Antimicrobial Selection, Administration and Dosage
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Continuing education — Voortgesette opleiding Antimicrobial selection, administration and dosage J Desmond Baggota following general mechanisms: ABSTRACT (i) Selective inhibition of bacterial cell Various types of information contribute to the selection of an antimicrobial agent. Initial wall synthesis (penicillins, cephalo- requirements are diagnosis of the site and nature of the infection, assessment of the severity sporins, bacitracin, vancomycin). of the infectious process and medical condition of the diseased animal; these are embodied Following attachment to receptors in clinical experience. Additional considerations include identification of the causative (penicillin-binding proteins), beta- pathogenic microorganism, knowledge of its susceptibility to antimicrobial agents (micro- lactam antibiotics inhibit transpepti- biological considerations) and of the pharmacokinetic properties of the drug of choice and dation enzymes and thereby block the alternative drugs, and their potential toxicity (pharmacological considerations) in the final stage of peptidoglycan synthesis. animal species. Select an antimicrobial drug and dosage form appropriate for use in the This action is followed by inactivation particular animal species. Usual dosage regimens may be applied, except in the presence of renal or hepatic impairment, when either modified dosage or a drug belonging to another of an inhibitor of autolytic enzymes in class should be used. The duration of therapy is determined by monitoring the response the bacterial cell wall. Bacitracin and both by clinical assessment and bacterial culture. A favourable clinical response is the vancomycin inhibit early stages of ultimate criterion of successful therapy. peptidoglycan synthesis. (ii) Inhibition of cell membrane function : animal therapy, antimicrobial selection, dosage. Key words by disrupting functional integrity of Baggot J D Antimicrobial selection, administration and dosage. Journal of the South African the bacterial (polymyxins) or fungal Veterinary Association (1998) 69(4): 174–185 (En.). Preclinical Veterinary Studies, University (antifungal azoles and polyenes) cyto- of Zimbabwe, PO Box MP 167, Mount Pleasant, Harare, Zimbabwe. plasmic membrane. Antifungal azoles (e.g. ketoconazole, miconazole, fluco- nazole) act by inhibiting the bio- INTRODUCTION class generally have the same mechanism synthesis of fungal membrane lipids, For the treatment of a bacterial infec- of action, a broadly similar spectrum of especially ergosterol. Polyenes (e.g. tion, the antimicrobial agent selected antimicrobial activity (Table 1) and amphotericin B, natamycin) require must have activity against the causative reasonably similar disposition (i.e. extent ergosterol as a receptor in the fungal pathogenic microorganism and must of distribution and elimination processes) cell membrane in order to exert their attain effective concentrations at the site (Table 2). Individual drugs within a class effect; this sterol is absent from the of infection. The ultimate criterion of differ quantitatively in antimicrobial bacterial cell membrane. Polyene anti- successful therapy is a favourable clinical activity and, when mainly eliminated by biotics and the synthetic antifungal response to the treatment. Such a response hepatic metabolism, in the rate of elimina- azoles act on fungi, whereas the depends on the interrelations between tion (usually expressed as half-life). polymyxins act on gram-negative the causative pathogenic microorganism Bioavailability, which refers to the rate bacteria. the antimicrobial drug selected and and extent of absorption, and the with- (iii)Inhibition of protein synthesis dosage used, and the animal receiving drawal period, vary with the dosage form through an action on certain subunits treatment. Inadequacy of host defense of a drug and may differ between animal of microbial ribosomes (aminoglyco- mechanisms, particularly in neonatal species. Selective tissue binding (e.g. sides, tetracyclines, chloramphenicol foals and in immuno-compromised aminoglycosides) is a cause for concern in and its derivatives, macrolides and animals, could contribute to a discrep- terms of the pathological lesion that may lincosamides). Each class of anti- ancy between the expected and actual be produced in the particular tissue and microbial agent attaches to a different response to antimicrobial therapy. In the persistence of drug residues (a long receptor site, apart from macrolides these animals, it is preferable to use withdrawal period is required). and lincosamides, which bind to the antimicrobial agents, alone or combined, same site on the 50S subunit of the that produce a bactericidal effect. MECHANISMS OF ACTION microbial ribosome. Antimicrobial action usually depends (iv)Inhibition of nucleic acid synthesis. ANTIMICROBIAL CLASSIFICATION on the inhibition of biochemical events Fluoroquinolones block the action of Antimicrobial agents are classified on that exist in or are essential to the bacterial DNA gyrase; rifampin binds strongly the basis of molecular structure, which pathogen but not the host animal. Unfor- to DNA-dependent RNA polymerase; determines their chemical nature and tunately, the action of antimicrobial metronidazole, following chemical related physico-chemical properties agents is not selective for pathogenic reduction of the nitro group of the (pKa/pH-dependent degree of ionisation, microorganisms and the balance between molecule within anaerobic bacteria or lipid solubility). The drugs within each the commensal flora can be seriously sensitive protozoal cells, produces a disturbed, particularly in the colon of bactericidal effect by reacting with horses (doxycycline, macrolides and various intracellular macromolecules. aPreclinical Veterinary Studies, University of Zimbabwe, lincosamides). (v) Inhibition of folic acid synthesis in PO Box MP 167, Mount Pleasant, Harare, Zimbabwe. The actions of antimicrobial agents can susceptible microorganisms and ulti- Received: March 1998. Accepted: October 1998. be adequately distinguished by the mately the synthesis of nucleic acids. 174 0038-2809 Jl S.Afr.vet.Ass. (1998) 69(4): 174–185 Table 1: Spectrum of antimicrobial activity (semi-quantitative). Antimicrobial class Usual effecta Gram-positive Gram-negative Anaerobic bacteria Other microorganisms Penicillinsb C Penicillin G +++ (+) +(+) – Aminobenzyl-penicillin ++ +(+) + – Carboxy-penicillin + +(+) + – Isoxazolyl-penicillin ++ – – – Cephalosporinsc C 1st generation ++ + + – 2nd generation + ++ ++(cefoxitin) – 3rd generation + ++(+) +(ceftizoxime) – Aminoglycosides C (+) +++ – (Mycoplasma spp.) Fluoroquinolones C +(+) +++ – Mycoplasma spp. Chlamydia spp. Trimethoprim/sulphonamide C+++++Chlamydia spp. Protozoa: Toxoplasma spp. Tetracyclines S+++++Mycoplasma spp. Chlamydia spp. Rickettsia spp. Protozoa: Theileria spp., Eperythrozoon spp., Anaplasma spp. Chloramphenicol S ++ +(+) ++ (Mycoplasma spp.) (Chlamydia spp.) Rickettsia spp. Macrolides S ++ (+) (+) Mycoplasma spp. (Tylosin) Lincosamides S ++ – ++(clindamycin) (Mycoplasma spp.) Rifampin C ++ –/(+) +(+) Chlamydia spp. Rickettsia spp. Metronidazole C – – +++ – Protozoa: Trichomonas foetus, Giardia lamblia, Histomonas meleagridis Sulphonamides S + (+) + Chlamydia spp. aC = bactericidal; S = bacteriostatic. bPenicillins Penicillin G: phenoxymethyl penicillin (penicillin V) – acid-stable. Aminobenzyl penicillins: ampicillin, amoxillin and pro-drugs. Carboxypenicillins: ticarcillin, carbenicillin – anti-pseudomonal (P. aeruginosa). Isoxazolyl penicillins: cloxacillin, oxacillin, nafcillin, methicillin – relatively resistant to staphylococcal beta-lactamase; acid-stable. cCephalosporins 1st generation: cefadroxil, cephalexin (both oral); cefazolin, cephalothin (both parenteral). 2nd generation: cefuroxime (oral); cefoxitin (IV). 3rd generation: cefixime (oral). Cefotaxime, ceftizoxime, cefoperazone, ceftriaxone, ceftazidime (all IV). By competing with para-aminobenzoic Knowledge of the mechanisms of action antimicrobial agent are clearly distin- acid (PABA) for the enzyme dihydropte- of antimicrobial agents is required for guishable and due to different mecha- roate synthetase, sulphonamides prevent understanding resistance acquired nisms, although lack of a favourable the incorporation of PABA into dihydro- through chromosomal mutation and clinical response (therapeutic failure) is folate, while trimethoprim, by selectively selection, and forms the basis of selecting the invariable outcome. inhibiting dihydrofolate reductase, antimicrobials for concurrent use, prevents the reduction of dihydrofolate either as combination preparations or Inherent resistance to tetrahydrofolate (folic acid). Animal separately. Inherent resistance largely limits the cells, unlike bacteria, utilise exogenous spectrum of activity of an antimicrobial sources of folic acid. Pyrimethamine ANTIMICROBIAL RESISTANCE agent, while acquired resistance invari- inhibits protozoal dihydrofolate reduc- There are many different mechanisms ably decreases the quantitative suscepti- tase, but is less selective for the microbial whereby microorganisms might exhibit bility of pathogenic microorganisms. enzyme and therefore more toxic than resistance to antimicrobial drugs. In order to reach receptors (penicil- trimethoprim to mammalian species. Inherent and acquired resistance to an lin-binding proteins), beta-lactam 0038-2809 Tydskr.S.Afr.vet.Ver. (1998) 69(4): 174–185 175 Table 2: Extent of distribution and processes of elimination of antimicrobial agents. Antimicrobial