New Perspectives on Antimicrobial Therapy and Resistance: The New Quinolones
Michael S. Niederman, M.D., Chairman, Department of Medicine, Winthrop University Hospital, Mineola, NY, Professor of Medicine, State University of New York at Stony Brook, Stony Brook, NY
Community-acquired respiratory tract infections, including community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB) are common illnesses that have a great impact on patient morbidity, quality of life and lifestyle. In addition, these illnesses have a major economic impact, due to the direct costs of patient care as well as the indirect healthcare costs associated with lost productivity, days off from work, and time away from usual activities. As we treat these illnesses, we must do so in a cost-conscious manner as we face the challenges presented by changing microbial patterns of infection (including a new appreciation for the role of atypical pathogens), rising rates of antibiotic resistance among common pathogens, and the availability of new antimicrobial treatments in a number of drug classes (e.g., fluoroquinolones, ketolides, oxazolidinones).
The new fluoroquinolones have the potential to help us face many of the challenges mentioned above. These new agents, which include gatifloxacin, levofloxacin, moxifloxacin, and gemifloxacin, are able to provide coverage for gram-positive, gram-negative, and atypical pathogens, generally with once daily dosing. In addition, the new fluoroquinolones penetrate well into respiratory secretions, reaching levels in lung tissue and epithelial lining fluid that exceed serum levels. Because of high oral bioavailability, the same serum levels can result with oral therapy as with intravenous therapy. In clinical practice, this may mean that fluoroquinolones can be used to keep certain "borderline" patients (e.g., moderately severe CAP, nursing home residents with CAP) with respiratory infection out of the hospital. The use of these new treatment options provides added confidence for the physician since the agents can achieve good drug concentrations in both the serum and at the site of infection, even with oral dosing. In addition, these agents have excellent activity against drug-resistant pathogens such as drug-resistant S. pneumoniae (DRSP), and Я-lactamase producing strains of H. influenzae and M. catarrhalis, all organisms that are more likely to be present in complex patient populations.
In the treatment of AECB, this spectrum of antimicrobial activity is ideal, especially for the more complex patient who can harbor such organisms, and who needs therapy active against these pathogens in order to avoid treatment failure and its associated adverse consequences (e.g., hospitalization, respiratory failure). Complex patients who can most benefit from such therapy typically present with one or more of the following:
• Acute and symptomatic exacerbation
• > 65 years old
• Comorbid illness
• Frequent courses of antibiotics (> 4 exacerbations/year)
• Severe obstructive disease (forced expiratory volume in 1 second (FEV1) < 50% predicted)
• Patients using corticosteroids
In this population, therapy should not only be effective for the acute episode, but it should ideally prolong time until the next exacerbation, a benefit that has been seen in the past with the use of quinolone therapy.1,2
The following report summarizes two studies of a new respiratory fluoroquinolone in late stage clinical development, gemifloxacin, showing that as an oral formulation, this agent can achieve many of the desirable endpoints for patients with either CAP or AECB.
The first study compared oral therapy with gemifloxacin to intravenous (IV) ceftriaxone therapy and optional macrolide [clarithromycin] in patients admitted to the hospital with CAP. The second study evaluated patients with AECB and compared both acute and long-term benefits of gemifloxacin to clarithromycin.
In the CAP study, oral gemifloxacin was compared to IV ceftriaxone plus an optional macrolide (clarithromycin), with switch to oral therapy as indicated. Although most patients in the study had mild-moderate illness, 47 of the 237 who were enrolled fell into high mortality risk groups (groups IV and V by the PORT Pneumonia Prognostic Scoring Index), and some patients were bacteremic. Overall, the study showed equivalence between both therapies, but oral gemifloxacin was as effective as IV therapy, even in patients with high mortality risk and those with bacteremia. I find these results quite interesting since they confirm an important role for fluoroquinolones in the therapy of CAP, which could translate into real clinical and economic benefits. Although fluoroquinolone therapy was no better than a cephalosporin/macrolide combination, the fact that oral therapy was equally efficacious to IV therapy, even in more seriously ill patients, suggests the safety and feasibility of treating some patients, who are currently hospitalized with CAP, as "out patients" with a reliable oral fluoroquinolone. In addition, the efficacy of oral therapy for bacteremia confirms other previous similar findings3,4 and suggests that even a bacteremic hospitalized patient can be managed with (or switched to) oral therapy and discharged if there is a good clinical response to treatment and the treatment involves a highly bioavailable agent such as a fluoroquinolone. Gemifloxacin is not unique in its ability to serve this role, but it may be an important agent in the future, since on an MIC [minimum inhibitory concentration] basis, it is the most active pneumococcal quinolone, and one that is active against pneumococci that are resistant to other quinolones.
The second study was an evaluation of patients with AECB, and it showed a real advantage for gemifloxacin compared to clarithromycin. Although there was overall equivalence of clinical success for both regimens, there was a more rapid eradication of H. influenzae with gemifloxacin, which in turn translated to higher bacteriologic success, particularly at the long-term follow-up point (days 25-38 after start of therapy). These findings, although interesting, take on greater clinical relevance because 438 of the 709 patients who were enrolled, agreed to be followed for up to 26 weeks. When that time frame was evaluated, more gemifloxacin treated patients remained free of recurrences and fewer of them required hospitalization. Not surprisingly, gemifloxacin treated patients had lower costs of care, both direct and indirect. These findings are particularly exciting since they show real outcome differences between two antibiotics used for AECB. This finding suggests that maybe different therapies should be used for different patient populations, and also corroborates previous findings of quinolones prolonging disease free interval, when compared to other agents.1,5 Although similar findings might occur with other quinolones, only gemifloxacin has the data to show its efficacy at improving the long-term health status of patients with AECB. We still need to understand the mechanism for this effect, but it may relate to the rapid killing of bacteria that can be achieved with an agent that is highly active against the target pathogen.
I hope you find this report of interest. I do think that both studies illustrate the potential value of fluoroquinolones for the therapy of complex patients with community-acquired respiratory infections. The good results that are reported with gemifloxacin suggest that this agent, in its oral form, may be a valuable agent in our efforts to manage difficult infections in an effective and cost-efficient manner.
Community Acquired Pneumonia and the Fluoroquinolones
Community-acquired pneumonia (CAP) represents a common and significant public health problem, affecting 1.2% of the US population.6,7 Each year, approximately 5-6 million cases of CAP result in 1.1 million hospital admissions.8 Due to the debilitating nature of CAP, approximately 80% of patients > 65 years old diagnosed with CAP require hospitalization.9 Overall mortality is 45,000 patients per year.9
Multiple pathogens are responsible for CAP, including Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella spp, necessitating the use of effective, broad spectrum antibiotics. Penicillin may no longer be considered adequate treatment by many, as many strains of S. pneumoniae are resistant to penicillin as well as other conventional antibacterial agents and coinfection with atypical pathogens can occur. S. pneumoniae accounts for 20-60% of cases of CAP,9 more than any other pathogen. Viruses cause another 12.2%, followed by H. influenzae (7.3%) and Legionella species (5.7%). However, prospective studies evaluating the causes of CAP in adults have failed to identify the cause of 40-60% of cases of CAP and have detected > 2 etiologies ranging from 2-5%10,11,12,13,14 up to 38.4% of CAP cases.15 For the hospitalized CAP patient, recommended guidelines9,16 [American Thoracic Society, Infectious Diseases Society of America] suggest initial therapy with either a Я-lactam/macrolide combination or monotherapy with an antipneumococcal fluoroquinolone.
The evolving patterns of microbial resistance in key pathogens such as S. pneumoniae and H. influenzae have lead to the development of new, more potent antimicrobials. The "respiratory quinolones" are quinolones with expanded coverage against gram-positive bacteria (including penicillin-resistant and macrolide-resistant S. pneumoniae), as well as atypical pathogens (Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella species.) Some also have some activity against tuberculous and nontuberculous mycobacteria. These drugs include levofloxacin (Levaquin, Ortho-McNeil), gatifloxacin (Tequin, Bristol-Myers Squibb), and moxifloxacin (Avelox, Bayer). They are widely used for CAP and acute exacerbations of chronic bronchitis (AECB).
A new addition to the list of highly potent fluoroquinolones is gemifloxacin (GEMI) (Factive, GlaxoSmithKline), a fluoroquinolone in late stage clinical development. GEMI has high potency in vitro against S. pneumoniae, including penicillin-resistant and macrolide-resistant strains. It is also highly effective against H. influenzae, M. catarrhalis, and atypical pathogens (e.g., Mycoplasma pneumonia, Legionella pneumophila, C. pneumoniae, C. psittaci). In a recent study conducted by Chen et al,17 GEMI had superior in vitro activity compared to other selected fluoroquinolones against 75 pneumococcal isolates with minimal inhibitory concentrations (MICs) of ciprofloxacin > 4 ug/ml. Other investigational fourth generation fluoroquinolones include D61-1113, PGE-9262932, and T-3811ME/BMS-284756 (a 6-desfluoroquinolone).
In an effort to establish an effective oral therapy for moderate to severe CAP in hospitalized patients, Lode et al18 performed a randomized, open label, multi-center study comparing oral GEMI (320 mg/day, 7-14 days) to ceftriaxone (CTX) (2 grams intravenously/ day, 1-7 days) followed by oral cefuroxime (CFU) (500 mg BID, 1-13 days). The CTX/CFU group could also receive concurrent macrolide treatment. The investigators determined dosing duration based on the patient's clinical condition up to a maximum of 14 days.
In order to participate in the study, patients had to have a clinical and radiologic diagnosis of CAP. Clinical criteria included at least two of the following; new or increased cough, purulent sputum or change in sputum characteristics, rales, evidence of pulmonary consolidation, dyspnea, tachypnea, fever, hypothermia, elevated total peripheral white blood cell (WBC) count, > 15% immature neutrophils, leukopenia (< 4,500 WBC cells/mm3), or PaO2 < 60 mmHg on room air. Eligibility also required radiographic abnormalities at screening or within 48 hours of randomization. These included new or progressive infiltrates on chest x-ray, consolidation or pleural effusion, consistent with pneumonia.
Patients with hypersensitivity to study drugs, at high risk of drug interactions, pregnant, or who had received prior antibiotic treatment for the current infection lasting longer than 24 hours could not participate.
The study consisted of 4 visits over 6 weeks. Patients were screened on Day 1-0 for Visit 1. Visit 2 occurred on Day 1-5 while the patient was on therapy. Patients were assessed on Day 0-6 post therapy for Visit 3. Follow-up concluded on Day 19-41 post therapy for Visit 4.
Clinical response (success or failure) in the clinical per protocol (PP) population at the follow-up (FU) visit 19-41 days post therapy was the primary efficacy parameter. Secondary efficacy parameters included clinical response at end of therapy (EOT), bacteriologic response at EOT and at FU, radiologic response at FU, combined clinical and radiologic response at FU, and time to hospital discharge. Patients were defined as a clinical success if there were "sufficient improvement or resolution of the signs and symptoms of CAP recorded at screening such that no additional antibacterial therapy was indicated for this episode of CAP." Bacteriologic success was defined as "all initial pathogens eradicated or presumed eradicated at the follow-up assessment with no new infections, but with or without colonization." Radiologic success was defined as "an improvement or resolution of the radiologic signs of CAP." Time to discharge from the hospital was calculated from the first dose of medication to discharge, regardless of re-admissions.
In order to assess bacterial etiology and response to therapy, sputum and/or respiratory samples were collected. Blood cultures were also obtained. Samples were processed for gram stain, culture and identification, and antimicrobial susceptibility according to the National Committee for Clinical Laboratory Standards (NCCLS) guidelines.
Two hundred and thirty seven patients comprised the clinical per protocol (PP) FU population. There were 116 patients treated with GEMI and 121 treated with CTX/CFU. Thirty eight percent (46/121) of the CTX/CFU-treated patients received concomitant macrolide therapy. Ninety-four percent (116/123) of the GEMI group and 94% (121/129) of the CTX/CFU patients completed treatment and were available for evaluation at follow-up.
Patients in both clinical treatment groups had high clinical success rates. The per patient clinical success rate in the PP FU population was 107/116 (92.2%) for GEMI and 113/121 (93.4%) for CTX/CFU ± macrolide (treatment difference -1.15; 95% Confidence Interval (CI) -7.73, 5.43). The clinical success rates at end of therapy were also high, 95.9% for GEMI and 96.1% for CTX/CFU ± macrolide (treatment difference -0.19; 95% CI -5.01, 4.64). In the most severely ill patients (Fine risk classes IV and V; n = 47), GEMI was efficacious in 20/23 (87.0%), compared to 20/24 (83.3%) treated with CTX/CFU ± macrolide.
The bacteriologic PP EOT population included 67 patients in the GEMI group and 65 in the CTX/CFU ± macrolide group. Ninety-six percent (64/67) in the GEMI group and 97% (63/65) in the CTX/CFU ± macrolide group were available at FU. The per patient bacteriological success rate at follow-up was 58/64 (90.6%) of the GEMI group, and 55/63 (87.3%) of the CTX/CFU ± macrolide group (treatment difference 3.32, 95% CI -7.57, 14.21).
As expected, the most common pathogen isolated at screening was S. pneumoniae. GEMI had a success rate of 18/20 (90%) for S. pneumoniae compared to 17/19 (89.5%) for CTX/CFU ± macrolide. GEMI had a success rate of 100% for infections with Mycoplasma pneumoniae (19/19), Haemophilus parainfluenzae (8/8), and Legionella pneumophila (3/3) identified at screening, compared to 93.3%, 100%, and 100% with CTX/CFU ± macrolide, respectively.
Radiologic success rate at follow-up was similar in both treatment arms. The combined clinical and radiologic success rates at follow-up were also comparable.
Thirty-eight percent of the CTX/CFU patients also took at least one macrolide antibiotic. Macrolide therapy did not appear to influence clinical response of the clinical PP FU population (94.7% success without macrolides, 93.4% success all patients).
Overall, the clinical efficacy of oral GEMI administered 320 mg once daily for 7-14 days was equally efficacious as that of intravenous CTX 2 grams followed by oral CFU 500 mg BID +/- macrolide for 7-14 days in hospitalized patients with moderate to severe CAP. The availability of an oral formulation provides several potential advantages over intravenous therapy: reduced hospital costs of medication administration, ability to initiate oral therapy, ability to switch patient to oral formulation once stabilized and possible early discharge of the patient. Additionally, for patients who are not hospitalized, oral formulations offer efficacious therapy and ease of administration improving patient compliance. Oral GEMI was as effective as CTX/CFU in subgroups of patients who were bacteremic or classified Fine IV-V.
Acute Exacerbations of Chronic Bronchitis and the Fluoroquinolones
Acute exacerbations of chronic bronchitis (AECB) are far more common than CAP, occurring in approximately 13 million people, each with an average of 3 exacerbations/year, in the US19 and is associated with considerable morbidity and mortality. Repeated infections in the same individual damage lung tissue and can progressively diminish pulmonary function. Episodes are characterized by increased dyspnea, cough, sputum production and purulence,20 and an estimated 50-75% are caused by bacterial pathogens.21 Patients require frequent visits to health care professionals and experience a reduced quality of life for several months after an exacerbation.
In a recent double-blind, randomized, controlled trial22 of antibiotics in 709 patients aged > 40 years with chronic bronchitis, clinical success rates at end of therapy of 5 days of GEMI 320 mg once daily (n = 351) were similar to 7 days of clarithromycin (CLARI) 500 mg twice a day (n = 358) (91.3% vs. 91.4%, respectively). GEMI had a higher bacteriological success rate, especially for H. influenzae, compared to CLARI at EOT [day 8-12] (93.6% vs. 81.5%, respectively; 95% CI = -0.4, 24.6), at FU [day 13-24] (86.7% vs. 73.1%, respectively; 95% CI = -2.0, 29.2) and a statistically significant superiority at long-term FU [day 25-38] (81.8% vs. 62.0%, respectively; 95% CI = 2.2, 37.5; p < 0.05).
GEMI also had a faster time to eradication of H. influenzae (p = 0.02). No H. influenzae was detected in the sputum of any GEMI-treated patient after one day of treatment. In contrast, H. influenzae was recovered from two-thirds (66%) of the CLARI-treated patients after one day, and from one-third (33%), after 6 days of treatment with CLARI. Both medications were generally well tolerated. The most frequently observed adverse events (> 5% of patients) were diarrhea, headache, nausea, rhinitis, and taste perversion. Taste perversion only occurred in the CLARI-treated group (18/358, 5% vs. 0/351, respectively; p < 0.01).
Patients who continued in the study for up to 26 weeks (n = 438) provided data on long-term outcomes.23 GEMI-treated patients had fewer hospitalizations for respiratory tract infection (RTI) related conditions 5/214 (2.3%) compared to CLARI-treated patients 14/224 (6.3%) (treatment difference = -3.91%, 95% CI = -7.67%, -0.15%; Fisher's exact test: p = 0.059). GEMI-treated patients also had a lower number of hospital days, 20 days per 100 patients versus 37 days per 100 CLARI-treated patients. GEMI-treated patients also had significantly fewer recurrences requiring antibiotic treatment (120/169, 71% vs. 100/171, 58.5%, respectively; 95% CI = 2.5, 22.6; p = 0.016).
During the 26 weeks of follow-up, GEMI-treated patients had lower direct costs than CLARI-treated patients ($247 versus $374).24 Total costs (direct and indirect) were also lower for GEMI-treated patients ($1,413 vs. $1,742, respectively). From the payer perspective, GEMI had an 87% probability of being both more effective and cost saving compared with CLARI.
Investigators assessed health status at 26 weeks in 364 smokers or ex-smokers25 with the St. George's Respiratory Questionnaire (SGRQ).26,27 GEMI-treated patients had a mean improvement from baseline of 15 points on the Total score, compared to only 12.4 points for the CLARI patients. GEMI-treated patients had a mean improvement of 26.3 units on the Symptoms score, compared to only 20 units for the CLARI group.
GEMI is an effective treatment for both CAP and AECB. GEMI has demonstrated efficacy as compared to intravenous Я-lactam/macrolide combination therapy in a convenient and cost-saving oral formulation. Additionally, GEMI has demonstrated faster bacterial eradication [H. influenzae] and better long-term health outcomes than clarithromycin therapy in the treatment of AECB. The availability of an oral formulation offers direct and indirect healthcare cost savings. In addition to reducing hospital administration costs (nursing, pharmacy), potential savings could be realized in earlier patient discharges and improvements in patient compliance resulting in better patient quality of life.
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18. Lode et al. Comparative Efficacy of Oral Gemifloxacin (GEMI) and Intravenous Ceftriaxone (CTX) Followed by Oral Cefuroxime (CFU) (+/- Macrolide) in the Treatment of Community-Acquired Pneumonia. Presented at the 67th Annual Scientific Assembly of the American College of Chest Physicians, Philadelphia, PA. November 4-8, 2001.
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22. Wilson et al. Efficacy of Once-Daily Gemifloxacin for 5 Days Compared With Twice-Daily Clarithromycin for 7 Days in the Treatment of AECB. Presented at the 7th International Symposium on New Quinolones, Edinburgh, Scotland, UK, June 10-12, 2001. Abstract 116.
23. Wilson et al. Gemifloxacin Long-Term Outcomes in Bronchitis Exacerbations (GLOBE) Study - An Assessment of Health Outcome Benefits in AECB Patients Following 5 Days' Gemifloxacin (GEMI) Therapy. Presented at the 7th International Symposium on New Quinolones, Edinburgh, Scotland, UK, June 10-12, 2001. Abstract 108.
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25. Jones et al. Greater Improvement in Health Status of Smokers and Ex-Smokers Treated for AECB With Gemifloxacin Versus Clarithromycin: The GLOBE Study. Presented at the 7th International Symposium on New Quinolones, Edinburgh, Scotland, UK, June 10-12, 2001. Abstract 106.
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