The clinical impact of in vitro antibiotic resistance has been difficult to assess, given that most community-acquired RTIs are treated in the outpatient setting, in which microbiological data are rarely collected before treatment is begun. The most compelling evidence to date surrounds the possible association between macrolide resistance and adverse clinical outcomes. Reviews of the published literature have described a number of cases of empirical macrolide treatment failure (resulting in hospitalization of patients with breakthrough bacteremia) that were associated with infection by macrolide-resistant strains of S. pneumoniae.

Rzeszutek et al. reviewed cases of macrolide treatment failure published between 1990 and 2002. Of the 33 cases listed, 31 involved patients who had received macrolides as outpatients and who had required hospitalization as a result of therapy failure. The other two cases involved previously healthy hospitalized patients who did not respond to intravenous (IV) macrolide therapy and who subsequently died after their clinical condition deteriorated. In both of these cases, macrolide-resistant S. pneumoniae were isolated from blood cultures taken during macrolide therapy.

Further evidence supporting a link between macrolide resistance and adverse clinical outcomes emerged from case-control studies of hospitalized patients with breakthrough bacteremia. Two such studies showed that treatment failure occurred more frequentlyin patients infected with a macrolide-resistant S. pneumoniae strain than in those infected with a macrolide-susceptible strain. Although the clearest evidence of an association between macrolide treatment failure and macrolide resistance has come from studies of patients hospitalized with breakthrough bacteremia, the true incidence of macrolide treatment failure is probably much higher than that suggested by the case reports and observational studies published to date. Again, this is a result of the lack of microbiological testing in the outpatient setting. It is in this setting where most patients receiving macrolides are treated.

Most evidence to date applies to the clinical use of macro-lides; however, failure of empirical treatment with levofloxacin attributable to fluoroquinolone resistance has also been reported in patients with pneumococcal RTIs, and infection with penicillin-resistant S. pneumoniae has been reported to lead to an increased risk of suppurative complications.

Clinical treatment failures contribute to substantial health care expenditure associated with RTIs. Direct costs of treatment failure include those associated with additional prescriptions, extra tests and procedures, and hospitalizations; indirect costs may be incurred by patients experiencing increased disability and loss of productivity.
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Klepser and colleagues assessed the economic impact of infection with penicillin-nonsusceptible strains of S. pneumo-niae in a study of hospitalized patients. The results from this analysis indicated that infection with a nonsusceptible isolate was associated with significantly higher costs (total, $10,309; room, $3,771; and nursing, $3,859) than infection with a susceptible isolate (total, $7,802; room, $2,829; and nursing,

$2,886).