In evaluating the PK/PD approach as a tool to predict the emergence of resis-
tance, we should also be mindful of the impact of body fluids on PD. There are two
issues to be considered: (1) the concentration of drug in the infected tissue; and (2)
the influence of body fluid on the PD indices. For example, there can be as large as a
fourfold greater concentration of many antimicrobials in gingival fluid versus
serum (Conway et al. 2000 ; Lavda et al. 2004 ). This higher tissue site concentration
has been attributed to the active transport of drugs, such as the fluoroquinolones and
tetracyclines, by gingival fibroblasts (Yang et al. 2002 ).
Body fluids may impact on PD in a positive or negative manner. As an example
of a positive effect, bacterial growth rate in serum tends to be slower than in broth
(e.g. Bedenic et al. 2005 ). Therefore, studies that consider in vitro killing effects or
bacteriostatic activity in artificial fluids are likely to produce conservative estimates
of the killing or duration of static activity seen in vivo. An example of a negative
influence is the impact of urine on fluorquinolone activity (Boy et al. 2004 ; Naber
2001 ; Well et al. 1998 ). Possible reasons for this include the effect of pH (ionisation
reduced permeability of drug into the bacterial cell) or the effect of ions (chelating
the drug and thereby reducing permeation into the bacteria (Zhanel et al. 1991 ). The
impact of urine on antimicrobial activity has been addressed by generating data in
an ex vivo model by determining the urinary bactericidal titres (Boy et al. 2004 ;
Naber 2001 ; Well et al. 1998 ). Comparison of MIC and MBC values for amoxicil-
lin, florfenicol, marbofloxacin, oxytetracycline and tulathromycin against several
strains of the calf pathogensM. haemolyticaandP. multocida, revealed differences
between the matrices serum and Mueller-Hinton broth for all drugs; these were
particularly marked for oxytetracycline and tulathromycin( Illambas et al. 2009 ;
Potter et al.2009a,b).
Another example of a negative interaction between drug and body fluid is the
relationship between daptomycin concentrations in blood versus lungs and the
resulting activity against pulmonary pathogens. Daptomycin has excellent in vitro
activity against a large range of Gram-negative and Gram-positive bacteria. It was
also found to be highly effective in reducing the number of CFUs ofS. pneumoniae
in a neutropenic mouse thigh infection model (Safdar et al. 2004 ). Although
daptomycin is indicated for the treatment of complicated skin and skin structure
infections caused by susceptible strains of Gram-positive microorganisms:Staphy-
lococcus aureus(including methicillin-resistant strains),Streptococcus pyogenes,
Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis and
Enterococcus faecalis(vancomycin-susceptible strains only) (FDA New Drug
Application #21-572), it is not effective against community-acquired pneumonia.
The reason for this is the binding and inactivation of daptomycin by human lung
surfactants (Silverman et al. 2005 ).
4.5 Clinical Susceptibility Breakpoints
When samples are sent to the clinical laboratory for culture and susceptibility evalua-
tion, the laboratory uses established “breakpoints” for making recommendations
Antimicrobial Drug Resistance 249