim/sulfamethoxazole (TMP/SMX) and the fluoroquinolones) has also become manifest with S. pneumoniae in the US.^4-6 Resistance to these agents is the result of alternative mechanisms, each specific to a particular antibiotic class. Interestingly, despite different mechanisms of resistance, defined both phenotypically and genotypically, resistance to multiple antibiotic classes often occurs within the same strain of S. pneumoniae. Such strains are referred to as multi-drug resistant.

There are two mechanisms of macrolide resistance with S. pneumoniae: an efflux pump (encoded for by the mefA gene)^7-10 and altered ribosomes as a result of ribosomal methylation (encoded by the ermB gene).¹¹ Strains with efflux as their resistant determinant express modest levels of resistance to macrolides (MIC 0.5-32 µg/mL), but remain susceptible to clindamycin and streptogramin B antimicrobials; such strains are referred to as having the M phenotype. Strains with altered ribosomes typically express high levels of macrolide resistance (MIC > 256 µg/mL) and are also resistant to clindamycin and streptogramin B agents; they are referred to as having the MLS_B phenotype. The M phenotype is most prevalent in the US with 70-75% of macrolide-resistant strains having efflux as their resistance determinant. Despite high rates of macrolide resistance with S. pneumoniae in the US as determined in the laboratory, it is not clear what macrolide resistance, especially efflux-mediated resistance, means from a clinical perspective.^12,13

The most important mechanisms of fluoroquinolone resistance are chromosomal mutations in the genes encoding the polypeptide subunits of topoisomerase IV and DNA gyrase, two enzymes necessary for DNA replication in S. pneumoniae, and overexpression of endogenous multi-drug transporters (i.e. efflux pumps). The first mechanism results in diminished binding of fluoroquinolones to their enzyme targets of action. The presence and enhanced expression of endogenous efflux pumps leads to active extrusion of fluoroquinolones from within the bacterial cytoplasm resulting in reduced levels of intracellular accumulation.

Currently in the US, the following approximate overall resistance rates apply to S. pneumoniae and non-Я-lactam antimicrobial agents: macrolides, 25.9%; tetracyclines, 16.4%; chloramphenicol, 8.4%; trimethoprim/sulfamethoxazole, 30.3%; and clindamycin, 8.8%.² [see Figure 1] Furthermore, approximately 22.5% of S. pneumoniae clinical isolates are multi-drug resistant. Although an emerging problem in certain other countries, fluoroquinolone resistance has not yet emerged as a problem with S. pneumoniae in the US.^4,14-18

Figure 1.

Causes of Resistance

The question arises: "What are the factors that have influenced the emergence of drug resistant S. pneumoniae in the US during the past decade?" One important consideration relates to the observation that the emergence of resistance to antibiotics is often a direct result of antibiotic use. Specifically, the rising prevalence of antibiotic resistance is a consequence of the selective pressure exerted by use of antibiotics.^19-22 The correlation between increasing antibiotic use and increasing prevalence of resistance has been shown most clearly in the hospital^23,24 but has also been demonstrated in the community setting.^25,26

A major contributing factor to increasing antibiotic resistance is inappropriate use of antibiotics. It has been estimated that 20 to 50% of antibiotic prescriptions issued in the community setting are unnecessary.^27,28 One recent report²⁹ attributed inappropriate antibiotic prescribing to unreasonable patient expectations or demands, inadequate physician time to explain why antibiotics are unnecessary, and misdiagnosis of nonbacterial infections. Even when physicians know that the use of antibiotics is likely to have marginal, if any, clinical value (e.g., in viral infections), they prescribe antibiotics in an effort to placate and thus maintain good relationships with their patients.³⁰ Furthermore, with the increasing pressures of managed care, physicians may not be accorded the opportunity to spend sufficient time with patients to explain why antibiotics may be unnecessary, indeed, why they may actually be harmful (i.e., side-effects and resistance). It is often the path of least resistance to prescribe an antibiotic. Ironically, this may also be the path to greatest resistance.

The problem of resistance is complicated by the widespread use of antibiotics as growth enhancers in the food animal industry. Although the precise mechanism by which antibiotics promote animal growth is not well understood, more than 40% of antibiotics manufactured in the US are used in animals.³¹ This type of use creates a circumstance for selecting resistant bacteria in animals that may, in turn, be passed to the human population.³² A panel of World Health Organization consultants has recommended the gradual discontinuation of antibiotics as growth promoters in animals.³³

Theoretical Application

Not all antimicrobial agents have the same potential for selecting for drug resistant S. pneumoniae. Generally speaking, the more potent an antimicrobial agent, the less likely it is to select for resistance.³⁴ This may be explained by the observation that antimicrobial potency is an important determinant not only in achieving a favorable therapeutic outcome, but also in the context of the emergence of antimicrobial resistance. Potency is the product of both antibacterial activity and the ability to deliver an antimicrobial agent in adequate concentrations to the site of infection for bacterial eradication. The most refined in vitro measure of antibacterial effect is determination of MICs. Drug delivery is a product of the pharmacokinetic properties of specific agents. The relationship between in vitro activity (i.e., MICs) and drug delivery (i.e., pharmacokinetics) is referred to as pharmacodynamics.³⁵ Antibiotic potency is best considered from the perspective of the pharmacodynamic properties of given drug versus a specific pathogen. In effect, the emergence of antimicrobial resistance is influenced by the pharmacodynamic potency of antimicrobial agents. One of the best examples of this concept pertains to the macrolide (e.g., erythromycin, clarithromycin, azithromycin) antimicrobial class.

Azithromycin is consistently 3 to 4-fold less active than clarithromycin for S. pneumoniae (i.e., azithromycin MICs are typically 3-4 times higher than clarithromycin MICs for S. pneumoniae).^36,37 [see Figure 2] Additionally, peak serum levels of azithromycin are roughly one-tenth those of clarithromycin.³⁸ In other words, azithromycin is inferior to clarithromycin in terms of both in vitro activity and pharmacokinetics. It has been suggested that tissue levels rather than serum levels are most important in pharmacodynamic analyses. In the case of azithromycin and clarithromycin, however, serum levels closely parallel drug levels in lung epithelial lining fluid.^39-42 As a result, serum levels with these two macrolides provide a reasonable basis for pharmacodynamic comparisons related to S. pneumoniae vis-а-vis patients with bronchopulmonary infections.

Figure 2.

Adapted from Doern GV. CID 2001;33(Suppl 3):S187-S192.

There exists evidence from several studies that usage of azithromycin is much more likely to select for macrolide resistance with S. pneumoniae than is usage of clarithromycin.^43-49 If the mechanism of macrolide resistance that is selected for by azithromycin usage happens to be ermB-mediated alterations in ribosomal targets, the resulting strains are now cross-resistant at high levels to all macrolides including the most potent agent in this class--clarithromycin.^50,51 In effect, then, use of marginally active agents to select for resistance may lead to a compromise in the utility of more potent agents and ultimately, the erosion of an entire antimicrobial class. This may take on critical importance with the emerging evidence of macrolide-resistant S. pneumoniae exhibiting dual macrolide resistance mechanisms.⁵² However, the relation between drug resistance and failure of the infection to respond to treatment in patients with pneumococcal pneumonia has not been established.^53-56

Addressing Increasing Resistance

The application of pharmacodynamic analyses in assessing the potency of different antimicrobial agents provides an objective basis for optimizing antibiotic therapy in patients with respiratory tract infections. This approach represents one example of the application of evidenced-based medicine in the care of patients with infection in the community. In addition, a number of medical societies have recently developed and published treatment guidelines that, among other things, advocate the judicious use of antimicrobials in the outpatient setting. For example, guidelines for the management of CAP have been issued by the American Thoracic Society⁵⁷, the Infectious Diseases Society of America⁵⁸, and the Canadian Infectious Diseases Society/Canadian Thoracic Society.⁵⁹ Application of pharmacodynamic analyses in optimizing outpatient oral antimicrobial therapy and use of care pathways based on nationally-endorsed management and treatment guidelines have the potential for dramatically impacting on the problem of antibiotic resistance with S. pneumoniae.

Epilogue

Oral antimicrobial usage is a major determinant in the development of antimicrobial resistance with S. pneumoniae. Clearly, judicious use of antimicrobial agents must be emphasized. In patients who truly warrant therapy, consideration must be given to utilization of the most potent agent in a particular antimicrobial class as the most effective means of achieving a favorable therapeutic outcome and preventing the emergence of antimicrobial resistance.

Additional Suggested Reading

Lynch JP, Martinez FJ. Clinical Relevance of Macrolide-Resistant Streptococcus pneumoniae for Community-Acquired Pneumonia. Clin Infect Dis 2002;34(Suppl 1):S27-S46.

File TM. Appropriate Use of Antimicrobials for Drug-Resistant Pneumonia: Focus on the Significance of Я-Lactam-Resistant Streptococcus pneumoniae. Clin Infect Dis 2002;34(Suppl 1):S17-S26.

Hooton T, Levy S. Antimicrobial Resistance: A Plan of Action for Community Practice. Am Fam Physician 2001;63:1087-1096, 1097-1098.

Hellinger W. Confronting the Problem of Increasing Antibiotic Resistance. South Med J 2000;93(9):842-848.

Doern G. Antimicrobial Resistance with Streptococcus pneumoniae in the United States. Sem Resp Crit Care Med 2000;21(4):273-284.

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Disclosure
Susan E. Boruchoff, MD
Has no significant relationships to disclose.

Gary V. Doern, PhD: Grant/Research Support-Abbott Laboratories, GlaxoSmithKline, Pfizer, Ortho McNeil, Bayer; Consultant-Abbott Laboratories, GlaxoSmithKline, Pfizer, Ortho McNeil, Bayer; Speakers' Bureau-Abbott Laboratories, GlaxoSmithKline, Pfizer, Ortho McNeil, Bayer

David C. Howard
Has no significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Abbott Laboratories.

Medical Writer
David C. Howard, BS Pharmacy, Director of Research, Millennium Medical Communications, Inc., Hampton, NH

UMDNJ Medical Reviewer
Susan E. Boruchoff, MD, Associate Professor of Medicine, Division of Allergy, Immunology and Infectious Diseases, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Respiratory Infectious Disease Express Report includes discussion of treatment and indications outside of current approved labeling. This Respiratory Infectious Disease Express Report was made possible through an unrestricted educational grant from Abbott Laboratories.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education