Antimicrobial Selection, Administration and Dosage

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 agent Extent of distribution (comment) Elimination process(es)a

Beta-lactams Limited – low intracellular concentrations E (r), except nafcillin, cefoperazone and ceftriaxone, E(r+h) Aminoglycosides Limited – mainly ECF (selective binding to renal cortex; inner ear) E(r) Fluoroquinolones Wide (developing cartilage) M(h) + E(r+h) Trimethoprim Wide M(h) + E(r) Sulphonamides Moderate M(H) + E(r), except sulfisoxazole, E(r) + M(h) Tetracyclines Wide (sites of ossification; developing teeth) E(r+h), except doxycycline, E(f) Chloramphenicolb Wide M(h) + E(r) Metronidazoleb Wide M(h) + E(r) Erythromycinb Wide – high intracellular concentration M(h) + E(h) Clindamycin Wide M(h) + E(r) Rifampinc Wide – high intracellular concentration, including phagocytes M(h) + E(h+r) aE(r) = excretion (renal); M(h) = metabolism (hepatic); E(r+h) = excretion (renal and hepatic in bile); E(f) = excretion (in faeces). bInhibits hepatic microsomal enzymes. cInduces hepatic microsomal enzymes. antibiotics must penetrate the outer The inherent resistance of aerobic bacte- adenylation, acetylation or phosphory- layers of the bacterial cell envelope. ria to metronidazole may be attributed to lation. This type of resistance is usually Inherent resistance of many gram- the absence of an anaerobic environment plasmid-mediated. Plasmids code for the negative bacteria to penicillin G for activation (chemical reduction of the enzyme acetyltransferase that inactivates (benzylpenicillin) is due to low bacterial nitro group) of the drug to take place. chloramphenicol. Florfenicol, an ana- permeability, lack of penicillin-binding logue of thiamphenicol, is less susceptible proteins and/or a wide variety of Acquired resistance than chloramphenicol to inactivation by beta-lactamase enzymes. Gram-negative The potential for genetic exchange bacterial acetyltransferase. Defective bacteria have an outer phospholipid between bacteria, combined with their active transport of tetracyclines across membrane that may hinder passage of short generation time, can rapidly lead to the inner cytoplasmic membrane of beta-lactam antibiotics. Some (such as resistant bacterial populations. Acquired, microorganisms that have acquired resis- ampicillin and amoxicillin) pass through genetically based resistance may be due tance may be plasmid-mediated. Since pore molecules in this outer barrier more to chromosomal mutation (altered struc- the plasmid genes that code for tetracy- readily than penicillin G. Owing to their tural target or metabolic pathway essen- cline resistance are closely associated with higher capacity to penetrate cell mem- tial for antimicrobial action) or, more those for chloramphenicol and amino- branes, 3rd-generation cephalosporins importantly, the acquisition, by bacterial glycosides (especially streptomycin), (except cefoperazone) have activity conjugation, of resistance (R) plasmids16. multiple drug resistance may result. against an expanded range of gram- Resistance plasmids (transferable genetic Multiple drug-resistance plasmids, which negative aerobic bacteria and reach infec- material) may be present in bacteria commonly occur in Enterobacteriaceae tion sites in the central nervous system. as extrachromosomal circular DNA such as Salmonella, E. coli and Proteus, will Streptococci have a natural permeability molecules that replicate independently be maintained in a population by the use barrier to aminoglycosides. Their pene- of, but synchronously with, chromosomal of any antibiotic to which resistance is trative capacity can be enhanced by the DNA. Plasmid genes for antimicrobial encoded by the plasmid genes. simultaneous presence of a cell wall- resistance often control the formation of The spread of multiple drug resistance active drug, such as a penicillin. bacterial enzymes that are capable of has serious implications on account of its Most gram-negative aerobic bacteria, either inactivating antimicrobial agents persistence. Plasmid-mediated resistance with the notable exception of Brucella or decreasing bacterial membrane to lincosamides and macrolides is the spp., are relatively impermeable and permeability to antimicrobials11. result of methylation of the shared recep- therefore inherently resistant to rifampin; Plasmid-mediated resistance to penicil- tor site on the 50S subunit of the bacterial the site of action of rifampin is intra- lins and cephalosporins (beta-lactam ribosome. Plasmid-transferable resis- cellular. Microbial susceptibility to antibiotics) is due to the formation of tance has recently been reported for tetracyclines depends on the attainment beta-lactamase enzymes by S. aureus or fluoroquinolones13. of high intracellular drug concentrations. enteric gram-negative rods. Some Chromosomal mutants are commonly Individual tetracyclines differ in lipid beta-lactamases can be firmly bound by resistant by virtue of a change in a struc- solubility. A distinction must be made compounds such as clavulanic acid (com- tural receptor for an antimicrobial agent. between microorganisms that have low bined with amoxycillin or ticarcillin) and Resistance to beta-lactam antibiotics capacity for penetration by tetracyclines sulbactam (combined with ampicillin) (penicillins and cephalosporins) may be (inherently resistant) and those that and can thus be prevented from attacking attributed to the loss (or alteration) of acquire resistance through defective hydrolysable penicillins. Gram-positive penicillin-binding proteins. Chromo- active transport of these drugs across the bacteria, apart from staphylococci, gener- somal resistance to aminoglycosides inner cytoplasmic membrane. Since ally lack the ability to acquire R plasmids. (including amikacin) is associated with mycoplasmas are bounded by a triple- Gram-negative bacteria that are resis- the deletion (or alteration) of a specific layered ‘unit membrane’ and lack a rigid tant to aminoglycosides produce receptor (protein) on the 30S ribosomal cell wall, these microorganisms are inher- enzymes that inactivate drugs in subunit. Resistance to fluoroquinolones ently resistant to beta-lactam antibiotics. this class, apart from amikacin, by (especially in coagulase-positive staphy-

176 0038-2809 Jl S.Afr.vet.Ass. (1998) 69(4): 174–185 Table 3: Empirical antimicrobial drug selection based on knowledge of pathogenic microorganism.

Microorganism Drug of choice Alternatives

Gram-positive aerobic bacteria Streptococcus spp. Penicillin G 1st-generation cephalosporin: trimethoprim/sulphonamide Staphylococcus, non-penicillinase-producing Penicillin G 1st-generation cephalosporin Staphylococcus, penicillinase-producing Isoxazolyl penicillins 1st-generation cephalosporin; fluoroquinolone; amoxycillin/clavulanate Staphylococcus, methicillin-resistant Fluoroquinolone Trimethoprim/sulphonamide Bacillus spp. Penicillin G Erythromycin Erysipelothrix rhusiopathiae Penicillin G Erythromycin Corynebacterium spp. Penicillin G Erythromycin Listeria monocytogenes Aminobenzyl-penicillin Chloramphenicol; trimethoprim/sulphonamide Nocardia spp. Trimethoprim/sulphonamide Minocycline (± sulphonamide) Mycobacterium tuberculosis Rifampin + isoniazid Streptomycin Gram-negative aerobic bacteria Coliforms (E. coli, Klebsiella spp., Proteus spp., enterobacter spp.) Gentamicin (or amikacin) Fluoroquinolone; 3rd-generation cephalosporin Salmonella spp. Trimethoprim/sulphonamide Fluoroquinolone; aminobenzyl-penicillin Pasteurella multocida Aminobenzyl-penicillin Aminoglycoside; fluoroquinolone Actinobacillus spp. Trimethoprim/sulphonamide Fluoroquinolone; amoxycillin/clavulanate; tetracycline Leptospira spp. Aminobenzyl-penicillin Erythromycin; streptomycin Helicobacter spp. Erythromycin Fluoroquinolone Bordetella bronchiseptica Tetracycline Trimethoprim/sulphonamide; chloramphenicol; gentamicin Pseudomonas aeruginosa Gentamicin ± ticarcillin (or carbenicillin) Ciprofloxacin; 3rd-generation cephalosporin Moraxella bovis Oxytetracycline Cephalothin; chloramphenicol; aminoglycoside Anaerobic bacteria Clostridium spp. Penicillin G 1st-generation cephalosporin; (clindamycin) Actinomyces spp. Penicillin G Erythromycin; trimethoprim/sulphonamide Fusobacterium spp Metronidazole Penicillin G; clindamycin; 1st-generation cephalosporin Bacterioides spp. (other than B. fragilis) Metronidazole Penicillin G; clindamycin; cefoxitin Bacterioides fragilis Metronidazole or clindamycin Chloramphenicol; ampicillin/sulbactam; cefoxitin Other microorganisms Mycoplasma spp. Tylosin or tiamulin Fluoroquinolone; tetracycline Chlamydia spp. Tetracycline Trimethoprim/sulphonamide Rickettsia spp. Tetracycline Chloramphenicol

lococci and Pseudomonas spp.) may be due use of antimicrobials does not induce tetracyclines have the same basic to mutation of the target enzyme, DNA resistance but rather provides an intense structure, cross-resistance between gyrase. The rapid development of high- selection pressure that, by destroying tetracyclines is to be expected. Although level resistance to rifampin, associated the susceptible bacteria in the host lincosamides and macrolides are with its use as the sole antimicrobial animal, allows the resistant bacteria to structurally unrelated, they share the agent, results from chromosomal muta- proliferate9. The gravity of this adverse same receptor-binding site, have the tion of bacterial RNA polymerase. In situation lies in the fact that, once devel- same mechanism of plasmid-mediated sulphonamide-resistant mutants the oped, multi-resistant organisms can resistance, and cross-resistance between affinity of dihydropteroate synthetase for persist in the individual or exposed drugs in these 2 classes is common. p-aminobenzoic acid may exceed that for animal population and in the environ- Because of its unique action (inhibition of sulphonamide, which is a reversal of the ment. The control of antimicrobial resis- RNA polymerase), cross-resistance situation in sulphonamide-sensitive tance, in so far as is possible, depends on between rifampin and other anti- microorganisms. At least some the judicious selection and appropriate microbial agents does not occur. sulphonamide-resistant bacteria can, like use of antimicrobial agents. mammalian cells, utilise preformed folic APPROACH TO THERAPY acid for nucleic acid synthesis. Cross-resistance Having diagnosed the presence of a Microorganisms that are resistant to a bacterial infection, appropriate speci- Significance of transferable drug certain antimicrobial agent may also be mens should be properly collected to resistance resistant to other antimicrobials with the identify the causative pathogenic micro- Acquired resistance to several antibiot- same mechanism of action or share the organism(s) and, when considered ics is of particular concern in Enterobac- same receptor-binding site. Cross- necessary, to determine its susceptibility. teriaceae and is increasingly found in resistance mainly applies to antimicrobial Perform immediate examination of the non-enteric gram-negative bacterial agents that are closely related structur- specimen, including (whenever feasible) pathogens, as well as in the commensal ally, i.e. are within the same class (e.g. a Gram-stained direct smear. The value of flora. A causal relationship has been aminoglycosides, fluoroquinolones, immediate examination of clinical shown between the use of antimicrobials lincosamides, sulphonamides, chloram- specimens in the initial selection of and the development of resistance. The phenicol and its derivatives). Since all an antimicrobial agent cannot be

0038-2809 Tydskr.S.Afr.vet.Ver. (1998) 69(4): 174–185 177 Table 4: Suggested guideline for the interpretation of MIC (µg/m ) of various antimicrobial agents based on bacterial isolates of equine origin, apart from fluoroquinolones which relate to isolates of canine origin.

Antimicrobial agent Susceptible Moderately susceptible Resistant

Penicillin G ≤0.125 0.25–16 >16 Ampicillin ≤1 2–16 >16 Amoxycillin ≤1 2–16 >16 Gentamicin ≤2 4–8 >8 Amikacin ≤4 8–16 >16 Fluoroquinolonesa ≤1 2–4 >4 Erythromycin ≤0.5 1–4 >4 Tetracycline ≤1 2–4 >4 Chloramphenicol ≤4 8–16 >16 Trimethoprim/sulfamethoxazole ≤0.5/10 1/20–2.5/50 >3/75

aQuantitative susceptibility of bacterial pathogens varies between individual fluoroquinolones, e.g. the minimum inhibitory concentration of ennofloxacin for the majority of susceptible E. coli strains isolated from calves is 0.25 µg/m .

Table 5: Usual dosage for antimicrobial preparations used in dogs and cats.

Drug preparation Route of administration Dosing rate Dose (mg/kg) Interval (h)

Penicillin G, sodium IV,IM,SC 20 000–40 000 IU/kg 4–6 Penicillin G, procaine IM, SC 25 000 IU/kg 24 Penicillin V, calcium PO 10–20 8 Ampicillin sodium IV, IM, SC 10–20 8 Ampicillin PO 25 8 Hetacillin or pivampicillin PO 20–30 8 Amoxycillin trihydrate PO 12.5–25 8–12 Amoxycillin trihydrate/clavulanate, potassium PO 12.5–25 8–12 Cloxacillin sodium PO 25–35 8 Cefadroxil PO 20–30 8–12 Cephalexin monohydrate PO 20–30 8–12 Cefazolin sodium IV 10–20 8 Gentamicin sulphate IM/SC 3–5 8–12 (dogs) (12–24 cats) Amikacin sulphate IM/SC 6–10 8–12 Enrofloxacin PO 5–10 12 Marbofloxacin PO 2–4 24 Trimethoprim/sulphadiazine PO 5/25 12 Trimethoprim/sulphamethoxazole PO 5/25 12 Tetracycline hydrochloride PO 20 8 Oxytetracycline hydrochloride PO 20 12 Oxytetracycline dihydrate PO 40 12 Doxycycline hydrochloride PO 5 12 Chloramphenicol PO 25 8 (dogs) 12 (cats) Chloramphenicol palmitate PO 25 8 (dogs) Metronidazole PO 10–20 8–12 Erythromycin PO 10–20 8–12 Erythromycin estolate PO 10–20 8–12 Clindamycin hydrochloride PO 5–10 8–12 Sulfisoxazole PO 50 8 Sulfasalazine PO 25 8 (dogs) Ketoconazole PO 5–10 12–24 Griseofulvin (micronised) PO 25–50 12–24

overemphasised. Initial (empirical) treatment drug for initial therapy is largely based on Blood culture is a valuable, although not Since there will be some delay in obtain- clinical experience, the nature (and site) invariably certain, technique for making a ing laboratory results, antimicrobial of the infectious disease process and microbiological diagnosis of septicaemia therapy should be initiated on an epidemiological pattern in the herd or in neonatal foals. informed empirical basis. The choice of geographical region, but should be

178 0038-2809 Jl S.Afr.vet.Ass. (1998) 69(4): 174–185 supported by the findings of specimen should be understood that the method 90 % of isolates tested, compared over examination. A suggested choice of drug relates antimicrobial drug concentrations different time periods (e.g. on an annual for initial therapy, based on knowledge achieved in the serum of human beings basis), would reveal the pattern of resis- (although tentative at this stage) of the given usual dosages to the susceptibility tance to a drug. pathogenic microorganism, is presented pattern of populations of fast-growing in Table 3. While the drug of choice pre- aerobic bacteria15. The MIC of an organ- Maintenance therapy sented in this table is generally applicable, ism can be extrapolated from inhibitory The choice of drug for maintenance selection of the antimicrobial agent must zone diameters, and these MIC values therapy rests with the clinician and is be related to the site of the infection, the have been used to define breakpoints to based on the severity, site and nature of animal species and the readily available describe bacteria as susceptible or resis- the infection, knowledge of the suscepti- dosage forms. tant. The disk-diffusion method provides bility of the causative pathogenic micro- Provide supportive measures that a qualitative or, at best, semi-quantitative organism and the pharmacokinetic would complement antimicrobial effec- indication of susceptibility, since some properties of the drug in the animal tiveness and assist recovery of the animal antimicrobials become concentrated species, and on clinical experience. from the infection. In neonatal animals, while others penetrate poorly into certain Consideration must be given to the toxic care must be taken to avoid a too-rapid body fluids and tissues; furthermore, the potential of the antimicrobial agent of rate of intravenous fluid administration. disposition of many antimicrobial agents choice, the dosage forms that would Fever may serve a useful purpose in infec- differs between human beings and be suitable for administration to the tious diseases and the change in body animal species. Owing to the aforemen- individual animal, the ease of repeated temperature may be used to assess the tioned limitations of the disk-diffusion administration (which often determines progress of the infection. In the presence method, it is necessary to determine owner compliance), and the overall cost of an infectious disease, the only indica- quantitative susceptibility, using the of the likely course of therapy. Due tion for an antipyretic drug, e.g. aspirin or broth dilution method (which measures account should be taken of the value, paracetamol (acetaminophen) in dogs but MIC), of pathogenic microorganisms of according to the owner, of the animal in not in cats, or dipyrone or sodium salicy- frequently unpredictable susceptibility. making the final choice of antimicrobial late administered intravenously to They include coagulase-positive staphy- agent and the dosage form. horses, is to decrease body temperature to lococci (S. aureus and S. intermedius) and Apply the usual dosage regimen for the below a dangerous level, 41 °C (105.8 °F). enteric microorganisms (E. coli, Klebsiella, drug preparation (dosage form) selected, Concurrent therapy with a non-steroidal, Proteus and Salmonella spp.). The determi- or apply a dosage regimen tailored to the anti-inflammatory drug and an amino- nation of quantitative susceptibility could individual animal and based on the glycoside antibiotic increases the risk of be considered essential for bacteria that quantitative susceptibility (MIC) of the nephrotoxicity. If the infection is sus- have developed multiple drug resistance. causative pathogenic microorganism. pected to be contagious, isolate the Quantitative susceptibility varies The latter approach to dosage (specific diseased and in-contact animals. between bacterial genera and species, as therapy) assumes greater importance in When an appreciable quantity of pus or well as between strains of a particular the treatment of severe systemic infec- a foreign body is present, the appropriate species. Moreover, individual drugs tions (such as septicaemia). surgical intervention is indicated. within a class differ quantitatively in Advise the owner regarding supportive antimicrobial activity. Tetracyclines measures that should be provided and, in Bacterial culture and susceptibility might constitute an exception, in that the case of food-producing animals, the testing differences in clinical efficacy between specified withdrawal period for the drug After the pathogenic microorganism tetracyclines are largely attributable to preparation selected. The withdrawal has been isolated by bacterial culture features of bioavailability, distribution period for a drug may vary with the (performed under various incubation and excretion. Suggested interpretative preparation (dosage form) as well as conditions) and identified, the decision guidelines for MIC breakpoint values are between food-producing animal species. can be made as to whether susceptibility presented (Table 4). The choice of It is stated on the label (and package testing (particularly the determination antimicrobial agent for systemic therapy insert) of authorised drug preparations. of minimum inhibitory concentration, is almost invariably limited to drugs to MIC) is necessary. The susceptibility of which the bacterial pathogen is suscepti- DRUG ADMINISTRATION AND certain commonly isolated bacteria is ble. For treatment of canine urinary tract DOSAGE generally predictable. For example, infections, the range of antimicrobial The route of administration of an beta-haemolytic Streptococci isolated agents can be extended to include antimicrobial drug depends on the site from horses are susceptible to penicillin drugs to which the bacterial pathogen is and severity of the infection as well as on G, as are anaerobes, except Bacterioides moderately susceptible provided urinary the animal species, but is often governed spp. In mixed infections and abscesses, concentrations exceeding 4 times the MIC by the dosage forms that are available. It is the presence of anaerobic bacteria should could be maintained during therapy. because bacterial susceptibility (MIC) always be considered. The fostering of a Knowledge of the susceptibility of a can be determined in vitro and drug close working relationship with the clini- pathogenic microorganism is most useful disposition processes are quantifiable (in cal microbiology laboratory is important for selecting the antimicrobial agent of pharmacokinetic terms) that dosing rates with regard to the relevance of the tech- choice and can be applied in tailoring for antimicrobial drugs can be calculated. niques performed to the clinical situation dosage of the drug for an individual However, various formulations may and the interpretation of the laboratory animal but, even though in vitro suscepti- differ significantly from a standard results. bility (particularly MIC) generally corre- (reference) formulation in bioavailability Concerning susceptibility testing, the lates well with clinical efficacy, it cannot of the drug substance (active moiety). disk (agar)-diffusion method is satisfac- be relied upon to predict response to Only drug preparations that are bio- tory only when a microorganism is either therapy. Accumulated data on MIC90, equivalent in the target species would be very susceptible or very resistant. It which is the MIC breakpoint value for expected to have similar clinical efficacy.

0038-2809 Tydskr.S.Afr.vet.Ver. (1998) 69(4): 174–185 179 Table 6: Influence of food on the oral bioavailability of antimicrobial agents in tion from the former injection site could dogs and cats. be attributed to wider spread of the parenteral preparation (aqueous suspen- Antimicrobial class/preparation Effect on oral bioavailabilitya sion or non-aqueous solution) providing greater access to a larger absorptive surface area and possibly to higher blood Most penicillins, apart from ↓ flow to tissues in this region. At least a amoxycillin and – ampicillin pro-drugs – portion of the volume injected is more Cephalosporins ↓ likely to be deposited between muscles Fluoroquinolones – (intermuscular), which would facilitate Trimethoprim/sulphonamide ↓ spread of the preparation along fascial Most tetracycline, apart from ↓ planes, in the neck than in the buttock. doxycycline ↑ Even though the usual dosage interval for Chloramphenicol – oxytetracycline dihydrate (a long-acting Chloramphenicol palmitate ↑ (cats) parenteral formulation) is 48 h, the intra- Metronidazole ↑ (dogs) muscular injection of 2 doses (20 mg/kg, Erythromycin base ↓ 72 h apart) can be recommended for the Erythromycin stearate ↓ treatment of infectious bovine kerato- ↑ Erythromycin estolate conjunctivitis, caused by Moraxella bovis6. ↑ Erythromycin ethylsuccinate Antimicrobial agents are administered to Erythromycin enteric-coated formulations – pigs either in the feed or drinking water, Clarithromycin – or by intramuscular injection, provided Nitrofurantoin ↑ (dogs) Ketoconazole ↑ injection site damage is not produced Griseofulvin (micronised) ↑ (Table 8). Parenteral preparations should be formulated in a manner such that their aOral bioavailability of an antimicrobial agent may vary with formulation of the oral dosage form. intramuscular injection does not cause tissue damage with persistence of drug residues at the injection site. Ante- Selected features of the plasma concen- tetracyclines, erythromycin base or mortem methods for evaluating the tration-time profiles are used for stearate). The oral bioavailability of some extent of tissue irritation and rate of bioequivalence assessment of formula- antimicrobial agents (e.g. amoxycillin, resolution at the injection site include the tions of an antimicrobial agent12. fluoroquinolones) is indifferent to the use of ultrasonography2 and determina- Oral administration is used, particularly time of feeding relative to dosing. tion of the kinetics of plasma creatine in dogs and cats, in the treatment of mild Many of the antimicrobial agents that kinase (CK) activity1,19. and moderate infections or when a pro- are given orally to dogs are administered The systemic availability of antimicro- longed duration of therapy is anticipated by intramuscular injection, depending on bial agents administered orally (pastes) or (Table 5). The oral bioavailability of many the availability of parenteral prepara- by nasogastric tube (aqueous suspen- antimicrobial agents is affected by the tions, to ruminant animals (Table 7). The sions) to horses is significantly decreased temporal relationship between feeding systemic availability (extent of absorp- by feeding before dosing. Food should be and dosing (Table 6). Depending on this tion) of an antimicrobial agent from a withheld for up to 2 h after drug adminis- relationship, food should either be given parenteral formulation injected intra- tration. Metronidazole, which is most 1 h before dosing (e.g. with doxycycline, muscularly is generally higher when the useful for the treatment of anaerobic erythromycin estolate, ketoconazole) or site of injection is the lateral neck com- infections (e.g. pleuropneumonia, liver be withheld for up to 2 h after dosing (e.g. pared with the buttock (M. semiten- abscesses, peritonitis), is an exception in with most penicillins, cephalosporins, dineus)14,17. Better antimicrobial absorp- that the drug is well absorbed from the

Table 7: Usual dosage regimens for antimicrobial preparations used in cattle, sheep and goats.

Drug preparation Route of administration Dosing rate Dose (mg/kg) Interval (h)

Penicillin G, sodium IV, IM 25 000 IU/kg 6–8 Penicillin G, procaine IM 25 000 IU/kg 24 Ampicillin sodium IV, IM 10–20 8 Ampicillin/sulbactam IM 10 8–12 Amoxycillin trihydrate IM 10 12 Trimethoprim/sulphonamide IM 4/20 12 Enrofloxacin IM 2.5–5 12 Oxytetracycline hydrochloride IV, IM 10 12 Oxytetracycline dihydrate (long-acting) IM 20 48 Erythromycin lactobionate IV, IM 5 8–12 Lincomycin hydrochloride IM 10 12 Tylosin IM 20 12 Sulphamethazine (10 % oral solution) PO 50 12

180 0038-2809 Jl S.Afr.vet.Ass. (1998) 69(4): 174–185 Fig. 1: Mean plasma penicillin concentration time curves after 20 000 IU procaine penicillin G/kg was administered to five animals (4 horses, 1 pony) at five different sites (after Firth et al. 19865).

Table 8: Usual dosage regimens for antimicrobial preparations used in pigs.

Drug preparation Route of administration Dose Interval Feed Water (mg/kg) (h) (g/US ton) (mg/ )

Ampicillin sodium IM 10–20 8 – – Penicillin G, procaine IM 20 000 – 40 000 IU/kg 24 – – Amoxycillin trihydrate/clavulanate potassium PO 10–15 12 – – Streptomycin sulphate IM 10 8 – – Kanamycin sulphate IM 10 8 – – Gentamicin sulphate IM 2–4 8 – 12.5 Apramycin sulphate PO 10–20 12 150 100 Neomycin sulphate PO 10 8 140 100 Enrofloxacin IM 2.5–5.0 12 – – Trimethoprim/sulphonamide IM 4/20 12 – – Sulphamethazine (10 % oral solution) PO 50 12 – 80–120 Oxytetracycline hydrochloride IM 10 12 200–800 – Oxytetracycline dihydrate (long-acting) IM 20 48 – – Lincomycin hydrochloride IM 10 12 100–200 30 Tylosin IM 20–30 12 100 80 Tiamulin IM 10–15 24 200 60 Virginiamycin – – – 100 – Bacitracin – – – 250 – Monensina – – – 100 – aNB: concurrent use of monensin and tiamulin must be avoided, otherwise toxicity will very likely occur. gastrointestinal tract (systemic availabil- occupies a unique position in the treat- administration to horses but care must be ity, 60–90 %) of fasted and fed horses. The ment of equine bacterial infections. This taken to avoid inadvertent intravenous addition of an antimicrobial agent to the long-acting parenteral dosage form administration. The intramuscular injec- feed (as a powder) is an unreliable (aqueous suspension) of penicillin G pro- tion of procaine penicillin G in the neck method of dosing horses. Usual dosage vides effective plasma concentrations of region (M. serratus ventralis cervicis) regimens for antimicrobial preparations the antibiotic for at least 12 h, owing to produces a higher peak plasma concen- that may be used in horses are presented slow absorption from the intramuscular tration and higher systemic availability of in Table 9. Parenteral (IV or IM) therapy injection site, and has high activity penicillin G than injection of the with conventional (immediate-release) against commonly isolated equine bacte- long-acting product at other locations5 dosage forms is required in the treatment rial pathogens. It is the only long-acting (Fig. 1). The prime site for intramuscular of severe infections. Procaine penicillin G antimicrobial preparation suitable for injection in the neck of the horse appears

0038-2809 Tydskr.S.Afr.vet.Ver. (1998) 69(4): 174–185 181 Table 9: Usual dosage regimens for antimicrobial preparations used in horses.

Drug preparation Route of administration Dosing rate Dose (mg/kg) Interval (h)

Penicillin G, sodium IV, IM 15 000 – 30 000 IU/kg 6 Penicillin G, procaine IM 25 000 IU/kg 12 Ampicillin sodium IV, IM 10–20 8 Ticarcillin sodium/clavulanate potassium IV (slowly) 50 8 Cefadroxil PO 25 8 Cephalexin monohydrate PO 25 8 Cefazolin sodium IV 10–20 8 Gentamicin sulphate IM 2–4 8–12 Amikacin sulphate IM 4–8 8–12 Trimethoprim/sulphadiazine PO 5/25 12 Chloramphenicol palmitate PO 50 8 Chloramphenicol sodium succinate IV, IM 25 6 Metronidazole PO 20 12 Oxytetracycline hydrochloride IV (slowly) 3 12 Rifampin PO 5 12 Erythromycin estolate PO 20–25 8(foals) Ketoconazole PO 10 12–24

Table 10: Suggested dosage regimens for antimicrobial preparations that may be used in reptilesa.

Drug preparation Species Route of administration Dosing rate Dose (mg/kg) Interval (h)

Ampicillin sodium Tortoise IM 50 12 Carbenicillin Snakes IM 400 24 Tortoise IM 400 48 Gentamicin sulphate Alligator IM 1.75 72–96 Snakes IM 2.5 72 Tortoise IM 2.5 48 Amikacin sulphate Alligator IM 2.5 96 Snakes IM 5.0 72 Tortoise IM 5.0 48 Enrofloxacin Hermann’s tortoise IM 10.0 24 Gopher tortoise IM 5.0 24 Ciprofloxacin Snakes PO 2.5 48–72 Trimethoprim/sulphadiazine All species IM 5/25 First 2 doses 24 h apart: thereafter 48 Tylosin All species IM 10 24 Ketoconazole Tortoise PO 15–30 24

aSource: Jacobson (1993: adated from Table 29.4)10. to be at the level of the 5th cervical verte- intramuscular injection should be the at 10 °C; 33 h at 24 °C), cattle (2.5 h), horse bra, ventral to the funicular part of the anterior half of the body; most reptilian (3.6 h), dog (5.6 h) and human being ligamentum nuchae but dorsal to the species have a well-developed renal (9.9 h). Oxytetracycline is slowly elimi- brachiocephalic muscle3. The location of portal system. This also applies to birds. nated by glomerular filtration because the the intramuscular injection site does not Fish, in common with reptiles, are drug undergoes enterohepatic circula- affect the bioavailability (refers to rate and poikilothermic (cold-blooded) animals tion. The half-life of oxytetracycline is extent of absorption) of gentamicin and ambient temperature may have a 89.5 h in rainbow trout (Salmo gairdneri) (50 mg/ml solution), nor does gentamicin pronounced influence on the rate of drug at 12 °C and 80.3 h in African catfish bioavailability differ following intramus- elimination, particularly when bio- (Clarias gariepinus)at25°C8, compared cular or subcutaneous injection7,20. transformation is the principal process of with half-lives in the range 3.4–9.6 h in Owing to the slow elimination (long elimination. The half-life of trimetho- domestic animals. In fish and reptiles, the half-life) of antimicrobial agents in prim, administered intravenously as elimination of antimicrobial agents reptiles, dosage intervals are substantially trimethoprim/sulphadiazine combina- increases with increase in ambient longer in reptilian compared with tion, differs widely between carp temperature. When developing drug mammalian species10 (Table 10). In order (Cyprinus carpio L) and mammalian products for use in farmed fish (food- to avoid significantly decreased systemic species: carp (40.7 h at 10 °C; 20 h at 24 °C), producing animals), studies of the availability of drugs that are eliminated cattle (1.25 h), horse (3.2 h), dog (4.6 h) and relationship between pharmacokinetics by renal excretion (e.g. beta-lactam and human being (10.6 h). Sulphadiazine of the drugs and ambient (water) temper- aminoglycoside antibiotics), the site of half-life similarly differs widely: carp (47 h ature should be performed.

182 0038-2809 Jl S.Afr.vet.Ass. (1998) 69(4): 174–185 Table 11: Activity of concurrently used antimicrobial drugs.

Antimicrobial agents Activity

Combination preparations Trimethoprim/sulphonamide Synergistic: bactericidal against susceptible microorganisms Ampicillin/sulbactam Enhanced (broader) activity of the penicillin Amoxyllin/clavulanate Enhanced (broader) activity of the penicillin Ticarcillin/clavulanate Enhanced (broader) activity of the penicillin Administered separately Ampicillin (or amoxycillin) – gentamicin May be synergistic, depending on the microorganism Ticarcillin (or carbenicillin) – gentamicin Synergistic against some strains of: Pseudomonas, Proteus, Enterobacter, Klebsiella spp. Erythromycin – rifampin Synergistic; Rhodococcus equi Isoniazid – rifampin Prevents emergence of resistant strains Mycobacterium tuberculosis Doxycycline – rifampin Brucella melitensis (human beings) Minocycline – rifampin (or streptomycin) Brucella canis (dogs) Oxytetracycline – rifampin (or streptomycin) Brucella abortus (horses) Clindamycin (or metronidazolea) – gentamicin Additive; mixed gram-negative + anaerobic infections Lincomycin – spectinomycin Additive; bacterial respiratory infections in cattle aUse metronidazole in horses.

ANTIMICROBIAL COMBINATIONS drug to prevent the rapid emergence of inhibitory concentrations following The mechanisms of action as well as the strains resistant to rifampin. In mixed exposure of susceptible bacteria to drug susceptibility of microorganisms underlie infections with anaerobic involvement, concentrations above the minimum the type of interaction that may occur the concurrent use of clindamycin (or, in inhibitory concentration (MIC). (generally additive, but may be synergis- horses, metronidazole) and gentamicin is Aminoglycosides inhibit ribosomal tic or antagonistic) when antimicrobial the treatment of choice. protein synthesis in susceptible bacteria agents of different classes are used con- Unless specifically indicated, which by inducing misreading of the genetic currently (either as combination prepara- implies synergistic action and/or the code on the messenger RNA template tions or administered separately). prevention of acquired resistance, or (30S ribosomal subunit). Fluoroquino- Useful combination preparations there is circumstantial evidence to sup- lones block nucleic acid synthesis in include trimethoprim/sulphonamide port the clinical effectiveness of anti- susceptible bacteria by selectively inhibit- that, through synergistic action, produces microbial combinations, the concurrent ing DNA gyrase, an intracellular enzyme. a bactericidal effect (at least in vitro), use of antimicrobial drugs should be Both classes of antimicrobial agent amoxycillin/clavulanate and ticarcillin/ avoided. When 2 antimicrobial agents are produce a concentration-dependent clavulanate (Table 11). The concurrent used concurrently, not as a combination bactericidal effect. use of ampicillin (or amoxycillin) and preparation, they must be administered The clinical effectiveness of amino- gentamicin is likely to provide synergistic independently at usual dosing rates. glycosides and fluoroquinolones is action at least against streptococci (have a influenced both by the height of the peak natural permeability barrier to amino- RELATIONSHIP BETWEEN PLASMA plasma concentration relative to the glycosides), while ticarcillin (or carbeni- CONCENTRATION AND CLINICAL minimum inhibitory concentration cillin) and gentamicin used concurrently EFFECTIVENESS (Cmax:MIC ratio) and the area under the act synergistically against some strains of Penicillins and cephalosporins act by plasma concentration-time curve that is Pseudomonas, Proteus, Enterobacter and causing selective inhibition of bacterial above the MIC during the dosage interval Klebsiella spp. (i.e. gram-negative rods). cell wall synthesis; they interfere with the (AUIC = AUC/MIC). The former is rela- Note that penicillins and gentamicin final stage of peptidoglycan synthesis. tively more important for fluoroquino- should not be mixed in vitro, since activity Beta-lactam antibiotics produce a lones; maximum activity is achieved of the aminoglycoside would be time-dependent bactericidal effect on when peak plasma concentration is in the decreased (owing to chemical interac- susceptible bacteria. The overall effective- range 5–10 times the MIC. The clinical tion). The concurrent use of a bacterio- ness of therapy with penicillins (and effectiveness of the aminoglycosides is static drug and a bactericidal drug, cephalosporins) is largely influenced by mainly determined by the area under the especially a beta-lactam antibiotic, the aggregate time, though not necessar- inhibitory plasma concentration-time generally results in antagonism. ily continuous, during which effective curve (AUIC). The area under the inhibi- Chloramphenicol and a fluoroquinolone plasma concentrations (> MIC for patho- tory concentration curve indicates the are antagonistic. However, erythromycin genic microorganism) are maintained; degree of exposure of a microorganism to and rifampin act synergistically against peak height determines the rate of the drug. Aminoglycosides and fluoro- Rhodococcus equi, while tetracycline and penicillin penetration into the site of quinolones induce a post-antibiotic rifampin (or streptomycin) used concur- infection. The clinical effectiveness of sub-MIC effect on some species of rently provide enhanced clinical efficacy discontinuous dosage regimens for gram-negative aerobic bacteria. On against Brucella spp. in human beings, penicillins could be attributed to the account of its variable duration, generally horses and dogs. While rifampin is post-antibiotic sub-MIC effect they exert from 1–6 h, the post-antibiotic effect is not particularly useful against macrophage- on gram-positive bacteria. The post- taken into account when calculating associated (intracellular) susceptible antibiotic sub-MIC effect (PASME) refers dosage regimens. For the treatment of microorganisms, it should always be used to a temporally limited suppression of systemic bacterial infections caused by concurrently with another antimicrobial bacterial growth that occurs at sub- susceptible microorganisms, the usual

0038-2809 Tydskr.S.Afr.vet.Ver. (1998) 69(4): 174–185 183 dosage intervals are 8–12 h for amino- therapy is largely governed by the should be based on monitoring the glycosides, injected IM or SC, and 12 h for responsiveness of host defense mecha- response both by clinical assessment of fluoroquinolones (with the exception of nisms. This applies particularly to drugs the animal and bacterial culture of marbofloxacin, 24 h), administered orally, that produce a bacteriostatic effect. The properly collected specimens. By in dogs. Some authors contend, from both concentration attained by an anti- adopting the approach outlined in this a safety and clinical efficacy standpoint, microbial agent at the site of infection paper, the success of antimicrobial that the dosage interval for amino- may be influenced by disease-induced therapy will likely be increased and the glycosides could be 24 h18,21. Since amino- changes in the disposition of the drug as indiscriminate use of antimicrobial agents glycosides are potentially ototoxic and well as by local changes associated with will be reduced. Moreover, the animal nephrotoxic and can accumulate, due to tissue inflammation or abscess formation. owner will become increasingly aware of their prolonged terminal elimination, the Disease states that may alter the disposi- the fact that there is far more to monitoring of trough serum/plasma tion of drugs include fever, dehydration, antimicrobial therapy than the adminis- concentrations (Cmin), which should not hypoalbuminaemia (associated with tration of an empirically selected be allowed to exceed 2 µg/m , is important chronic liver disease) and uraemia antimicrobial preparation and will particularly in the presence of renal (chronic renal failure). The bactericidal ultimately appreciate the longterm bene- impairment. activity of aminoglycosides and fluoro- fits and cost-effectiveness of the scientific It is highly desirable for bactericidal quinolones (apart from difloxacin) approach. drugs (e.g. beta-lactam antibiotics, against gram-negative aerobic bacteria is aminoglycosides, fluoroquinolones) and greater in an alkaline than in an acidic REFERENCES 1. Aktas M, Lefebvre H P,Toutain P L, Braun J essential for bacteriostatic drugs (e.g. environment. In the presence of impaired P 1995 Disposition of creatine kinase tetracyclines, chloramphenicol and its renal function, which may be detected by activity in dog plasma following intrave- derivatives, macrolides and lincosa- urinalysis (proteinuria and the presence nous and intramuscular injection of skeletal mides) to maintain plasma concentra- of casts), dosage regimens for amino- muscle homogenates. Journal of Veterinary tions above the minimum effective glycosides should be adjusted (preferably Pharmacology and Therapeutics 18: 1–6 2. Banting A L, Baggot J D 1996 Comparison of concentrations for the duration of by increasing the dosage interval in the pharmacokinetics and local tolerance of therapy. The terms bactericidal and accordance with the decrease in glomeru- three injectable oxytetracycline formula- bacteriostatic are relative, not absolute. lar filtration rate) in order to avoid drug tions in pigs. Journal of Veterinary Pharmacol- accumulation with attendant toxic effects ogy and Therapeutics 19: 50–55 (acute tubular necrosis and cochlear 3. Boyd J S 1987 Selection of sites for intramus- DURATION OF THERAPY cular injections in the neck of the horse. The Antimicrobial therapy must be main- damage in dogs or vestibular damage in Veterinary Record 121: 197–200 tained for an adequate duration, which is cats). An indication of the extent of a 4. Finco D R, Brown S A, Vaden S L, Ferguson based on monitoring the response both decrease in the glomerular filtration rate D C 1995 Relationship between plasma by clinical assessment (resolution of fever, (GFR) may be obtained by measuring creatinine concentration and glomerular leukocytosis and other signs of inflamma- endogenous creatinine clearance. In dogs filtration rate in dogs. Journal of Veterinary Pharmacology and Therapeutics 18: 418–421 tion) and bacterial culture. Definitive with decreased renal function (GFR < 5. Firth E C, NouwsJFM,Driessens F, diagnosis at an early stage of infection 3m/min/kg; in normal dogs, GFR = 4.07 Schmaetz P,Peperkamp K, Klein W R 1986 and the application of specific therapy, ± 0.52 m /min/kg), the reciprocal of serum Effect of the injection site on the pharmaco- based on knowledge of the causative creatinine concentration provides a clini- kinetics of procaine penicillin G in horses. American Journal of Veterinary Research 47: pathogenic microorganism and its cally useful estimation of the glomerular 2380–2384 4 susceptibility, will decrease the overall filtration rate that could serve as a guide 6. George L W, Smith J A 1985 Treatment of duration of treatment and minimise for dosage interval adjustment of amino- Moraxella bovis infections in calves using a residual sequelae. Therapy with an glycoside antibiotics. The monitoring of long acting oxytetracycline formulation. aminoglycoside should not be extended trough serum/plasma concentrations of Journal of Veterinary Pharmacology and Therapeutics 8: 55–61 beyond the duration required to treat the an aminoglycoside is highly desirable in 7. Gilman J M, Davis L E, Neff-Davis C A, infection. The speed of clinical response is animals with severe infections or renal Koritz G D, Baker G J 1987 Plasma concen- generally inversely related to the length impairment and is essential in animals tration of gentamicin after intramuscular or of time the infection was present before with changing renal function. subcutaneous administration to horses. initiating therapy. After an infectious disease has been Journal of Veterinary Pharmacology and Thera- peutics 10: 101–103 There are certain infections that, owing diagnosed in an animal, the decision has 8. Grondel J L, Nouws J F M, Schutte A R, to the relative inaccessibility of the caus- to be made as to whether an antimicrobial Driessens F 1989 Comparative pharmaco- ative microorganisms to antimicrobial agent should be administered. When the kinetics of oxytetracycline in rainbow trout agents, invariably require a prolonged answer is positive, and following proper (Salmo gairdneri) and African catfish (Clarias duration (3–5 weeks, rather than 5–8 collection of appropriate specimens, the gariepinus). Journal of Veterinary Pharmacol- ogy and Therapeutics 12: 157–162 days) of therapy. They include prostatitis, treatment should be promptly initiated 9. Hinton M 1986 The ecology of Escherichia osteomyelitis and skin infections in dogs, with an antimicrobial selected on an coli in animals including man with particu- and Rhodococcus equi pneumonia in foals informed empirical basis. The microbio- lar reference to drug resistance. The Veteri- (6–16 weeks of age). In the treatment of logical and clinical chemistry results from nary Record 119: 420–426 these infections, preference should be the samples submitted for analysis, in 10. Jacobson E R 1993 Antimicrobial drug use in reptiles. In Prescott J F, Baggot J D (eds) given to the use of orally-effective conjunction with the response of the Antimicrobial therapy in veterinary medicine antimicrobial agents. animal to the initial treatment, provide (2nd edn). Iowa State University Press, the requisite information for selecting the Ames, Iowa: 542–552 VARIABLES THAT INFLUENCE antimicrobial agent to use for the continu- 11. Jacoby G A, Archer G L 1991 New mecha- ation of treatment. The usual dosage nisms of bacterial resistance to antimicro- CLINICAL RESPONSE bial agents. New England Journal of Medicine Even when the antimicrobial drug of regimen for the particular antimicrobial 324: 601–612 choice is administered at the recom- preparation selected can generally be 12. Martinez M N, Berson M R 1998 Bio- mended dosing rate, the outcome of applied, while the duration of treatment availability/bioequivalence assessments. In

184 0038-2809 Jl S.Afr.vet.Ass. (1998) 69(4): 174–185 Hardee G E, Baggot J D (eds) Development Iowa State University Press, Ames, Iowa non-invasive and quantitative method and formulation of veterinary dosage forms 17. RutgersLJE,VanMiertASJPAM,Nouws for the study of tissue injury caused by (2nd edn). Marcel Dekker, New York: J F M, Van GinnekenCAM1980 Effect of intramuscular injection of drugs in horses. 429–467 the injection site on the bioavailability of Journal of Veterinary Pharmacology and Thera- 13. Martinez-Martinez L, Pascual A, Jacoby G A amoxycillin trihydrate in dairy cows. Jour- peutics 18: 226–235 1998 Quinolone resistance from a transfer- nal of Veterinary Pharmacology and Therapeu- 20. Wilson R C, Duran S H, Horton C R, Wright able plasmid. Lancet 351: 797–799 tics 3: 125–132 L C 1989 Bioavailability of gentamicin in 14. NouwsJFM,Vree T B 1983 Effect of 18. Swan G E, Guthrie A J, Mulders M S G, dogs after intramuscular or subcutaneous injection site on the bioavailability of an Killeen V M, Nurton J P,Short, C R, Vanden injections. American Journal of Veterinary oxytetracycline formulation in ruminant Berg J S 1995 Single and multiple dose Research 50: 1748–1750 calves. The Veterinary Quarterly 5: 165–170 pharmacokinetics of gentamicin adminis- 21. Zhanel G G 1993 Once daily aminoglyco- 15. Prescott J F, Baggot J D 1985 Antimicrobial tered intravenously and intramuscularly in side dosing: the result of research on susceptibility testing and antimicrobial adult conditioned Thoroughbred mares. antimicrobial pharmacodynamics. Ameri- drug dosage. Journal of the American Veteri- Journal of the South African Veterinary Associa- can Journal of Pharmaceutical Education 56: nary Medical Association 187: 363–368 tion 66: 151–156 156–167 16. Prescott J F, Baggot J D 1993 Antimicrobial 19. Toutain P L, Lassourd V,Costes G, Alvinerie therapy in veterinary medicine (2nd edn). M, Bret L, Lefebvre H P, Braun J P 1995 A

Note added in proof Foals treated with erythromycin and rifampin for Rhodococcus equi infection (pneumonia) could serve as a potential reservoir of Clostridium difficile and excrete the microorganism, resistant to both antimicrobial agents, in the faeces. It would appear that erythromycin is the offending drug; it may promote the growth of C. difficile in the intestine of the foal, and a variable fraction of the oral dose, seemingly irrespective of the dosage form, is excreted in the faeces (Baverud et al. 1998 Clostridium difficile associated with acute colitis in mares when their foals are treated with erythromycin and rifampin for Rhodococcus equi pneumonia. Equine Veterinary Journal 30: 482–488). Coprophagic behaviour of mares housed with erythromycin-treated foals would lead to ingestion of the resistant microorganism and the antibiotic, which could severely disrupt the commensal flora of the large intestine, resulting in acute colitis in the mares. The available evidence suggests that this scenario is nosocomial infection.

Obituary

Henri Pieter Albert de Boom — 16 October 1914 – 30 August 1998

Just after midnight on Sunday morning, 30 August, 1st-year student at Onderstepoort, where he qualified veterinary science’s best-loved and respected teacher in 1936. Until then his career literally ran parallel to that passed on. He is survived by his children Marcella, of another well-known colleague, Prof. Mike de Lange. Carin and Jannie and 8 grandchildren. He lost his wife, Sarie, in 1991. During the last years he fought valiantly against deafness and increasing blindness due to a retinal injury sustained in a serious motor accident during the 1980s. From January 1937 until his retirement in 1974, 37 years later, Boompie was attached to Onderstepoort, initially as a research officer, later as a temporary lecturer in the Department of Anatomy, Faculty of Veterinary Science, until lecturing posts were changed from part-time to full-time. In October 1955 he succeeded Prof. Cecil Jackson as professor and head of the Department of Anatomy. His very earliest memory, he said, was an unforgetta- ble day when, as a toddler, he sat on the steps in front of his parents' home in Pretoria. His mother brought him something to drink and, as he turned towards her, he tumbled head over heels down the steps. He recalled that it was like a vivid slow-motion movie as he stood on his head and observed how fascinating the upside- down world appeared. This conscious sense of wonder about everything remained with him throughout his life. Born in Pretoria, he started and completed his schooling at ‘Oosteindschool’. He was head boy when he matriculated in 1931. The next year, he enrolled as a

Continued on p. 186

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