The VADS system approach to pharmacodynamics of lincosamides

 

In the event that pharmacodynamic relationships have been shown with experimental data generated in domestic species with veterinary pathogens using veterinary-approved antimicrobials, those relationships will be used to generate dose recommendations.  In the absence of that information, data from laboratory animal and human retrospective and prospective studies (including neutropenic models), as well as in vitro models such as time-kill studies, will be used to extrapolate the relationship.

 

There is a paucity of data related to the pharmacodynamics of the lincosamides (clindamycin, lincomycin).  It is often stated in review articles that agents that inhibit protein synthesis most likely require serum concentrations above the MIC for long portions of the dosing interval, but no specifics on percentages have been tested for lincosamides.  In vitro microbiological factors such as the static or cidal nature of antimicrobials is also often used as justification for the importance of T>MIC.  However, the in vitro/in vivo correlation is not 100%, the property may change depending on organism, and the cidal or static nature may not guarantee success. (Pankey 2004)  For example, it has been assumed by clinicians that a cidal drug was required for meningitis, when in fact, therapy has been successful with chloramphenicol and tetracycline.  (Pankey 2004) 

 

Nonetheless, examples of reports on the cidal vs. static status of clindamycin and lincomycin are presented for completeness. 

 

Drug	Pathogen	Results	RefID
clindamycin	Mycoplasma pneumoniae	MBC:MIC = 4	8087
	Gardnerella vaginalis, Lactobacillus acidophilus	MBC:MIC = 2	8080
	Clostridium perfringes	MBC:MIC = 1	5772
	beta-Streptococcus		8091
	Staph. epidermidis	MBC:MIC = 2	8088
	Staph. aureus	MBC:MIC = 2-4	8090
lincomycin	Serpulina hyodysenteriae	MBC:MIC = range 1-4, although many strains had MICs reported as “>”, so the ratio could be higher	3363
	Staph. pyogenes	MBC:MIC ranged from 1-4 for 67% of the strains (112 strains tested)	8086
	Staph. aureus, E. coli		heman-ackah 1975

 

In one report using clindamycin, the investigators found no difference in rate or extent of killing of Bacteroides fragilis when in vitro concentration were 1X, 4X, 16X or 64X MIC, so-called concentration-independent (8078).  Another groups found no difference in rate or extent of killing of Staph. aureus and Strep. pneumoniae by clindamycin with changes in dosing that allowed differing C_max, but concentrations > MIC for 100% of dosing interval (concentration-independent) (6848).  This suggests T>MIC is the parameter of interest.  However, the lowest C_max:MIC ratio was 14, and the lowest AUC_0-24 was 113, so these could not be completely ruled out as important parameters.

 

PAEs have been studied for clindamycin: They correlated with AUC (increase in AUC resulted in an increase in PAE, after a 3-hour exposure time to different concentrations, 2 strains with the same MIC), and ranged from 0.4-3.9 hrs for 21 strains (exposure time of 1 hr, concentration of 4X or 8X MIC depending on strain) (8079). 

 

Other PAEs reported for clindamycin:

 

Pathogens	PAE	RefID
Bacillus anthracis	2 hr	athamna 2004
Bacteroides fragilis	none, except with very high AUCxMIC (>30)	8103
Staph. epidermidis	2.2 hr.	8097
Staph. aureus	0.4-3.9 hr.	8079
Staphylococcus aureus, Streptococcus pyogenes, Strep. pneumoniae, Haemophilus influenzae	Haemophilus influenzae: 1-2 hr Staphylococcus aureus: 2.5-5 hr Streptococcus pyogenes: 0.5-5 hr Strep. pneumoniae: 2.5-4.9 hr	8098

 

Given the above evidence, and given the mechanism of action of lincosamides (protein-synthesis inhibition), we have elected to use a time above MIC of 100% of the dosing interval.