The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs. More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens [pharmacodynamics (PD)] has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy. This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility. PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC(0-24)) and minimum inhibitory concentration (MIC), maximum plasma concentration (C(max)) and MIC and time during which plasma concentrations exceed the MIC have been particularly useful in optimizing efficacy and minimizing resistance. Antimicrobial drugs have been classified as concentration-dependent where increasing concentrations at the locus of infection improve bacterial kill, or time-dependent where exceeding the MIC for a prolonged percentage of the inter-dosing interval correlates with improved efficacy. For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy. The PK/PD relationship for each group of antimicrobial drugs is 'bug and drug' specific, although ratios of 125 for AUC(0-24):MIC and 10 for C(max):MIC have been recommended to achieve high efficacy for concentration-dependent antimicrobial drugs, and exceeding MIC by 1-5 multiples for between 40 and 100% of the inter-dosing interval is appropriate for most time-dependent agents. Fluoroquinolones, aminoglycosides and metronidazole are concentration-dependent and beta-lactams, macrolides, lincosamides and glycopeptides are time-dependent. For drugs of other classes there is limited and conflicting information on their classification. Resistance selection may be reduced for concentration-dependent antimicrobials by achieving an AUC(0-24):MIC ratio of greater than 100 or a C(max):MIC ratio of greater than 8. The relationships between time greater than MIC and resistance selection for time-dependent antimicrobials have not been well characterized.
Evidence for the influence of trace elements on disease resistance in ruminants is reviewed with emphasis on susceptibility to infection in vivo during the more common deficiencies (copper, selenium and cobalt). Copper deficiency associated with increases in pasture molybdenum increased the susceptibility of lambs to microbial infections. Under experimental conditions, dietary molybdenum decreased the establishment of abomasal and intestinal nematodes but not their pathogenicity to lambs. Molybdenum may enhance inflammatory responses leading to parasite rejection by the host. Decreased incidence of metritis in selenium-treated dairy cows provides a rare example of an association between selenium deficiency and decreased disease resistance. Improved antibody responses following selenium administration have also been found in sheep. Cobalt deficiency has reduced lamb survival and increased susceptibility to parasitic infection transiently in cattle and lastingly in sheep. In copper-, selenium- or cobalt-deficient sheep and cattle, there are many reports of impaired leucocyte and lymphocyte responses to in vitro challenges, but their relevance to disease resistance in vivo is unproven. Disease resistance may have priority for limited micronutrient supplies, leaving other processes vulnerable.
The degradation of several protein substrates, including the blood proteins haemoglobin, albumin and fibrinogen, by proteinases present in extracts of adult Haemonchus contortus was examined over a broad pH range. These proteinases were further characterized on the basis of substrate specificity, inhibitor sensitivity and molecular size by spectrophotometric and substrate gel analysis. The majority of the proteinases capable of degrading the blood proteins tested were active at acidic pH and could be ascribed to the cysteine proteinase class. In addition, evidence is presented that these proteinases are differentially recognized and inhibited by immune sera and that parasites capable of withstanding protective host immune responses exhibit modified expression of proteinases.
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