Clinical and Microbiological Concepts of Antibiotic Resistance

Microbial resistance causes a great deal of confusion when choosing an empirical treatment for pneumonia. Strictly speaking, the term resistance refers to the in vitro susceptibility of a pathogen to various antibiotics; however, in vitro data do not necessarily translate into in vivo efficacy. Favorable pharmacokinetic/pharmacodynamic (PK/PD) parameters and high concentrations of antimicrobials at the site of infection may explain the good clinical outcomes achieved despite MIC values in vitro that appear to be "resistant" or "nonsusceptible".

In vitro susceptibility testing by the microbiology laboratory assumes the isolate was recovered from blood, and is being exposed to serum concentrations of an antibiotic given in the usual dose. Resistance levels are always defined in relation to these serum concentrations based on the National Committee for Clinical Laboratory Standards (NCCLS) breakpoints—now known as the Clinical Laboratory Standards Institute (CLSI)—and they do not make reference to tissue concentrations at the site of infection. Susceptibility breakpoints proposed by NCCLS (NCCLS, 1997) for S. pneumoniae were derived from laboratory and clinical data relating to the treatment of the most serious and difficult to treat clinical infections, such as meningitis, and not to otitis media, sinusitis, or pneumonia. According to these values, S. pneumoniae was classified as susceptible (MIC < 0.06 mg/l), of intermediate susceptibility (MIC 0.1-1 mg/l) and resistant (MIC > 2 mg/l). These breakpoints are meant to be considered for infections in which borderline penetration makes these levels significant. In meningitis, for instance, the penicillin concentrations reached in cerebrospinal fluid (CSF) might barely reach the 2 mg/l level established for high-degree penicillin resistance (Musher et al., 2001). In contrast, in pneumococcal pneumonia, the drug levels reached in serum and lung tissue exceed the MIC of the microorganism because there is no anatomical barrier hindering access of antimicrobials to the infection site (Craig, 1998a). Knowing the origin of these definitions helps to resolve the apparent paradox that infections of the respiratory tract due to seemingly P-lactam-resistantpneumococci may still respond well to standard doses of these drugs (Kaplan and Mason, 1998; Heffelfinger et al., 2000). Such inconsistencies have prompted the NCCLS to revise its breakpoints for S. pneumoniae susceptibility testing, which differentiate between meningeal and non-meningeal sites of pneumococcal infection (Heffelfinger et al., 2000). (See Table 1.1).

Recently, Weiss and Tillotson (2005) have suggested that the definition of clinical resistance, rather than strictly relying on NCCLS criteria, should be linked to the inability of an antibiotic agent to reach a concentration high enough at the site of infection to inhibit local bacterial replication, and to the need for a second antibiotic prescription 72 h after starting therapy because of the deterioration or nonsignificant improvement of the initial medical condition.

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