(Shryock et al. 1998 ) and anti-inflammatory activity (Dalhoff and Shalit 2003 ) can
play an important role in promoting a positive therapeutic outcome. For example,
Slocombe et al. ( 1985 ) showed that the tissue damage associated with acute bovine
pleuropneumonia, caused by Mannheimia haemolytica, is due to neutrophil-
mediated damage to the bovine pulmonary parenchyma. In general, despite the
obvious importance of the host immune response in combating acute infections, the
excessive synthesis and secretion of inflammatory mediators can lead to increased
morbidity and mortality. Therefore, antimicrobial drugs that minimise the secretion
of these pro-inflammatory cytokines may provide a significant therapeutic benefit
(Labro 1998 ).
Numerous classes of antimicrobials have been shown to provide therapeutic
advantages that are attributable to actions in addition to their antimicrobial activ-
ities. For example, some antimicrobial drugs interfere with or induce the secretion
of cytokines, thereby controlling the pro-inflammatory process (Reato et al. 2004 ).
Mechanisms through which drugs can directly interfere with the host immune
response include (van den Broek 1989 ):
l The inhibition of phagocytosis by binding of tetracyclines and bacitracin to
divalent cations
l An interference of phagocyte H 202 production by sulfonamides and trimethoprim
l An increase in phagocyte uptake ofStreptococcus pyogenesby the effect of
sub-MIC concentrations of clindamycin and lincomicin on bacterial surface
proteins
l A depression of chemotactic activity of granulocytes when filtrates ofPropio-
nibacterium acnesare exposed to gentamicin, erythromycin and minocycline
l Sub-MIC concentrations of tetracyclines decrease chemotaxis by binding to
divalent cations
Because of the rapid rise in antimicrobial resistance, alternative strategies are
being developed. In an attempt to minimise the proliferation of resistant strains, as
encouraged through the therapeutic use of antimicrobial drugs, new therapeutic
approaches are being sought. While traditional approaches target in vitro and
in vivo pathogen viability (e.g. static and cidal compounds), new approaches target
functions that contribute to pathogen virulence. Most importantly, such novel
compounds are unlikely to present with the significant resistance concerns currently
associated with traditional antimicrobial therapies. Examples of mechanisms of
action currently being explored are provided in Table 4.
One of the difficulties associated with these novel approaches is that they often
require that the clinician has an exact diagnosis of the cause of the infection.
Moreover, traditional methods for evaluating appropriate therapies (i.e. in vitro
susceptibility test procedures) will not be useful for evaluating the ability of these
methods to counteract disease-causing virulence factors because such effects
cannot be evaluated in the absence of the host environment. Clearly, these
technologies, while holding much promise, also present many new and exciting
challenges.
256 M. Martinez and P. Silley