Allan S. Wagman and Mary Lee MacKichan Chiron Corporation, Small Molecule Drug Discovery, 4560 Horton Street, M/S 4.5, Emeryville, CA 94608-2916
Introduction - Community-acquired respiratory tract infections (CARTIs) represent one of the most globally prevalent classes of infection. Acute RTIs account for approximately 75% of all antibiotic prescriptions and 20% of all medical consultations (1). Community-acquired upper respiratory tract infections (CAURTI) (pharyngitis/tonsillitis, laryngitis, otitis media and sinusitis) and viral RTIs (rhinorrhea/the common cold, influenza A/B, adenovirus, parainfluenza and syncytial virus) are typically not life-threatening unless complicated by a coinfection or an immunocompromised host (e.g. meningitis, HIV, etc.). Generally, CAURTIs respond well to front-line antibiotics such as penicillins, erythromycin, azithromycin, amoxicillin/clavulanate or cefpodoxime. Viral RTIs are usually self-limiting and only require symptomatic support (2,3). Of greater concern are lower respiratory tract infections (LRTI) which include community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB). These LRTIs account for nearly half of all reported community-acquired infections, can be challenging to treat, place a considerable burden on the health care system, and exhibit significantly higher rates of morbidity and mortality (4). This review will present select current topics in the epidemiology and treatment of CARTIs (ca. 2000-2003).
Morbidity and Mortality - In 2000, the National Centers for Disease Control and Prevention (CDC) reported that influenza and pneumonia as a combined category were the 7th leading cause of death (5). Influenza viral pneumonia is one of the risk factors leading to bacterial invasion and severe bacterial pneumonia (especially Staphylococcus aureus) (6). Mortality for ambulatory outpatient treated CAP is low (<1%), although about 20% of diagnosed CAP cases eventually require hospitalization (7). Mortality rates increase dramatically to 10-25% for serious cases of CAP which typically have a bacterial etiology, while acute CAP requiring intensive care unit (ICU) admission is associated with a mortality rate of almost 40% (1,7). Other CARTIs, while not as deadly as CAP, are a leading cause of serious infection. Incidence rates for CAP in 1996 were 18 per 1000 persons, while acute bronchitis and other acute URTIs (e.g. sinusitis) which required medical attention were 46 and 113 per 1000 persons respectively (8). Associated with colds, it is estimated that about 20 million cases of otitis media and sinusitis are caused by acute bacterial complications of viral rhinosinusitis (9). CAURTIs share a common microbiology with CAP and bronchitis with Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis representing some of the most frequently identified pathogenic bacteria (4,10)
Treatment Guidelines. Diagnoses and Pathogens - There is no shortage of CARTI (especially CAP) treatment guidelines, guideline summaries or expert opinions on specific syndromes, comorbidities or local case studies (6,11-13). In general, all of the guidelines for CAP recommend monotherapy with a macrolide for outpatients or inpatients having no risk factors for drug-resistant S. pneumoniae (DRSP) or gramnegative pathogens. For those patients with either cardiopulmonary disease or risk factors for DRSP, a combination therapy of a p-lactam and macrolide (e.g. erythromycin, clarithromycin or azithromycin) or monotherapy with an
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antipneumococcal quinolone (e.g. levofloxacin, gatifloxacin or moxifloxacin) is recommended. First-line p-lactams for outpatient use include cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanate and ceftriaxone iv followed by oral cefpodoxime. For inpatients, acceptable p-lactams are cefotaxime, ceftriaxone, amoxicillin/sulbactam and high-dose amoxicillin. Certain agents are listed in guidelines as alternatives for pneumococcal infection, such as imipenem, meropenem, cefepime and piperacillin/tazobactam because of their activity against resistant bacteria and Pseudomonas aeruginosa. Recommendations suggest that these agents should be reserved for serious CAP patients with risk factors for resistant gram-negative pathogens. Vancomycin has excellent utility for DRSP infections, but, like linezolide, should be reserved for difficult cases of resistant gram-positive infections such as S. aureus.
Treatment guidelines arise from the need for empiric therapies based on the lack of fast, accurate and cost effective diagnostic tests, as well as a need to improve patient outcomes and lower mortality (6). The most identified causative agent in nearly all studies of CAP was S. pneumoniae (14). From a variety of studies, other common microorganisms associated with CAP are H. influenzae, influenza viruses, other viruses, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella spp. with the first two representing by far the most identified pathogens (4,14-16). Other important causes of pneumonia are M. catarrhalis in AECB and COPD patients, Klebsiella pneumoniae with chronic alcoholism, Gramnegative bacilli and S. aureus in nursing home and inpatients (17). The etiology of acute sinusitis and chronic bronchitis is similar to CAP, except for a greater incidence of M. catarrhalis and Gram-negative bacilli with chronic bronchitis. Pharyngitis is nearly always attributed to either Streptococcus pyogenes or viral pathogens (4,17).
Developments in antibacterial research across a wide assortment of drug classes were recently reviewed (18), as well as research directed toward overcoming resistant pathogens (19,20). The current progress of many of the most promising new agents in clinical development was also evaluated (21).
Penicillins and Cephalosporins - Agents in these two classes of p-lactam are generally considered the drugs of choice for the treatment of CARTIs due to a variety of attractive features including their broad spectrum of activity, fast bactericidal action, safety profile and oral dosing. While penicillin is typically used for treating pharyngitis, many CARTIs, including CAP, are treated with oral amoxicillin/clavulanate or an oral cephalosporin such as, cefpodoxime, cefdinir, cefproxil, or cefuroxime. Since many of these agents (alone or in combination with a p-lactamase inhibitor, e.g. ampicillin/sulbactam) are available in both oral and iv forms, they are ideal for transition therapy for patients hospitalized with CAP or AECB (22). Unfortunately, p-lactam agents alone do not adequately cover atypical pathogens (23,24), and with the increase in p-lactam resistance, oral cephalosporins are no longer adequate for the treatment of CAP caused by intermediate resistant S. pneumoniae.
The increasing threat of multidrug-resistant Gram-positive and extended-spectrum p-lactamase producing Gram-negative pathogens fuels research into new cephalosporins which tends to yield potent, but narrow spectrum agents (25). Many current cephems developed as anti-MRSA agents will not adequately cover serious Gram-negative infections and are usually only suitable for parenteral administration (26). One of the few new oral penems, faropenem 1 which is sold in Japan, has potentially less liability for CNS side effects (27), excellent MICoos (0.008, 0.25 and
1) against U.S. strains of penicillin-susceptible, -intermediate, and -resistant S. pneumoniae strains and good activity against p-lactamase positive H. influenzae and M. catarrhalis (28). However, feropenem showed reduced activity in vitro against S. pneumoniae in the presence of human serum (29). A prodrug form, faropenem daloxate, is being investigated as a clinical candidate for CARTIs (30).
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