New Therapies Or Therapeutic Strategies

Optimal use of antimicrobials begins by selecting the most potent agent as the first choice for therapy. Pharmacodynamic data from experimental models and clinical studies allow comparisons among members of each antibiotic class to predict the agents that are most likely to effect the greatest bacterial eradication and result in the least selection of resistant mutants (75,76). Sub-optimal exposure to any antimicrobial may occur through inadequate dosing, duration of administration, and failure to consider the antimicrobial concentrations at the site of infection. Inadequate antibiotic therapy contributes to carriage of DRSP that in turn promotes spread of resistant clones (77-79).

Beta-lactams work in a time-dependent manner, which means that the duration of time during which their concentration stays above the MIC at the site of infection is critical to their success. Currently, all parenteral beta-lactams recommended for the treatment of pneumococcal pneumonia can achieve a time above MIC of 40% to 50% against organisms with a MIC of <2 mg/mL using standard dosing, although some, such as cefuroxime, barely reach this critical value (54). Largely on the basis of the clinical and pharmacodynamic data presented thus far, the CLSI has instituted new interpretive breakpoints against non-meningeal isolates. Using these new breakpoints, a much greater proportion of pneumococci are now considered susceptible (80). Since, penicillin-resistance in S. pneumoniae is due to step-wise alteration in PBPs, and not due to beta-lactamases, administration of higher doses of beta-lactams would therefore overcome resistance. Highly active beta-lactams effective against S. pneumoniae include high-dose amoxicillin (90-100 mg/kg/day), cefdinir, cefpodoxime, cefprozil, and cefuroxime. Effective parenteral agents include ceftriaxone and cefotaxime, while ceftazidime and ticarcillin should be avoided.

It is important to evaluate the in vitro activity of an antimicrobial against the pathogen in conjunction with achievable concentrations at the site of infection. Through exceptional tissue penetration and long tissue elimination half-lives, macrolides may achieve concentrations at the site of infection that are substantially greater than serum levels. In the case of pneumonia caused by S. pneumoniae, antimicrobial levels in the alveolar ELF (and, to a lesser extent, within leukocytes and alveolar macrophages) are thought to be more important in determining therapeutic efficacy than serum levels (81-83). Macrolides such as clarithromycin and azithromycin are concentrated in leukocytes and have higher concentrations in alveolar ELF tissues compared with plasma (84). Therefore, these agents are very active for pneumonias. The treatment of uncomplicated pneumonia caused by isolates with MICs as high as 4 mg/mL or even 8 to 16 mg/mL may be possible due to the exceptional tissue penetration of the macrolides. For now, macrolide monotherapy remains a reasonable alternative for outpatients without comorbid-ities. Continued monitoring of the clinical efficacy of the macrolides will be important as the prevalence and the magnitude of macrolide resistance continues to increase. Ketolides are generally active against MLS-resistant pneumococci due to a greater affinity for the ribosomal binding site and weaker induction of inducible erm expression. Telithromycin is also a weak inducer and poor substrate for the mefA efflux pump (85). In April 2004, telithromycin was approved in the United States for the treatment of CAP, AECB, and acute bacterial sinusitis. Despite the advanced targeting of telithromycin, safety signals have been detected with respect to blurry vision, unmasking and worsening of myasthenia gravis, and acute hepatotoxicity. This has led to loss of its indication for AECB and acute bacterial sinusitis. Though it still has an indication for CAP, it is not to be used in patients with myasthenia gravis. In the latest CAP guidelines, final recommendations for telithromycin are pending safety evaluation by the U.S. Food and Drug Administration (FDA) (86).

The newer fluoroquinolones, gemifloxacin and moxifloxacin, possess improved activity against S. pneumoniae. They have proven effective against penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. High clinical cure and bacterial eradication rates have been observed in clinical trials using fluoroquinolones for the treatment of community-acquired respiratory infections (87). For patients in which fluoroquinolones have been used to treat CAP or acute exacerbation of chronic bronchitis, the clinical cure rates are typically 90% (88). Moreover, the new fluoroquinolones may be dosed once-daily, increasing patient compliance (87). However, fewer genetic barriers are likely to result in more rapid development of resistance in S. pneumoniae under conditions of expanded use. The newer fluoroquinolones moxifloxacin and gemifloxacin combine the highest in vitro potency and the best pharmacokinetic profiles. These drugs require two spontaneous mutations (typically, 1 in gyrA, 1 in parC) before a "wild-type" organism develops clinically significant resistance. Thus these agents should not only be more effective, but also less likely to select for resistance. Peak levels for these drugs in serum exceed the MIC for first-step gyrA mutants (89,90). This rationale for preferential use of moxifloxacin and gemifloxacin is undermined if the infecting isolate already harbors a mutation in parC, as might occur after ciproflox-acin exposure. This isolate, while still susceptible to gemifloxacin and moxifloxacin, then requires only a single mutation in gyrA to acquire resistance to these agents. For reasons already discussed, such an event is probable during the treatment of CAP and may set the stage for selective amplification of the double mutant under continued fluoroquinolone pressure. Unfortunately, current routine methods for susceptibility testing are not sufficiently sensitive to detect such isolates harboring parC mutations (91). This logic therefore suggests that we should not be saving the most potent agents under the premise that patients who fail a less potent fluoroqui-nolone should still respond to most potent agents. It will be difficult to preserve the efficacy of the latter agents if resistance mutations enriched by less potent fluor-oquinolones continues to increase in prevalence.

TABLE 2 List of Various Options for Empiric Antimicrobial Treatment of Community-Acquired Pneumonia

Outpatient

Healthy and no antimicrobial use within 3 months Macrolide Doxycyline

Presence of comorbidities (chronic heart, lung, liver, renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs) or antimicrobial use within past 3 months

Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin) Beta-lactam and macrolide Inpatient Non-ICU treatment

Respiratory fluoroquinolone Beta-lactam and macrolide ICU treatment

Beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) and azithromycin Above beta-lactam and respiratory fluoroquinolone If Pseudomonas is a concern

Antipneumococcal, antipseudomonal beta-lactam (piperacillin/tazobactam, cefepime, imipenem, or meropenem), and fluoroquinolone (ciprofloxacin or levofloxacin—750mg) Above beta-lactam and aminoglycoside and azithromycin Above beta-lactam and aminoglycoside and antipneumococcal fluoroquinolone

Abbreviation: ICU, intensive care unit. Source: Adapted from Ref. 86.

In March 2007, new guidelines for the treatment of CAP were released by the American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC) (86). The guidelines for treatment of empiric outpatient and inpatient CAP were not changed significantly from previous guidelines. Ertapenem was added as an acceptable beta-lactam alternative for hospitalized patients with risk factors for Gram-negative infections other than Pseudomonas. Table 2 summarizes the 2007 CAP recommendations for outpatient and inpatient treatment.

Current immunization against pneumococcal pneumonia and influenza should reduce the incidence of CAP and other respiratory tract infections. Immunization against S. pneumoniae, with Pneumovax™ (pneumococcal vaccine polyvalent; Merck and Co., Inc., Whitehouse Station, New Jersey, U.S.A.) for adults or Prevnar™ (pneumococcal 7-valent conjugate vaccine; Wyeth pharmaceuticals, Inc., Philadelphia, Pennsylvania, U.S.A.) for children, can reduce the incidence of invasive infections as well as reduce nasopharyngeal carriage (92,93). Since more than 80% of resistant pneumococci and all six of the predominant MDRSP clones in the United States are covered by the vaccines (94), more appropriate use of both vaccines could play a very valuable role in reducing the spread of drug-resistant S. pneumoniae (40).

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