Editorial

Thomas M. File, Jr, MD, Professor of Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; Chief, Infectious Disease Service, Summa Health System, Akron, Ohio

Lower respiratory tract infections (LRTI) are among the most common type of infection managed by health care providers and they are of potentially great consequence. Community-acquired pneumonia (CAP) and acute exacerbation of chronic bronchitis (AECB) are significant causes of morbidity and death in the United States (U.S.); and despite substantial advances in management, the optimal approach to therapy remains controversial. The diminished susceptibility of bacterial etiologies of CAP to penicillin and other antimicrobials over the past decade has complicated the decision regarding the initial empirical antimicrobial management. Paradoxically, the progress previously made in dealing with the most common bacterial cause of respiratory infections, Streptococcus pneumoniae (S. pneumoniae) is now associated with a global explosion of drug-resistance that has made treatment decisions more difficult. Fortunately, treatment options for CAP have expanded over the past 5 years to include agents such as the new respiratory fluoroquinolones (e.g., gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin) that are active against both typical (including approximately 99% of drug-resistant S. pneumoniae isolates) and atypical pathogens. The question for practicing clinicians is: when should these new, potent agents be used in deference to other choices (such as macrolides or Я-lactams)? Given the variability of resistance patterns, clinicians must be vigilant and knowledgeable about antibiotic sensitivity patterns in their patients and community in order to answer this question appropriately. This report reviews pertinent issues concerning fluoroquinolone (FQ) resistance. Hopefully, awareness of clinicians should allow for more judicious use of these agents.

One of the issues concerning the increasing resistance of S. pneumoniae observed in recent surveillance studies is clinical relevance for LRTI, especially CAP. The real issue is whether resistance (or at what level of resistance) is associated with the greater likelihood of clinical failure. While this has been fairly well established for pneumococcal meningitis, it has been less clarified for pneumonia. Several studies have examined how CAP cases caused by 'nonsusceptible' isolates respond clinically. The results suggest that the Я-lactams remain effective for streptococcal pneumonia when the infecting pathogen has a penicillin MIC ≤ 2 µg/mL, presumably because the pharmacokinetic and pharmacodynamic (PK/PD) parameters associated with current dosing regimens are still sufficient for such infections. However, when the penicillin MIC is ≥ 4 µg/mL, increased rates of mortality (for patients who survive their first four days of hospitalization), treatment failures, and suppurative complications may occur. Currently, 3.5% to 7.8% of S. pneumoniae clinical isolates have MICs that fall in this latter class, but these rates may rise in the future. Certainly, the fluoroquinolones are appropriate options for such patients or for those patients who are at higher likelihood of drug resistant S. pneumoniae (DRSP) (i.e., older patients, recent patient use of antibiotics, recent patient hospitalization, exposure to daycare centers).

While the use of FQ offers definite advantages, a major concern is the potential for the development of resistance. While these new agents remain very active against approximately 99% of isolates of S. pneumoniae in the U.S. according to the results of recent surveillance studies, there is concern that overuse will lead to increasing resistance as has been observed in some parts of the world (e.g., Hong Kong). Adherence to evidence-based guidelines, continued use of preventative measures for all infectious diseases, including vaccination, and appropriate use of antimicrobials, can hopefully reduce the resistance trend. The importance of CAP has led to the recent publication of guidelines from several organizations in North America. Recommendations for empirical antimicrobial therapy from the Infectious Diseases Society of America (IDSA), American Thoracic Society (ATS), the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (DRSPTWG), and the Canadian Thoracic Society/Infectious Diseases society are summarized in the table on page 3 of this report. The selection of specific regimens for empirical therapy is based largely on the most likely pathogens, in-vitro activity, and clinical studies. Clearly, all groups recognize S. pneumoniae as the single most important pathogen. While there is variation in the specific positioning of the antimicrobial agents, the recommendations are actually very similar. For patients treated in the ambulatory setting, all statements variably recommend a macrolide, doxycycline or a new, antipneumococcal fluoroquinolone. The relative risk of DRSP is mentioned in each of the statements as a selection factor. In the Canadian and ATS statements, patients are specifically stratified according to the presence of modifying factors. The IDSA statement indicates that the selection between these options should be influenced by regional antibiotic susceptibility patterns for S. pneumoniae and the presence of risk factors for DRSP. The DRSPTWG statement is similar but stresses that fluoroquinolones should be reserved for cases associated with failure or because of allergy to other agents, or cases caused by documented DRSP. The rationale is that the fear of widespread use may lead to the development of fluoroquinolone resistance among the respiratory pathogens (as well as other pathogens colonizing treated patients).

Because of their excellent coverage of the common respiratory pathogens, short treatment durations, and excellent penetration into tissues, the respiratory fluoroquinolones are appropriate treatment options for many patients with LRTI. Given these considerations, appropriate dosing based on optimal PK/PD parameters is essential. Since the FQ exhibit concentration dependent killing, dosing which achieves maximal AUC/MIC or Cmax/MIC can be predicted to be associated with the best bacteriological response and possibly with prevention of mutant isolates. Presently, PK/PD parameters offer the best tool to predict clinical efficacy of an antibacterial and, although not proven, its impact on resistance. The appropriate choice of an antimicrobial agent should minimize the potential for the development of resistance and provide for the optimal, and cost-effective, outcome for our patients.

Introduction

S. pneumoniae is a major cause of morbidity and mortality in LRTI. It is the most common etiology of CAP, accounting for as many as 60% of cases with a defined etiology. CAP is an important public health problem, occurring in 5-6 million people in the U.S. each year,¹ resulting in 1.1 million hospital admissions¹ and 45,000 deaths.² AECB are even more common, affecting 13 million people in the U.S.³ Patients with chronic bronchitis may experience recurrent infections [exacerbations], which can lead to progressive lung damage and decreased pulmonary function.

The past decades have seen an increase in the prevalence of penicillin resistant S. pneumoniae. In 1988-9, only 2% of S. pneumoniae were penicillin resistant [minimum inhibitory concentration (MIC) ≥ 2 µg/mL]. However, by 2000, this number had increased to 21.5%.⁴ S. pneumoniae has also developed resistance to alternative therapies, such as macrolides, trimethoprim/sulfamethoxazole, and tetracyclines, rendering therapy more difficult. For example, in 1994, only 13% of S. pneumoniae isolates were erythromycin resistant (MIC ≥ 4 µg/mL). By 1999, this number had increased to 31%.⁵ Emerging resistance to older fluoroquinolones, such as ciprofloxacin, has also been demonstrated worldwide, ranging from 3% in Canada^6,7,8 and Spain⁹ to 12% in Hong Kong¹⁰ and 15% in Northern Ireland.¹¹

Understanding Resistance Trends

Data from the Alexander Project, a longitudinal, multi-country surveillance of clinical isolates of community-acquired lower respiratory tract infections since 1992, provides MIC data for 25 antibiotics, including Я-lactams, macrolides, and quinolones.¹² Data from calendar year 2000 includes 6545 clinical isolates from 35 centers in 22 countries. The prevalence of penicillin resistant S. pneumoniae strains (MIC ≥ 2 µg/mL) was 32% in the Northeastern U.S., 18% in the Southwestern U.S., 18% in Mexico, 3% in Brazil, 25% in Saudi Arabia, 15% in South Africa, and 75% in Hong Kong. Additionally, a high prevalence of Я-lactamase production by Haemophilus influenzae and Moraxella catarrhalis in resistant strains was seen.

Macrolide resistance, defined as erythromycin MIC ≥ 1 µg/mL, was 34% in the Northeastern U.S., 25% in the Southwestern U.S., 29% in Mexico, 3% in Brazil, 16% in Saudi Arabia, 19% in South Africa, and 81% in Hong Kong. Analysis of macrolide prescribing and resistance patterns indicates a correlation between increasing macrolide resistance and the increased use of newer, long-acting macrolides (e.g., azithromycin, clarithromycin).¹³ The application of pharmacodynamic concepts suggests that bacterial exposure to low and prolonged concentrations of these agents may have a role in the selection of resistance. The prevalence of S. pneumoniae macrolide resistance exceeds that of penicillin resistance in many countries.

In a case control study from 1987-2000, Lonks et al.¹⁴ reviewed all cases of pneumococcal bacteremia (n = 1,071) from 3 US hospitals and one Spanish hospital. Patients with erythromycin-resistant isolates (n = 86) were matched with erythromycin susceptible isolates (n = 141) for age, sex, location and year of bacteremia. Macrolide failure in pneumococcal invasive disease due to erythromycin-resistant S. pneumoniae ranged from 4.8% at Brigham and Women's Hospital, Boston, MA, to 15% at Rhode Island Hospital, Providence, RI. The most significant characteristic associated with macrolide resistance was prior history of macrolide utilization (p < 0.00000004).

Macrolide-resistant pneumococci are associated with penicillin-resistance^15,16,17 and are increasing worldwide. Two main mechanisms of macrolide resistance are the efflux pump (mef)^18,19,20,21 -M phenotype and the ribosomal methylase (encoded by ermAM) referred to as -macrolide-lincosamides-streptogramin (MLSB) phenotype.²² The M phenotype is prevalent in the U.S. (MIC usually < 32 µg/mL), while the MLS phenotype represents > 90% of all erythromycin resistant S. pneumoniae from southern European countries (MIC usually > 32 µg/mL).

The increasing resistance of S. pneumoniae to Я-lactam antibiotics has directed attention to the quinolones. In a case control study,²³ independent risk factors associated with colonization or infection with levofloxacin-resistant S. pneumoniae included nursing home residence (odds ratio [OR], 7.4), chronic obstructive pulmonary disease (COPD) (OR, 10.3), nosocomial origin of the bacteria (OR, 16.2), and prior exposure to fluoroquinolones (OR, 10.7).

Newer fluoroquinolones are much more potent in vitro against S. pneumoniae than older quinolones. For example, gemifloxacin has an MIC₉₀ [concentration inhibiting growth in 90% of organisms] of 0.03 µg/mL while ciprofloxacin has an MIC₉₀ of 2.0 µg/mL.²⁴ Moxifloxacin, gatifloxacin, and levofloxacin have values of 0.25, 0.5, and 1.0 µg/mL, respectively.²⁴ Gemifloxacin also has more potent in vitro activity against ciprofloxacin-resistant S. pneumoniae (defined as MIC ≥ 4 µg/mL); gemifloxacin 0.25 µg/mL MIC₉₀, moxifloxacin 4 µg/mL, gatifloxacin 4 µg/mL, levofloxacin 16 µg/mL, and ciprofloxacin 32 µg/mL.⁶

Antibacterial Mechanisms of Action of the Quinolones

Quinolones directly inhibit DNA synthesis by their interaction with complexes composed of DNA and either of two target enzymes: DNA gyrase and topoisomerase IV.²⁵ These enzymes are structurally related to each other, both being tetrameric with pairs of 2 different subunits. The GyrA and GyrB subunits of DNA gyrase are respectively homologous with the ParC and ParE subunits of topoisomerase IV. The dominant mechanisms of fluoroquinolone resistance are 1) chromosomal mutations [GyrA/ParC; GyrB/ParE] causing reduced affinity of DNA gyrase and topoisomerase IV for fluoroquinolones and 2) overexpression of endogenous multidrug resistance (MDR) pumps. The presence and enhanced expression of endogenous efflux systems that actively pump drug from the bacterial cytoplasm leads to resistance through reduced fluoroquinolone accumulation.

Many fluoroquinolones have differing potencies against DNA gyrase and topoisomerase IV. These differences correlate with relative drug sensitivities in several cases, the more sensitive of the 2 enzymes being the primary target defined by genetic testing.^26,27,28 For example, gemifloxacin is more active in vitro against both the wild type of S. pneumonia, with an MIC of ≤ 0.015 µg/mL, compared to moxifloxacin (MIC 0.12 µg/mL) and levofloxacin (MIC 0.5 µg/mL), as well as against mutated strains.²⁹ Against a first-step topoisomerase IV mutation, gemifloxacin had an MIC of 0.03-0.12 µg/mL, while moxifloxacin had an MIC of 0.12-0.25 µg/mL and levofloxacin had an MIC of 1-2 µg/mL. Against a first-step DNA gyrase mutation, gemifloxacin had an MIC of 0.06-0.12 µg/mL, while moxifloxacin had an MIC of 0.25-0.5 µg/mL and levofloxacin had an MIC of 1.0 µg/mL. Against a second-step mutation against both topoisomerase IV and DNA gyrase, gemifloxacin still maintained lower MICs (0.12-0.5 µg/mL) compared to moxifloxacin with an MIC of 1-4 µg/mL and levofloxacin with an MIC of 4-32 µg/mL.

Consequences of Antibiotic Resistance

The clinical relevance of penicillin resistance of S. pneumoniae is not conclusively established, but appears to be related to the level of MIC. Studies indicate that strains of intermediate susceptibility (penicillin MIC ≤ 1 µg/mL) do not appear to be associated with worse outcomes.³⁰ However, when the penicillin MIC is ≥ 4 µg/mL, increased rates of mortality (for patients who survive their first four days of hospitalization), treatment failures, and suppurative complications may occur. In a report by Feikin et al.,³¹ the adjusted odds ratio for death in patients with penicillin resistant invasive pneumococcal pneumonia increased 7.1 times, adjusted for age, geographic location, and underlying disease. Turett et al.³² found an independent association with mortality in patients infected with resistant (MIC ≥ 2 µg/mL) S. pneumoniae.

Clinical failures with levofloxacin have been reported in patients with S. pneumoniae respiratory infection. Two patients with penicillin-sensitive pneumococcal pneumonia were treated with levofloxacin 500mg/day with no clinical improvement. Susceptibility testing revealed the clinical isolate had a levofloxacin MIC ≥ 8 µg/mL.³³ A 53-year old man presented with penicillin-sensitive S. pneumoniae pneumonia. The patient was empirically placed on levofloxacin monotherapy (500mg/day IV) and failed to improve. Further susceptibility testing was ordered and the S. pneumoniae isolate was found to have a penicillin MIC of 0.23 µg/mL and a levofloxacin MIC of 6 µg/mL.³⁴

Treatment failures in pneumococcal pneumonia due to S. pneumoniae have also been reported with ofloxacin, ciprofloxacin and other older fluoroquinolones resulting in persistent infections, distant spread, superinfection and in vivo selection of resistant strains^35,36,37

Antibiotic resistance complicates therapy, as the treating physician typically must prescribe antibiotics before susceptibilities and the causative pathogen are known. Widespread increasing antibiotic use appears responsible for the development of antibiotic resistance, highlighting the need for a comprehensive approach to appropriate antibiotic usage.

Evidence-Based Data for a Comprehensive Approach to Appropriate Antibiotic Use

Clinical studies comparing fluoroquinolones to other antibiotics such as ceftriaxone ± erythromycin consistently reveal superiority or equivalence with respect to clinical and bacteriological response^38,39,40 Niederman et al.⁴¹ demonstrated mortality was significantly lower with a fluoroquinolone; trovafloxacin IV vs ceftriaxone IV ± erythromycin (mortality 3.6% for trovafloxacin and 7% for ceftriaxone ± erythromycin).

Marrie et al.⁴² reported that logistic regression analysis indicated symptom resolution in CAP correlated with younger age (rate ratio (RR) 1.2, 95% Confidence Interval (CI) 1.1, 1.3, p = 0.002), absence of asthma (RR 2.1, 95% CI 1.2, 3.8, p = 0.012), absence of COPD (RR 3.3, 95% CI 1.9, 5.6, p < 0.001), and new fluoroquinolone [levofloxacin] use (RR 1.7, 95% CI 1.1, 2.4, p = 0.01). Predictors of gastrointestinal symptoms [at 6 weeks] were asthma, renal disease, and macrolide use.

A study by Lode et al.³⁸ of hospitalized patients with CAP compared the effectiveness of oral gemifloxacin 320 mg once daily (7-14 days) to intravenous (IV) ceftriaxone 2 gm daily (1-7 days) ± a macrolide followed by oral cefuroxime 500 mg twice a day (1-13 days ). In the per protocol population at follow-up, the clinical success rate of the gemifloxacin-treated patients was 92.2% (107/116) compared to 93.4% (113/121) of the ceftriaxone/ cefuroxime-treated patients (treatment difference = -1.15, 95% CI = -7.7, 5.4). There was no significant difference in bacterial success rates between gemifloxacin (90.6%, 58/64) and the ceftriaxone/cefuroxime-treated group (87.3%, 55/63) (treatment difference = 3.32, 95% CI = -7.6, 14.2). In the ceftriaxone/cefuroxime-treated group, there was no difference in clinical response rate in patients treated concomitantly with a macrolide versus without a macrolide (91.3%, 94.7% respectively).

The Gemifloxacin Long-term Outcomes in Bronchitis Exacerbations (GLOBE) Study⁴³ compared the long-term clinical and health economic outcomes of AECB treatment with 5 days of gemifloxacin therapy to 7 days of clarithromycin therapy. Clinical assessments were conducted throughout the study for up to 26 weeks per study protocol. Gemifloxacin-treated patients were significantly more likely to be recurrence-free at 26 weeks (71%, 120/169) than patients treated with clarithromycin (58.5%, 100/171) (treatment difference = 12.5%, 95% CI = 2.5%, 22.6%, chi-squared test: p = 0.016). There was a trend toward more RTI-related hospitalizations in the clarithromycin-treated patients over the 26-week study period as compared to gemifloxacin-treated patients, 6.25% vs. 2.34%, respectively (treatment difference = -3.91%, 95% CI = -7.67%, -0.15%; Fisher's exact test: p = 0.059).

A cost-effectiveness analysis of the data from the GLOBE study⁴⁴ revealed that compared to clarithromycin, the mean, per-patient direct medical/indirect productivity cost savings with gemifloxacin were $329. Considering all costs, recurrence-free patients saved $8,888-$14,175. The probability of gemifloxacin treatment being both more effective and less costly than clarithromycin in cost-effectiveness analysis was calculated to be 87% from a payer perspective and 83% from a societal perspective. For AECB, gemifloxacin treatment resulted in significantly more recurrence-free patients, fewer hospitalized patients, and direct healthcare/indirect productivity savings. In addition, patient-reported quality of life scores were improved for performance at work and usual activities.

Conclusion

New fluoroquinolones demonstrate excellent intracellular and extracellular penetration into respiratory tissues. Bactericidal activity is high for key bacterial pathogens such as S. pneumoniae, H. influenzae, M. catarrhalis, as well as atypical pathogens (Mycoplasma, Chlamydia, and Legionella). Principles of empirical therapy for CAP include early treatment directed at the most likely pathogens (S. pneumoniae, H. influenzae, and atypical pathogens). Gemifloxacin appears superior to clarithromycin for preventing recurrences of acute exacerbations of chronic bronchitis.

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