Brief Informational Sketches of Some Other Mastitis Pathogens

Appendix G: The VADS system approach to pharmacodynamics of beta-lactams

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) will be used to extrapolate the relationship.

For therapy with beta-lactam antimicrobials, the preponderance of evidence suggests that there is a linear relationship between clinical or bacteriological cure (or log reduction in bacterial count in vitro) and the percentage of the dosing interval that the serum concentration of the antimicrobial must remain above the MIC of the pathogen.

What is not as clear is the optimal percentage for each drug/pathogen combination. Therefore, we have selected the following generalizations to apply to our pharmacokinetic modeling:

For gram-negative pathogens treated with beta-lactams, the time that serum concentration of the antimicrobial needs to remain above the MIC of the pathogen is 100% of the dosing interval.

For gram-positive pathogens treated with beta-lactams, the time that serum concentration of the antimicrobial needs to remain above the MIC of the pathogen is 50% of the dosing interval.

References on which these recommendations were made follow below:

Gram-negative pathogens

% OF DOSING INTERVAL	DRUG(S)	PATHOGEN(S)	RefID
100	ticarcillin	Pseudomonas	549*
>60 (increases in efficacy up to 100)	cefazolin	E. coli	549*
not reported; increased with increasing time	cefazolin, ceftazidime, imipenem	Klebsiella pneumoniae	6959*
increased % leads to increased efficacy (no breakpoint suggested)	cefazolin, ticarcillin, imipenem	Klebsiella pneumoniae, E. coli, Pseudomonas	6751*
bacteriostatic effect: 40; max killing 60-70	cefotaxime	Klebsiella pneumoniae	6694* (data source unverified, p. 92)

% OF DOSING INTERVAL	DRUG(S)	PATHOGEN(S)	RefID
continuous infusion better than intermittent dosing, even though serum conc. never reached MIC in continuous	ceftazidime	Klebsiella pneumoniae	6903
100 (but lower % not tested)	cefodizime, ceftriaxone	E. coli, Klebsiella pneumoniae, Haemophilus influenzae	4139
schaad article requested		meningitis
100 (total time drug remained above MIC was optimized rather than % of dosing interval)	cefaclor, ceftibutin	E. coli, Klebsiella pneumoniae	6677
16 (static effect for 24 hrs)	carbapenems	Pseudomonas	6755
27 (static effect for 24 hrs)	carbapenems	Non-Pseudomonas gram-negatives	6755
33 (static effect for 24 hrs)	mean across carbapenems, penicillins and cephalosporins	Klebsiella pneumoniae	6755
20-26 (static effect for 24 hrs)	carbapenems	Mean across multiple bacteria (gram positive and gram negative)	6755
28-34 (static effect for 24 hrs)	penicillins	Mean across multiple bacteria (gram positive and gram negative)	6755
35-55 (static effect for 24 hrs)	cephalosporins	Mean across multiple bacteria (gram positive and gram negative)	6755
17-25	ceftazidime	Klebsiella pneumoniae	6767
100 (and conc. was 2X MIC)	ceftazidime	Klebsiella pneumoniae	6767*
Lack of PAE for gram negative organisms	multiple	E. coli, Pseudomonas, Klebsiella	550, 6743
Clinical cure achieved at 60-100 in Group II, and 0-4 in Group I, although Group I did not achieve bacteriological cure	amoxicillin	Actinobacillus pleuropneumonaie	6676

% OF DOSING INTERVAL	DRUG(S)	PATHOGEN(S)	RefID
Efficacy equal for 75-100 for non-mucoid strains, but mucoid: even 100 not effective unless in combination with tobramycin	cefepime, ceftazidime	Pseudomonas	4113
Regrowth appears to recur when concentration went below the MIC, but not conclusively	cefoperazone	Pseudomonas	6715*
Linear increases up to 100	ticarcillin, ceftazidime	Pseudomonas	4134*

*neutropenic or immunocompromised patients

Gram-positive pathogens

% OF DOSING INTERVAL	DRUG	PATHOGEN	RefID
25	beta-lactams	Staph. aureus	6694, 6747, 6746
40-50	multiple drugs	Strep. pneumoniae	4156, 4114, 6681, 4112, 6682, 6678, 6701, 3873, 6694* (data source unverified, p. 92)
40-50%	cefpodoxime	Strep. pneumoniae	786
55% (>20 provided some efficacy)	cefazolin	Staph. aureus	549*
increases from 20-100 with no breakpoint	penicillin	Strep. pneumoniae	549*
2/3 or greater (free drug)	ceftriaxone	Strep. pneumoniae	6753*
1 log reduction at 25-30%	amoxicillin, amoxicillin-clavulanate	Strep. pneumoniae	6751*
23-29	Experimental cephalosporin	Staph. aureus	6746
35 (not max efficacy)	Experimental cephalosporin	Staph. aureus (VISA)	6747*

% OF DOSING INTERVAL	DRUG	PATHOGEN	RefID
increases with %; sterilization at 95-100 (over MBC)	ceftriaxone	Strep. pneumoniae (in CSF/meningitis)	6695
50	cefodizime, ceftriaxone	Staph. aureus	4139
100 (total time drug remained above MIC was optimized rather than % of dosing interval)	cefaclor, ceftibutin	Staph. aureus, Strep. pneumoniae	6677
Linear increases in efficacy with increased total time (effective dose regressed against extrapolated T>MIC), but no breakpoint	14 cephalosporins	Strep. pneumoniae	6708
24 (static effect for 24 hrs)	mean across carbapenems, penicillins and cephalosporins	Staph. aureus	6755
41 (static effect for 24 hrs)	mean across carbapenems, penicillins and cephalosporins	Strep. spp.	6755
20-26 (static effect for 24 hrs)	carbapenems	Mean across multiple bacteria	6755
28-34 (static effect for 24 hrs)	penicillins	Mean across multiple bacteria	6755
35-55 (static effect for 24 hrs)	cephalosporins	Mean across multiple bacteria	6755
Lack of PAE		Streptococcus pneumoniae	550*
Presence of PAE	ceftriaxone, imipenem	Streptococcus pneumoniae	8043
Presence of PAE	multiple (ceftriaxone, imipenem)	Staph. aureus	6743*, 8043
Presence of PAE	penicillin	Strep. pyogenes	452
Regrowth appears to recur when concentration went below the MIC, but not conclusively		Staph. aureus	6175*

*neutropenic or immunocompromised patients

Other pharmacodynamic parameters

There are multiple references which found parameters other than T>MIC associated with efficacy (452, 4115, 6741, 6702, 4111, 3701, 6744, 4124, 6677, 3701, 3724, 6687, 4134). However, there was no consistency among them, and therefore nothing on which to base exceptions to the generalizations below. In addition, none addressed veterinary pathogens and domestic animal species.