Respiratory Tract Infections

Two to three million cases of community-acquired pneumonia (CAP) are reported in the United States each year, resulting in approximately 10 million physician visits.54 In cases in which an etiologic agent is documented, Streptococcus pneumoniae is the leading cause. Attributable mortality and morbidity have remained essentially unchanged in recent decades, despite the emergence of new antimicrobial options and improvement in critical care medicine.54,55 Antimicrobial resistance results in high hospitalization rates, mortality, and costs.56 A large retrospective study concluded that infections caused by penicillin-resistant S. pneumoniae with penicillin minimum inhibitory concentration

(MIC) > 4 ^g/ml or cefotaxime MIC > 2 ^g/ml were associated with increased mortality in the multivariate model, but only after excluding short-term mortality (within 4 days), especially in bacteremic patients.57 Age less than 6 years and greater than 70 years, recent antimicrobial therapy, immunosuppression, HIV, presence of underlying disease, recent or current hospitalization, and institutionalization were some of the risk factors associated with resistant S. pneumoniae.58 As drug-resistant strains have increased, penicillin resistant S. pneumoniae isolates have reached 25-35% in the United States and have surpassed 40% in some areas of Europe.59-61 When penicillin resistance is identified, resistance to other antibiotics, like cephalosporins, macrolides, doxycycline, and co-trimoxazole, is generally anticipated.62 According to the 2002-2003 Tracking Resistance in the US Today (TRUST) 7 study, S. pneumoniae susceptibility was 96.1% for ceftriaxone, 93.4% for amoxicillin-clavulanate, 72.2% for azithromycin, and 99.1% for levofloxacin.63 In the TRUST 8 data, susceptibility rates were similar. In these two studies, it has been documented that resistance varies among geographic regions of the United States. In association with an increase in macrolide use from 1993 to 1999, macrolide resistance in S. pneumoniae rose up to 20.4% by the year 2002.64 Doern et al. reported a resistance rate around 30% for macrolides recently; in the same study 22.3% of S. pneumoniae was MDR.65

Other causative microorganisms of CAP are Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, Klebsiella pneumoniae, Legionella spp., viruses, and other Gram-negative rods.54 In patients hospitalized due to CAP, P. aeruginosa has also been recovered.55 H. influenzae and M. catarrhalis were shown to be significantly resistant to first-generation cephalosporins and other ß-lactams.63 Abdel-Rahman et al. reported ampicillin resistance in 20% and multidrug resistance in 5.4% of all isolates of H. influenzae in Saudi Arabia, where antibiotics are commonly sold over the counter.66 Being aware of the resistance rates observed in H. influenzae, clinicians should choose an antibiotic other than ampicillin, when empirical antibiotic therapy is needed.

Fluoroquinolone resistance of S. pneumoniae has not yet become a significant clinical and epidemiological problem, presenting an overall 1% resistance.63,67,68 However, the resistance of S. pneumoniae to ciprofloxacin doubled from 1999 to 2001 (from 1.2% to 2.7%) as well as to levofloxacin (from 0.6% to 1.3%).69 Recently, Bhavnani et al. reported a 50% increase in levofloxacin MIC values for S. pneumoniae from 1997 to 2001 and this increase was closely associated with the increase in levofloxacin use, which increased from 0.4 to 4 prescriptions per 100 people over 6 years.70

Acute exacerbation of chronic bronchitis is mainly due to H. influenzae and S. pneumoniae, but not atypical microorganisms. In severe cases, Gram-negative microorganisms may be involved such as Enterobacteriaceae and Pseudomonas. Severe exacerbations of chronic obstructive pulmonary disease generally require hospitalization. In addition, patients with significant compromise of lung function may develop respiratory failure as a consequence of an acute exacerbation, and up to 60% of these patients will require mechanical ventilation.71 In this group of patients, the bacterial etiology correlates closely with the severity of the accompanying lung disease.72 S. pneumoniae is the most common microorganism in patients with mild disease; H. influenzae, M. catarrhalis, Enterobacteriaceae, and Pseudomonas species are becoming more commonly encountered as disease severity increases.71,72 The major resistance for M. catarrhalis is caused by p-lactamases, and this is also the case for H. influenzae. Among both, penicillin-resistant strains have increased through the last two decades.58 Gatifloxacin, levofloxacin, and ciprofloxacin are active against all M. catarrhalis and H. influenzae isolates, and gatifloxacin and levofloxacin are active against > 99% of S. pneumoniae. Amoxicillin-clavulanate, cefuroxime axetil, tetracycline, and fluoroquinolones (namely, levofloxacin and ciprofloxacin) remain effective against both P. aeruginosa and Enterobacter cloacae; these agents are also more active against common pathogens than macrolides.73,74

Hospital-acquired pneumonia (HAP), VAP, and healthcare-associated pneumonia (HCAP) constitute the rest of the RTIs treated in the hospitals. About 300,000 cases of HAP occur annually, and HAP has an attributable mortality rate of approximately 33 to 50%.75 Compared to patients with CAP, patients with HAP are at greater risk for colonization and infection with a wider variety of MDR pathogens.76 The major clinical strategies for HAP, VAP, and HCAP include initial management of the disease on the basis of time of onset and risk for MDR pathogens, adequate dosing during empirical therapy for MDR pathogens, and broad-spectrum initial antibiotic therapy followed by appropriate antibiotic deescalation to limit development of resistance.76 Choosing the initial, appropriate antibiotic regimen is becoming much more difficult due to the rapid emergence of different types of MDR pathogens including P. aeruginosa, K. pneumoniae, Acinetobacter species, and MRSA. It is recommended that patients without MDR risk factors and early onset HAP or VAP initially be treated with ceftriaxone, ampicillin-sulbactam, ertapenem, or one of the fluoroquinolones (moxifloxacin, ciprofloxacin, or levofloxacin).76 Considering the increased frequency of both penicillin resistance and MDR among S. pneumoniae, levofloxacin and moxifloxacin are preferred over ciprofloxacin. Patients with late-onset HAP, VAP, and HCAP or those with known risk factors for MDR pathogens should be treated with an antipseudomonal cephalosporin (cefepime or ceftazidime), a carbapenem (imipenem or meropenem), or piperacillin-tazobactam.76 An antipseudomonal fluoroquinolone or an aminoglycoside might also be given. Linezolid or vancomycin should be added if there are risk factors for MRSA. In vitro resistance of the pathogen has been shown to correlate with clinical failure.77 K. pneumoniae, which is an important pathogen involved in nosocomial infections, has been a growing problem. K. pneumoniae producing ESBL has become more prevalent, and is difficult to eradicate, since these organisms develop resistance to multiple antibiotics.

Nosocomial pneumonia therapy in ICU often requires excessive antibiotic use because of the associated high mortality rates.63 An operational approach to reduce the amount and duration of antibiotic use in the ICU is to reevaluate the patients after initiation of therapy, using an operational criterion such as the clinical pulmonary infection score (CPIS). Reevaluation with CPIS has been shown to successfully identify patients for whom short-course therapy would be appropriate.74 This resulted in shorter durations and lower costs of antibiotic treatment and eventual decrease in antibiotic resistance.

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