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Infectious Diseases in Clinical Practice:
doi: 10.1097/01.idc.0000239722.78078.17
Original Articles

Streptococcus pneumoniae: Review of Factors Relevant to Development and Management of Fluoroquinolone Resistance in a Nursing Home Setting

Vaughan, David J. PhD*; Tillotson, Glenn S. PhD†; Klugman, Keith P. MD‡

Free Access
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Author Information

*David Vaughan Consultants, Pickering, Ontario, Canada; †Replidyne Inc, Milford, CT and ‡Hubert Department of Global Health, Rollins School of Public Health and Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, GA.

Dr Vaughan has received financial support from Oscient Pharmaceuticals.

Address correspondence and reprint requests to David J. Vaughan, PhD, David Vaughan Consultants, 456 Sheppard Avenue, Pickering ON Canada L1V 1E5. E-mail: dvaughan23@rogers.com.

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Abstract

Genetic analyses of Streptococcus pneumoniae clinical isolates causing invasive pneumococcal disease (IPD) have revealed within the "susceptible population" a significant proportion of strains harboring a single, principally parC mutation within the quinolone-resistance determining region. The occurrence of first-step mutants predisposes S. pneumoniae to a subsequent and more rapid second-step mutation resulting in elevated levels of fluoroquinolone resistance and clinical failure.

Fluoroquinolones are a common therapeutic choice for residents of long-term care facilities and/or elderly patients in the community at higher risk of IPD. Despite the advent of the pneumococcal conjugate vaccine, levofloxacin resistance among vaccine serotypes is increasing, and the majority of these isolates are closely related to widespread antibiotic-resistant clones.

Use of fluoroquinolones with activity against levofloxacin-nonsusceptible isolates of S. pneumoniae should be considered in the management of IPD among elderly patients in the community and long-term care residents and among at-risk patients with chronic pulmonary infections.

Streptococcus pneumoniae remains a challenging pathogen and is an important cause of pneumonia, bacteremia, and meningitis.1 Traditionally, β-lactams and macrolide antimicrobials have been the principal therapeutic options for pneumococcal infections. However, the emergence of pneumococci with reduced susceptibilities to these agents has emphasized the need for alternative therapies having high efficacy against respiratory pathogens, including resistant strains, and a low potential for resistance induction.2 As a result, fluoroquinolones with enhanced gram-positive activity particularly against S. pneumoniae are being used more frequently in the treatment of suspected or proven pneumococcal infections.

Pneumonia is a significant contributor to morbidity in adults and particularly in older residents of long-term care facilities (LTCFs). Because of age and underlying health problems, residents in LTCFs are at high risk for developing serious complications or dying from pneumococcal disease.3 Current estimates put the median incidence of pneumonia in long-term care residents at 1 to 1.2 per 1000 patient-days, a factor 10-fold greater than for adults in the community.3,4

Invasive pneumococcal disease (IPD) among the elderly, particularly those in LTCFs, is a serious concern. The introduction of pneumococcal conjugate vaccine has helped reduce the occurrence of IPD caused by vaccine serotypes in children.5,6 However, pneumococcal disease caused by nonvaccine serotypes may be increasing, and these invasive pneumococci also appear to have acquired quinolone-resistance determining region (QRDR) mutations, resulting in decreased susceptibilities to fluoroquinolones.7-9

Current guidelines for the management of nursing home-acquired pneumonia recommend a broad-spectrum antibiotic covering S. pneumoniae, Haemophilus influenzae, gram-negative rods (the relative importance of gram-negative rods as etiologic versus colonizing organisms is controversial), and Staphylococcus aureus.10 Currently acceptable choices for empiric therapy include an antipneumococcal fluoroquinolone, particularly where resistance of S. pneumoniae to penicillin is elevated, or an extended-spectrum β-lactam plus a macrolide.

Resistance among S. pneumoniae to fluoroquinolones arises principally via stepwise mutations in the QRDRs of genes encoding subunits of topoisomerase IV (parC) or DNA gyrase (gyrA).11 First-step mutations in either parC or gyrA result in low-level resistance, whereas second-step mutations in the initially nontargeted gene result in significantly higher levels of resistance.12 Although the current prevalence of fluoroquinolone nonsusceptibility (defined as having ciprofloxacin minimum inhibitory concentrations [MICs] of ≥4 μg/mL) among North America isolates of S. pneumoniae is less than 2%,7,13,14 reports of higher levels of resistance in other jurisdictions, including Hong Kong (14.3%), the Philippines (9,1%), Spain (7%), and Korea (6.5%), have been noted.15-19

Although in vitro MIC determinations and reported susceptible (S), intermediate (I), and resistant (R) values appear to support the concept of stable fluoroquinolone susceptibilities, molecular characterization of pneumococcal isolates would suggest that the incidence of S. pneumoniae harboring mutations in the QRDRs may be increasing.7,20 Thus, mutations among pneumococci, including β-lactam- and macrolide-resistant strains, predisposing the organism to fluoroquinolone resistance, are becoming more prevalent, and with the exception of telithromycin, no new oral agents are therapeutically available.

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MATERIALS AND METHODS

A MEDLINE search found surveillance, randomized controlled trials, outcome studies, and expert consensus opinion. Relevant articles were retrieved using MeSH terms S. pneumoniae, community-acquired pneumonia, LTCF, and resistance combined with fluoroquinolone. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy and the European Congress of Clinical Microbiology and Infectious Diseases were also reviewed. Recommended patient populations appropriate for fluoroquinolone therapy are based on level I (well-conducted, randomized, controlled clinical trials) and level III (expert opinion and case studies) evidence.

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RESULTS

Fluoroquinolone Susceptibilities and QRDR Mutations

Several surveillance programs and other more specifically focused studies have monitored the emergence of fluoroquinolone resistance among clinical isolates of S. pneumoniae. It is generally accepted that strains with ciprofloxacin MICs 8 μg/mL or more are indicative of pneumococci having sequential mutations in both parC and gyrA, and strains with levofloxacin MICs 2 μg/mL or more, although susceptible, tend to harbor first-step mutations.7,20,21

A recent study examined the in vitro potencies of 27 antimicrobial agents against 1817 S. pneumoniae isolates from 45 different US medical centers.20 Overall penicillin resistance was 34.2%, macrolide resistance ranged from 28.7% to 29.5%, but resistance to telithromycin, vancomycin, and linezolid was not observed. Among fluoroquinolones, gemifloxacin was the most potent (MIC90 0.06 μg/mL) and was 4 times more potent than moxifloxacin, 8 times more potent than gatifloxacin, and 16 to 32 times more potent than levofloxacin or ciprofloxacin, respectively. Strikingly, an estimated 21.9% of these recently tested S. pneumoniae isolates harbored mutations in parC (21%), gyrA (0.3%), or both (0.6%), an approximate 5-fold increase in QRDR mutations from those analyzed in 1997 to 1998. These include mutations shown to cause fluoroquinolone resistance, although not all of the observed mutations have been proven to be associated with resistance. Comparative distribution of fluoroquinolone MICs against recent clinical isolates of S. pneumoniae is shown in Figure 1.

Figure 1
Figure 1
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The molecular epidemiology of QRDR mutations among S. pneumoniae isolates in the United States has recently been investigated.7 Between 1999 and 2000, and 2001 and 2002, there was a 2-fold increase in the rate of ciprofloxacin resistance (MIC ≥ 4 μg/mL) from 1.2% to 2.7% and in the rate of levofloxacin nonsusceptibility (MIC ≥ 4 μg/mL) from 0.6% to 1.3%. Of 6549 isolates, the prevalence of strains with ciprofloxacin and levofloxacin MICs 4 μg/mL or more was 1.7% and 0.7%, respectively. There were 111 strains with QRDR mutations that were observed predominantly in parC (68%) and seen to a much less extent in gyrA (5%). Mutations in both parC and gyrA were found in 26% of the isolates analyzed.

The 111 isolates with parC and/or gyrA mutations represented 48 different molecular pulsed-field gel electrophoretic patterns and belonged to more than 17 different serotypes. Forty-three of the 111 isolates were levofloxacin nonsusceptible assigned to 29 different serotypes types, including 23F, 19F, 9V, 11A, 6A, 31, 6B, and 4. All levofloxacin-resistant isolates were gatifloxacin nonsusceptible, 78% were moxifloxacin nonsusceptible, 46% were penicillin nonsusceptible, and 38% were multidrug resistant. A similar Japanese study found that 22.6% of fluoroquinolone-resistant pneumococci were isolated in adults older than 20 years, and more than a quarter of patients older than 65 years harbored fluoroquinolone-resistant strains.8

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Invasive Pneumococcal Disease and Long-term Care Facilities

Although the etiology of most cases of nursing home-acquired pneumonia is undetermined, a recent study identified S. pneumoniae, H. influenzae, other gram-negative agents, S. aureus, and respiratory viruses as principal causative agents for pneumonia in this patient group.3,4 Accurate pathogen identification is hindered because of the inability of most patients to produce a suitable sputum sample and the difficulty in distinguishing between colonization and infection in viable specimens.

Factors increasing the risk of pneumonia and dissemination of pathogens among long-term care residents include malnutrition, chronic disease, functional impairment, medications, indwelling devices, and prolonged antimicrobial exposure.4 Additional risk factors include LTCF with low or waning immunization rates, excessive antimicrobial use, and widespread colonization of residents with antimicrobial-resistant organisms.22

Prompt diagnosis and rapid treatment with antimicrobial therapy are associated with improved outcomes. Current guidelines for the management of nursing home-acquired pneumonia include preventative measures, that is, vaccination against S. pneumoniae and influenza and prompt administration of antimicrobial therapy upon clinical diagnosis.10 Antibiotics for the treatment of pneumonia should principally cover S. pneumoniae, H. influenzae, and S. aureus, and currently recommended agents include fluoroquinolones or combination therapy with an extended-spectrum β-lactam plus a macrolide.

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Fluoroquinolone Susceptibilities and Invasive Pneumococcal Disease

The overall incidence of fluoroquinolone resistance among pneumococci responsible for systemic infections (IPD strains) has been monitored by the Centers for Disease Control and Prevention Active Bacterial Core Surveillance program.23 The incidence of fluoroquinolone-resistant strains (levofloxacin MICs ≥ 8 μg/mL) increased during the period 1998 to 2001 from 0.1% to 0.6% with a subsequent decrease to 0.4% in 2002. These rates are from a population of around 3000 strains tested each year. Table 1 illustrates the comparative potency of gemifloxacin against levofloxacin-resistant strains of S. pneumoniae whereby MIC90 values for gemifloxacin are 8 to 16-fold higher than those of moxifloxacin or gatifloxacin and significantly more potent than either levofloxacin or ciprofloxacin.

Table 1
Table 1
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In a separate study analyzing 2402 US-based cases of IPD requiring hospitalization, the disease rate for LTCF patients was 194.2 cases per 100,000 persons aged 65 years or older compared with 44.6 cases per 100,000 older community-living adults.3 Case fatality rates were 1.9 times higher for LTCF patients, and pneumococcal strains were significantly more likely to be nonsusceptible to levofloxacin than community-based adults (5.7% vs. 0.4%, P < 0.001). Similar observations on the age distribution of patients carrying fluoroquinolone-resistant S. pneumoniae have been reported in Canada, Hong Kong, Spain, and Japan.8,18,24,25

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Fluoroquinolone Treatment Failures in Pneumococcal Disease

A recent report of 4 community-acquired pneumonia patients investigated the extent of QRDR mutations among S. pneumoniae isolates to better understand why initial therapy with levofloxacin or ciprofloxacin was unsuccessful.26 As shown in Table 2, the induction of a second mutation within the QRDR dramatically increased resistance to levofloxacin, resulting in clinical failure. The in vitro activities of gatifloxacin and moxifloxacin were moderately affected, whereas gemifloxacin retained potency against all levofloxacin-resistant strains.

Table 2
Table 2
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More recently, 20 fluoroquinolone-resistant S. pneumoniae treatment failures (including the 4 cases discussed above) were reviewed.27 Of these 20 cases, 12 had community-acquired pneumonia, 5 had acute exacerbation of chronic bronchitis, 2 had nosocomial pneumonia, and 1 had sinusitis. The mean age of these patients was 68 years, with 12 older than 65 years. All patients were treated with ciprofloxacin or levofloxacin, and 7 patients had a history of recent fluoroquinolone use.

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Mechanism of Pneumococcal Resistance to Fluoroquinolones

Fluoroquinolones inhibit bacterial topoisomerase enzyme systems that are essential in packing DNA within the bacterial cell by the supercoiling process.11 In S. pneumoniae, there are 2 enzymes involved: DNA gyrase which consists of 2 components (encoded by the gyrA and gyrB genes) and topoisomerase IV (encoded by parC and parE genes).

Fluoroquinolone resistance among pneumococci is primarily caused by mutations in the QRDRs of parC and gyrA genes that encode subunits of type II topoisomerases.28,29 Most levofloxacin-resistant pneumococci (MIC ≥ 8 μg/mL) have mutations in parC and gyrA and are nonsusceptible to gatifloxacin and moxifloxacin.12,21,30 The population of isolates with first-step mutations in parC is important because, in comparison to pneumococci without parC mutations, they are more likely to develop resistance to most quinolone agents during therapy with acquisition of a second-step gyrA mutation.31 Efflux contributes primarily to lower levels of fluoroquinolone resistance either alone or to a lesser extent by complementing QRDR substitutions in parC and appears to play a minimal role in pneumococcal resistance development.12

Agents such as gemifloxacin that maintain potency against parC mutants reduce not only the risk for treatment failure caused by QRDR mutants, but also the emergence and further propagation of resistance. Figure 2 further illustrates the potency of gemifloxacin relative to other fluoroquinolones against levofloxacin-nonsusceptible strains of S. pneumoniae.

Figure 2
Figure 2
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Prevalence studies of mutations within the QRDR in clinical isolates of S. pneumoniae have confirmed that single parC (Ser-79→Tyr) or gyrA (Ser-81→Phe or Tyr) mutations contribute most significantly to pneumococcal resistance and that the level of resistance is further enhanced in the presence of changes within both parC and gyrA. Current observations suggest that mutations in parC occur much more commonly than those in gyrA, most likely resulting from broad usage of earlier fluoroquinolones (ciprofloxacin and levofloxacin) for which parC is the principal bacterial target.

Newer fluoroquinolones (gatifloxacin, moxifloxacin, and gemifloxacin) preferentially target gyrA. Recent data indicate that mutations in gyrA arise at a lower rate than those seen for parC.32

Recent serial passage work investigated the propensity of gatifloxacin, moxifloxacin, and gemifloxacin to select QRDR mutations in a quinolone-susceptible strain of S. pneumoniae.33 Single-step mutations in gyrA (Glu-85 and Ser-81) appeared after 4 and 7 passages for moxifloxacin and gatifloxacin, respectively. In comparison, no single-step QRDR substitution was detected with gemifloxacin, but rather, a multistep substitution was observed after 17 passages. Multistep substitutions appeared shortly after single-step substitutions for gatifloxacin and moxifloxacin, and for all fluoroquinolones, multiple QRDR alterations were apparent after 23 passages.

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Impact of Pneumococcal Conjugate Vaccine on Fluoroquinolone Resistance

Use of a 9-valent pneumococcal conjugate vaccine has shown that vaccination with such agents reduced the occurrence of pneumonia in children while also reducing the incidence of vaccine-serotype and antibiotic-resistant pneumococcal disease.5 More recently, temporal trends of IPD among children who had received the heptavalent pneumococcal vaccine, PCV-7, were assessed using data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention.6 Between 1998 and 2001, IPD was reduced most dramatically in children younger than 2 years with the rate of disease caused by vaccine and vaccine-related serotypes declining by 78% (P < 0.001) and 50% (P < 0.001), respectively, relative to baseline levels. Disease rates also fell 8% to 32% among adults and were age dependent. The rate of disease caused by penicillin-nonsusceptible strains decreased 35% during the study period. Similar decreases in macrolide resistance among S. pneumoniae were noted in a recent population-based surveillance study.34

A recent study found that during the past 15 years, hospitalization rates for pneumonia have increased 20% among US adults aged 64 to 74 years and aged 75 to 84 years.35 Among those aged 85 years or older, at least 1 in 20 patients was hospitalized each year because of pneumonia. The risk of death during a hospitalization for pneumonia compared with the risk of death during a hospital stay for the 10 other most frequent causes of hospitalization was 1.5 (95% CI, 1.4-1.7) and remained constant from 1988 to 1990, to 2000 to 2002. Measures to prevent pneumonia that could reduce preventable comorbid conditions improve vaccine effectiveness, and vaccination programs in elderly persons were deemed valuable.

Data suggesting that fluoroquinolone resistance may be emerging in pandemic clones of multiresistant pneumococci have come from an assessment of 29 fluoroquinolone-resistant isolates (ofloxacin MICs ≥ 4 μg/mL) of S. pneumoniae selected from a global surveillance program (Alexander Project, 1992-1997), from Hong Kong and from Northern Ireland (1997).36,37 Genetic analyses, using 11 well-characterized international pneumococcal reference clones, revealed a predominance of serotypes 9V and 23F, high-level fluoroquinolone-resistant strains indistinguishable from the pandemic Spain23F-1 and Spain9V-3 clones.

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Animal Studies

With the lack of human data, novel animal models have been informative with respect to differentiating fluoroquinolone activities against pneumococcal infection caused by strains with well-characterized mutations. In a murine pneumococcal pneumonia model, infection with a parC mutant (levofloxacin MIC 2 μg/mL, gemifloxacin MIC 0.06 μg/mL) was successfully treated with gemifloxacin.38 All gemifloxacin mice survived, and no bacterial counts were detected after 48 hours. In a sepsis model, the in vivo efficacies of levofloxacin, moxifloxacin, and gemifloxacin were assessed against 3 clinical isolates of S. pneumoniae.39 Strains included were serotype 6B (ciprofloxacin MIC 1 μg/mL). serotype 14 (parC mutation, ciprofloxacin MIC 32 μg/mL), and serotype 19F (gyrA mutation, ciprofloxacin MIC 64 μg/mL). Against serotypes 6B and 14, moxifloxacin and gemifloxacin demonstrated significantly higher activity than levofloxacin, but against serotype 19F, gemifloxacin was substantially more effective than either moxifloxacin or levofloxacin.

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DISCUSSION

Although trends of increasing fluoroquinolone resistance among pneumococci have been reported in several countries, the global prevalence of levofloxacin-resistant pneumococci remains low (1.0%-1.1%).19,40 Large surveillance studies suggest that the prevalence of levofloxacin-resistant pneumococci in the United States and Canada is less than 1%.5,6 The highest rates of levofloxacin resistance have been reported in Hong Kong (13.3%-14.3%) and are associated with the dissemination of a strain related to the Spain23F-1 clone.39 Reports of genetic heterogeneity among fluoroquinolone-resistant isolates from other regions suggest that fluoroquinolone resistance in S. pneumoniae has emerged primarily through de novo mutations in parC and/or gyrA.19,34,41-43 However, the emergence of these mutations may prime pneumococci toward the breakpoint of recognized levofloxacin resistance.

Elderly patients living in LTCFs are more often at risk than community-based individuals for IPD.3 Recently documented clinical failures in fluoroquinolone-treated patients with respiratory tract infections have raised concerns that the continued use of fluoroquinolones with suboptimal potency against S. pneumoniae, for example, ciprofloxacin and levofloxacin, may reduce the effectiveness of fluoroquinolones as a class for the treatment of pneumococcal infections.27,44 Although vaccination and strict infection control measures contribute to less intrafacility transmission of fluoroquinolone-resistant, multidrug-resistant S. pneumoniae, the use of less potent fluoroquinolones has been linked to a fluoroquinolone-resistant outbreak strain in LTCF.45,46

Both ciprofloxacin and levofloxacin contribute to the increasing number of S. pneumoniae strains harboring a Ser-79→Phe substitution in parC, increasing the likelihood that a second mutation in gyrA would render these isolates largely resistant to levofloxacin, gatifloxacin, and moxifloxacin. De novo or spontaneous mutations within the QRDR occur with all fluoroquinolones. However, there are significant differences within the fluoroquinolone class with respect to the frequency of resistance emergence and the QRDR target, especially those occurring at therapeutically achievable drug levels.

Although occasional failures were noted during clinical development, the subsequent lack of clinical reports of pneumococcal failures resulting from resistance development after therapy with gemifloxacin or moxifloxacin is consistent with the observed in vitro potency and animal model with these agents.

Therapeutic options for pneumococcal infections, particularly among elderly patients, should include agents such as gemifloxacin or other fluoroquinolones with proven high in vitro potency, appropriate pharmacokinetic/pharmacodynamic indices, and a lessened capacity for selection of second-step mutations. Although measures such as the pneumococcal conjugate vaccine afford a degree of management over fluoroquinolone resistance by reducing infection caused by some serotypes (eg, 19F), other serotypes (eg, 19A) currently not included in the vaccine are becoming more resistant to fluoroquinolones. Forty percent of isolates with QRDR mutations and 35% of levofloxacin-nonsusceptible S. pneumoniae were closely related to widespread pneumococcal clones reported to contribute to the spread of antibiotic resistance. The multidrug-resistant international Taiwan19F clone has also been associated with the emergence and spread of S. pneumoniae with dual erm(B) and mef(A) resistance determinants.47

Previous fluoroquinolone use along with pneumococcal acquisition in a nursing home or hospital or chronic obstructive pulmonary disease has been identified as risk factors associated with levofloxacin-resistant S. pneumoniae infection. Fluoroquinolone therapy in patients with IPD should account for the growing possibility of first-step mutations,20,48 and agents with retained potency against parC would be appropriate therapeutic options. From a pharmacokinetic/pharmacodynamic perspective, in vitro data and results from in vivo infection models associate efficacy against S. pneumoniae with 24-hour, free-drug area under the plasma concentration time curve/MIC (AUC0-24/MIC90) ratios of approximately 30.49 Standard gemifloxacin dosing yields AUC0-24/MIC90 ratios of 100 or greater, affording a therapeutic index of sufficient width to treat not only susceptible strains of pneumococci, but also the majority of strains expressing first-step QRDR mutations.50 Gemifloxacin AUC0-24/MIC90 ratios exceed those reported for the once-daily therapeutic doses of moxifloxacin (400 mg), gatifloxacin (400 mg), and levofloxacin (500 and 750 mg) and, as such, should be considered a valuable empiric therapeutic for IPD in nursing home patients.

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