Rational Selection of Antimicrobials for Use in Horses

Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS

W. David Wilson, BVMS, MRCVS, MS

1. Introduction following discussion emphasizes important aspects Antibiotics frequently play an important central or of antimicrobial use in horses, including the bacte- adjunctive role in the therapeutic management of rial species likely to be involved in particular disease horses and foals with a variety of illnesses, including syndromes, susceptibility profiles of bacterial iso- those requiring critical care, because diseases lates, and the antimicrobial spectrum, mode of ac- caused by primary or secondary bacterial infection tion, indications, dose, and adverse effects of are commonly encountered and may contribute to selected commonly used antibiotics. Knowledge re- failure of single or multiple organs. However, it garding adverse effects is particularly important be- should be understood that supportive therapy usu- cause the relative sparsity of antimicrobials ally plays a role at least as important as antimicro- approved for parenteral and oral use in horses fre- bials in promoting a positive outcome, and that the quently makes extra-label use necessary. Conse- adverse effects of antimicrobial drugs individually quently, much of the responsibility for adverse or in combination may actually lead to negative events rests with the prescribing clinician. consequences. Antibiotic use should be based on 2. Basic Principles of Antimicrobial Therapy sound rational principles involving thorough patient evaluation, good clinical judgment, overall medical The following principles should serve as a guide for knowledge, information regarding the individual pa- antimicrobial use in horses, but not all can be fol- 1-4 tient and the infecting agent(s), selection of an ap- lowed in the critical care patient. In particular, propriate drug, and formulation of a dosage regimen the identity and susceptibility of the etiologic agent appropriate to the patient and its caretaker after is rarely known when therapy is initiated, extra- assessment of the potential benefits and risks of that label drug use is frequently necessary, and combi- therapy.1 nation therapy with more than one antibiotic is The ultimate aim of antibiotic treatment is to often indicated in critical care patients. inflict an insult on infecting bacteria sufficient to kill the organism or render it susceptible to inactivation ● An infectious agent must be involved in the by natural host defenses or the local microenviron- disease process for antimicrobial therapy to be ment without adversely affecting the patient.1 The effective.

NOTES

AAEP PROCEEDINGS ր Vol. 47 ր 2001 75

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS ● Antimicrobial therapy is necessary to rid the c. Antibiotics approved for IM use: procaine host of the disease penicillin G, benzathine penicillin G, ceftio- ● The identity of the infecting organism is known fur (Naxcel), ampicillin or at least reasonably suspected d. Antibiotics approved for oral use: trimetho- a. Cytologic examination and culture of appro- prim/sulfadiazine (Tribrissen, Uniprim) priate samples e. Antibiotics approved for intrauterine use: ● The organism(s) is (are) susceptible to the amikacin, gentamicin, ticarcillin drug(s) selected as determined by ● Adverse reactions should be recognized, inves- a. MIC—quantitative susceptibility test (pre- tigated and reported to the manufacturer of ferred because this information is helpful for the drug and, in the US, to the FDA/Center selecting dose) for Veterinary Medicine (1-888-332-8387 or 1- b. Kirby Bauer—qualitative susceptibility test 888-FDA-VETS; www.fda.gov/cvm/), or to the ● Host defense mechanisms must contribute to Veterinary Practitioners’ Reporting Network the patient’s recovery (USPPRN) of the US Pharmacopeia (1-800-487- ● Therapeutic concentrations of the drug will be 7776 or 1-800-4-USPPRN; www.usp.org/). achieved at the site of infection and the microenvironment at this site will support activity of In critical care situations, there is insufficient the drug time to wait for results of culture and susceptibility ● Appropriate dose, dosage interval, administra- testing of samples before initiating antimicrobial tion route, and duration of therapy are used as therapy. The appropriate approach is therefore to dictated by a. Pharmacokinetic, pharmacodynamic, and ● Collect and submit appropriate samples toxic properties of the drug ● Begin treatment based on knowledge of bacte- b. Resolution of disease process as determined ria most likely to be involved in certain syn- by clinical status of the patient and labora- dromes/clinical presentations and their most tory monitoring likely susceptibility patterns ● Concurrent use of more than one antimicrobial ● Adjust therapy (antimicrobial, dose, route, fre- drug is appropriate in limited situations quency) based on initial response, physiologic a. Life threatening conditions (insufficient time status, adverse effects, or results of initial cul- to wait for culture and susceptibility results) ture and susceptibility tests b. Mixed infections—more than one drug is needed to provide appropriate antimicrobial 3. Bacteria Associated with Disease Syndromes 5 spectrum in Horses c. Need for synergistic activity The major pathogens of horses vary by body system, ● Causes of therapeutic failure should be investi- age, use, geographic location, and the type of facility gated on which the horses reside. In referral centers, a. The disease process did not have a bacterial nosocomial infection with resistant bacteria in- etiology cluding Salmonella sp, other enteric species, and b. Ineffective concentrations of antimicrobial at Staphylococcus sp influence the situation and the site of infection antibiotic-associated colitis involving Clostridium c. Infection in an inaccessible location or one sp or Salmonella sp is an ever-present concern. In with a poor blood supply general, the following are the most commonly en- d. Microenvironment at the site of infection is countered pathogens of horses: ␤-hemolytic Strep- not conducive to antimicrobial activity tococcus sp, Actinobacillus sp, Pasteurella sp, e. Pathogens were or have become resistant to Escherichia coli, Klebsiella pneumoniae, Enter- the chosen antimicrobial obacter sp, Pseudomonas aeruginosa, Bordetella f. Changes in the microbial environment at the bronchiseptica, Staphylococcus sp, non-hemolytic site of infection Streptococcus sp, Rhodococcus equi (in foals), and g. Continued contamination of the infection anaerobic bacteria, particularly Bacteroides sp and site Clostridium sp. h. Infection is no longer contributing to the clinical signs 4. Empirical Selection of Antimicrobials Based on ● Need for extra-label drug use (drug, dose, route, Bacterial Species and Likely Susceptibility Pattern duration) should be considered and reconsid- Antimicrobial susceptibility profiles for Gram-pos- ered itive and Gram-negative aerobic bacteria isolated a. Few antimicrobial drugs are licensed for par- from horses during 1998 at the Veterinary Medi- enteral administration to horses; therefore cal Teaching Hospital, University of California, extra-label use is often necessary Davis, are shown in Tables 1 and 2. Susceptibil- b. Antimicrobials approved for IV use in ity patterns of bacteria such as ␤-hemolytic Strep- horses: ampicillin, sulfadimethoxine, tri- tococcus sp, Actinobacillus sp, Pasteurella sp and methoprim/sulfadiazine 48% suspension anaerobes, with the exception of Bacteroides sp,

76 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted

Table 1. Susceptibility of Gram-Positive Bacteria Isolated from Horses at the University of California, Davis during 1998 to Antimicrobial Agents in the Percent Susceptible to Antimicrobial IVIS Organism (Number tested) PENG AMP OX AMXCLA CEPH CEFTIO CEFOX ERYTH RIF TET TMS GENT AMIK CHLOR ANTIMICROBIALS ENRO OF USE AND SELECTION IN CONCEPTS CURRENT DEPTH: IN

MIC breakpoint (␮g/ml) 8 8 2 8 8 2 8 0.5 1 4 2 4 16 8 0.5 website for Staphylococcus sp 0.003 4 for Streptococcus sp 0.25 0.25 2 4

Staphylococcus aureus (33) 30 67 88 91 69 36 76 94 36 55 48 94 97 94 with Proceedings Coag. negative Staph (31) 13 77 100 97 77 74 61 97 81 74 74 100 94 96 Strep. zooepidemicus (14) 100 100 100 100 100 100 100 71 100 7 0 100 the

Rhodococcus equi (8) 39 100 100 63 88 25 100 100 87 63 permission Enterococcus faecalis (10) 100 100 40 90 90 Enterococcus faecium (10) 90 90 10 70 80 of a

the Data compiled by Fitchorn J, Jang S, Hirsh D and reprinted with permission. ϭ ϭ ϭ ϭ ϭ ϭ ϭ PENG Penicillin G; AMP Ampicillin; OX Oxacillin; AMXCLA Amoxicillin/clavulanic acid; TICLA Ticarcillin/clavulanic acid; CEPH Cephalothin; CEFTIO Ceftiofur; of

Annual CEFOX ϭ Ceftizoxime; ERYTH ϭ Erythromycin; RIF ϭ Rifampin; TET ϭ Tetracycline; TMS ϭ Trimethoprim/sulfonamide; GENT ϭ Gentamicin; AMIK ϭ Amikacin; CHLOR ϭ AAEP Chloramphenicol; ENRO ϭ Enroﬂoxacin. Convention

Table 2. Susceptibility of Gram-Negative Bacteria Isolated from Horses at the University of California, Davis of during 1998 to Antimicrobial Agentsa the Percent Susceptible to Antimicrobial AAEP Organism (Number tested) PENG AMP AMXCLA TICLA CEPH CEFTIO CEFOX ERYTH TET TMS GENT AMIK CHLOR ENRO APPROCEEDINGS AAEP

2001 MIC Breakpoint (␮g/ml) 4 8 8 16 8 2 8 0.5 4 2 4 16 8 0.5/.25 E. coli (74) 68 93 94 73 94 97 71 60 86 100 91 100 Klebsiella pneumoniae (15) 14 79 87 66 100 100 54 67 67 100 80 100 Close Serratia marcescens (4) 0 0 0 75 100 50 0 0 0 0 100 Actinobacillus suis-like (26) 100 89 100 100 100 100 30 96 96 100 100 100

Actinobacillus equuli (7) 100 100 100 100 100 100 28 86 86 100 100 100 window Actinobacillus ligniersii (2) 100 100 100 100 100 100 0 100 100 100 100 100 Pasteurella sp (6) 100 100 100 100 83 83 33 100 100 100 100 100 83 ր o.47 Vol.

Salmonella sp (18) 30 100 67 100 100 100 73 34 49 100 36 100 to

Salmonella agona (13) 0 100 54 100 100 100 92 15 54 100 0 100 return S. typhimurium (11) 82 100 91 100 100 100 82 82 82 100 82 100 ր a 0177 2001

Data compiled by Fitchorn J, Jang S, Hirsh D and reprinted with permission. to ϭ ϭ ϭ ϭ ϭ ϭ ϭ

PENG Penicillin G; AMP Ampicillin; OX Oxacillin; AMXCLA Amoxicillin/clavulanic acid; TICLA Ticarcillin/clavulanic acid; CEPH Cephalothin; CEFTIO Ceftiofur; IVIS CEFOX ϭ Ceftizoxime; ERYTH ϭ Erythromycin; RIF ϭ Rifampin; TET ϭ Tetracycline; TMS ϭ Trimethoprim/sulfonamide; GENT ϭ Gentamicin; AMIK ϭ Amikacin; CHLOR ϭ Chloramphenicol; ENRO ϭ Enrofloxacin. Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS are somewhat predictable and do not show Salmonella sp great variation between different geographic First choices: amikacin or ceftiofur (or other locations. In contrast, Enterobacteriaceae, Pseudo- third-generation cephalosporins) monas sp, Bordetella sp, coagulase-positive Staphy- Second choices: cefazolin, enrofloxacin lococcus sp, alpha-hemolytic Streptococcus sp, and Alternate choices: gentamicin, tetracycline, Bacteroides fragilis have either unpredictable sus- ampicillin, ticarcillin/clavulanic acid, chlor- ceptibility or are predictably resistant to particular amphenicol, TMS antibiotics or classes of antibiotics.3 It is thus par- Bordetella bronchiseptica ticularly important to perform susceptibility tests on First choice: TMS these isolates. While it is acknowledged that there Alternate choices: gentamicin, tetracycline may be substantial variation in susceptibility pat- Klebsiella pneumoniae terns of bacteria between different geographical lo- First choice: amikacin cations, and organisms isolated from patients in Second choices: ceftiofur, enrofloxacin, ticar- hospitals or on farms where antibiotics are used cillin/clavulanic acid frequently are likely to show more resistance than Alternate choices: gentamicin, chlorampheni- bacteria isolated from horses on premises on which col, TMS antimicrobial use is not prevalent, Tables 1 and 2 Pseudomonas aeruginosa should provide a reasonable guide to the expected First choice: amikacin susceptibility patterns of the equine pathogens. Alternate choices: ticarcillin/clavulanic acid, gentamicin, imipenem Bacteroides sp (other than B. fragilis) are showing 5. Suggested Choices of Antimicrobials Based ␤ on Susceptibility of Bacterial Isolates increased evidence for -lactamase production First choice: metronidazole Second choice: chloramphenicol ␤-hemolytic Streptococcus sp Alternate choices: Penicillin G or Tetracycline First choice: penicillin G or Ceftiofur Second choices: ampicillin, ceftiofur, cefazolin Bacteroides fragilis (most isolates produce Alternate choices: trimethoprim/sulfonamide ␤-lactamase) (TMS), erythromycin, rifampin, chloramphenicol First choice: metronidazole Coagulase-positive Staphylococcus sp Alternate choices: chloramphenicol, tetracycline First choices: cefazolin, rifampin, amikacin, Clostridium sp, Fusobacterium sp, Peptostrepto- enrofloxacin coccus sp (Gram-positive anaerobes) Alternate choices: oxacillin, chloramphenicol, First choices: penicillin G, metronidazole ceftiofur, erythromycin Alternate choices: chloramphenicol, tetracy- Coagulase-negative Staphylococcus sp cline, ceftiofur First choices: cefazolin, rifampin, amikacin Alternate choices: chloramphenicol, enro- 6. Selection of Antimicrobials for Initiating Treatment floxacin, ceftiofur, gentamicin, tetracycline, Based on the Most Likely Etiologic Agent and oxacillin Probability of Susceptibility to Antimicrobial Agents Enterococcus sp First choice: ampicillin Neonatal Septicemia Alternate choices: chloramphenicol, tetracycline A high proportion of septicemic foals are infected Rhodococcus equi with Gram-negative bacteria, including E. coli in First choice: erythromycin ϩ rifampin about 50%, Actinobacillus suis-like sp, Klebsiella Alternate choices: erythromycin or arithromy- pneumoniae, Actinobacillus equuli, Enterobacter sp, cin alone or gentamicin ϩ rifampin Citrobacter sp, and Salmonella sp.6 As many as Corynebacterium pseudotuberculosis 50% of septicemic foals have polymicrobic infection First choice: penicillin G with more than one Gram-negative species or with a Alternate choices: TMS, erythromycin, rifam- Gram-negative bacterium along with a Gram-posi- pin, ceftiofur tive species, usually Streptococcus zooepidemicus, 6 Actinobacillus sp/Pasteurella sp Enterococcus sp, or Staphylococcus sp. Anaerobic First choices: TMS, gentamicin, ampicillin, bacteria are rarely involved in neonatal septicemia, ceftiofur except secondary to enterocolitis caused by Clostrid- Alternate choices: penicillin G, tetracycline, ium perfringens. chloramphenicol Escherichia coli Suggested Antimicrobial Protocols First choice: amikacin Treatment protocols for neonatal septicemia must Alternate choices: ceftiofur, gentamicin, en- include antimicrobials with a high level of activity rofloxacin, chloramphenicol, ticarcillin/clavu- against Gram-negative enteric bacteria. Use of lanic acid bactericidal agents that do not require extensive

78 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS hepatic metabolism is preferred, as is the parenteral Consequently, antimicrobials used in treatment route of administration. regimens should provide a broad spectrum of activity. Treatment regimens should also take into ac- First choice: amikacin ϩ ampicillin count the fact that anaerobic bacteria are involved Alternate choices: amikacin ϩ penicillin G; ami- in approximately 50% of cases and the most im- kacin ϩ cefazolin; gentamicin ϩ ampicillin, portant anaerobe, Bacteroides fragilis has a high penicillin G, or cefazolin; ceftiofur or other likelihood of resistance to penicillins and cephalo- third-generation cephalosporin; ticarcillin/cla- sporins, including ceftiofur.9 Mycoplasma sp is the vulanic acid; imipenem (for resistant infec- etiologic agent in sporadic cases, in which case use tions); TMS may be appropriate for continued of oxytetracycline, enrofloxacin, erythromycin, or oral therapy of infections caused by susceptible azithromycin may be necessary.10 organisms. Suggested Antimicrobial Protocols Pneumonia Pneumonia in neonatal foals frequently occurs in First choice: penicillin G or ampicillin ϩ genta- association with septicemia; therefore, the predom- micin Ϯ metronidazole inant bacterial isolates and antimicrobials recom- Alternate choices: penicillin or ampicillin ϩ ami- mended for use are the same as those listed above kacin Ϯ metronidazole; ceftiofur Ϯ metronidazole for neonatal septicemia. Polymicrobic infection is Special circumstances or continued therapy: Chlor- common, as it is in older foals in which the most amphenicol; TMS; Oxytetracycline; Enrofloxacin frequent bacterial isolate is S. zooepidemicus, followed closely by Gram-negative non-enteric bacteria Peritonitis (Actinobacillus suis-like sp and Pasteurella sp). Since abdominal surgery and enteric disease are E. coli, Klebsiella pneumoniae, other enteric bacte- frequently predisposing factors in the development ria, Pseudomonas aeruginosa, and Staphylococcus of peritonitis, Gram-negative enteric bacteria (espe- sp are less commonly involved. Rhodococcus equi cially E. coli and Klebsiella pneumoniae) are found is frequently the most common etiologic agent on in almost 50% of cases. Obligate anaerobic bacte- farms on which infection is endemic. ria are also commonly isolated from the peritoneal cavity.5 Actinobacillus sp can cause peritonitis Suggested Antimicrobial Protocols without other apparent predisposing factors, and Except in instances in which R. equi is the suspected ␤-hemolytic Streptococcus sp and Corynebacterium pathogen, the following guidelines for choice of an- pseudotuberculosis may be involved, particularly timicrobials to initiate treatment apply: when diffuse peritonitis occurs in association with an internal abdominal abscess. Clostridium per- First choice: penicillin G, ceftiofur, TMS fringens may induce peritonitis in foals in associa- Alternate choices: penicillin G, ampicillin ϩ gen- tion with necrotizing enterocolitis. tamicin Suggested Antimicrobial Protocols When R. equi is the suspected or confirmed pathogen: First choice: penicillin or ampicillin ϩ gentamicin First choice: erythromycin or azithromycin ϩ Alternate choices: ceftiofur; penicillin or ampi- rifampin cillin ϩ amikacin Alternate choices: rifampin ϩ gentamicin; erythromycin alone; azithromycin Internal Abdominal Abscess Because resolution of peritonitis frequently involves The distribution of bacterial species isolated from encapsulation and development of adhesions to wall adult horses with pneumonia is similar to that de- off infection, any of the infectious agents listed for scribed for older foals, except that R. equi is rarely peritonitis may cause internal abdominal abscesses. involved and anaerobic bacteria are much more com- However, S. zooepidemicus and S. equi are the most monly isolated from pneumonic adult horses than common causes of internal abscesses in most geo- from pneumonic foals (see Pleuropneumonia). graphic locations, except in western states where C. pseudotuberculosis is endemic, in which case the Acute Pleuropneumonia latter organism is involved at least as often as ␤-he- Polymicrobic infection is common in horses with molytic Streptococcus sp.11,12 pleuropneumonia and frequently involves combinations of Gram-positive aerobes (S. zooepidemicus), Suggested Antimicrobial Protocols Gram-negative aerobes (Actinobacillus suis-like sp Except where there is a history of abdominal sur- Pasteurella sp E. coli, or Klebsiella pneumoniae) gery or recent enteric disease, antibiotics active and anaerobes (Bacteroides fragilis, Bacteroides sp, against Gram-positive aerobic bacteria should be Fusobacterium sp, or Peptostreptococcus sp).7,8 selected to initiate treatment of internal abscess.

AAEP PROCEEDINGS ր Vol. 47 ր 2001 79

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS First choice: penicillin G or ampicillin ϩ In all cases of septic arthritis or synovitis, la- rifampin vage with or without arthroscopic debridement is Alternate choices: penicillin G alone; ceftiofur; important to remove inflammatory debris from the penicillin G ϩ gentamicin; rifampin ϩ TMS; synovial cavity. Thereafter, instillation of appro- penicillin G ϩ TMS priate antimicrobials, usually amikacin, gentamicin, or a third-generation cephalosporin, is Rifampin is recommended because of its high level indicated.14 More effective inactivation of bacte- of activity against causal Gram-positive organisms, ria in synovial cavities and bone may be accom- excellent ability to penetrate and remain active plished using the technique of regional limb within the environment present in abscesses, and perfusion.15,16 This technique involves application oral route of administration. Because of the poor of a tourniquet proximal to the involved structure, lipid solubility of penicillin and ampicillin, they pen- followed by intravenous or intraosseus injection of etrate abscesses poorly unless a high serum to tissue the appropriate antimicrobial to create local concen- concentration gradient is achieved by IV administrations of an antimicrobial that are much higher tration of high doses to initiate treatment. than can be achieved through conventional parenteral or oral dosing. Alternate approaches, partic- Septic Arthritis ularly in horses with septic osteomyelitis or physitis Septic arthritis, physitis, and polysynovitis in neo- lesions that have been debrided surgically, include natal foals most often occurs in association with or local instillation of antibiotic-impregnated sponges as a sequel to septicemia; therefore, the bacterial or polymethyl methacrolate beads that release the species involved and recommended antimicrobials antimicrobial into the local environment.17,18 are the same as those listed for septicemia. Strep- tococcus zooepidemicus is more commonly isolated Osteomyelitis and Orthopedic Infection from older foals than from foals less than 3 weeks of Selection of antimicrobials for treatment of osteomy- age and may be the sole etiologic agent in these elitis secondary to trauma or surgical intervention cases. Rhodococcus equi should be considered in follows the same principles as outlined above for cases of septic arthritis, synovitis, or osteomyelitis septic arthritis in adult horses because the distribu- in foals aged 1 to 8 months on farms with endemic R. tion and species of bacteria isolated are similar in equi infection, particularly when the individual foal the two conditions. Enterobacteriaceae, Strepto- has also shown signs of R. equi pneumonia. When coccus sp, and Staphylococcus sp each account for 20 R. equi is the suspected or confirmed pathogen, to 25% of bacterial isolates.19 treatment with erythromycin or azithromycin ϩ rifampin is indicated. Urinary Tract Infection Septic arthritis or synovitis in adult horses most Infection of the urinary tract most often manifests often occurs secondary to trauma, intrasynovial in- as cystitis and generally occurs secondary to infec- jection, or surgical intervention.13 The mechanism tion that ascends via the urethra. Consequently, by which infection was introduced influences the Gram-negative enteric bacteria, particularly E. coli, distribution of bacterial species isolated. Staphylo- are involved in more than 50% of cases and Pseudo- coccus sp account for more than 50% of the isolates monas aeruginosa is isolated from approximately from synovial structures infected by injection or sur- 10%. Gram-positive bacteria, predominantly ␤-he- gery, whereas Gram-negative enteric bacteria and molytic Streptococcus sp and Staphylococcus sp, can anaerobes predominate in synovial structures in- be isolated from approximately 20% of cases, often fected via a wound.13 Pseudomonas sp, ␤-hemo- in association with Gram-negative organisms. lytic Streptococcus sp, non-hemolytic Streptococcus sp, and Actinobacillus sp are also commonly isolated Suggested Antimicrobial Protocols from infected synovial structures. Polymicrobic in- A high proportion of the administered dose of most fection is common in joints that become infected via ␤-lactam and aminoglycoside antibiotics and TMS is a wound.13 eliminated in the active form in urine. Therefore, concentrations of these antibiotics in urine are gen- Suggested Antimicrobial Protocols erally much higher than those achieved in serum, The high likelihood of involvement of penicillinase- allowing them to kill bacteria that would otherwise producing Staphylococcus sp and Enterobacteriaceae be considered resistant by virtue of a minimal inhib- should be considered when initiating treatment of itor concentration (MIC) higher than the standard septic arthritis or septic tenosynovitis in adult breakpoint for susceptibility. This concept, termed horses. conditional susceptibility, can be exploited in the treatment of infections of the urinary tract. First choice: cefazolin or cephalothin ϩ amikacin First choice: gentamicin ϩ penicillin G or Alternate choices: cefazolin or cephalothin ϩ ampicillin gentamicin; oxacillin ϩ gentamicin or amikacin; Alternate choices: TMS; gentamicin alone; rifampin ϩ amikacin; enrofloxacin ceftiofur

80 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS Cellulitis Suggested Antimicrobial Protocols Cellulitis involving the limbs may be clinically in- distinguishable from acute lymphangitis because First choices: ceftiofur both conditions result in marked swelling, heat, Alternate choices: penicillin or ampicillin ϩ gen- pain, and lameness. It is frequently not possible to tamicin; TMS, penicillin, ampicillin ϩ amika- isolate bacteria from such cases because a successful cin; cephalothin or cefazolin therapeutic outcome relies upon aggressive antimicrobial therapy early in the disease course before Acute Colitis in Adult Horses development of abscesses or skin sloughs that In many instances, the etiology of acute colitis is not provide material for culture. Coagulase-positive determined. Clostridium difficile, and to a lesser Staphylococcus sp are most often involved, espe- extent C. perfringens, should be considered the cially in racehorses,20 while ␤-hemolytic Streptococ- likely cause of colitis in horses that have a history cus sp, coagulase-negative Staphylococcus sp, Gram- of antimicrobial administration, particularly if negative aerobic bacteria, and anaerobic bacteria the resulting diarrhea has a foul “spoiled fish” are involved less often. In areas of the western US odor.22,23 Salmonella sp also cause diarrhea in where C. pseudotuberculosis infection is endemic, stressed horses, particularly those that have under- this organism is an important cause of external ab- gone surgery or have experienced another stressful scesses and limb cellulitis, as well as sporadic cases illness and have been treated with antimicrobials, of ulcerative lymphangitis.11 Anaerobic bacteria, but can also cause outbreaks of diarrhea in other- particularly Clostridium perfringens and C. septi- wise healthy horses.24 Ehrlichia risticii should be cum, are important causes of cellulitis when it oc- suspected when signs of colitis occur in horses, par- curs in association with myositis secondary to ticularly pastured horses, residing in endemic areas contaminated intramuscular injections or deep during the summer and fall. puncture wounds involving muscle. Suggested Antimicrobial Protocols Suggested Antimicrobial Protocols In general, administration of antimicrobials should Treatment protocols for limb cellulitis should take be discontinued in horses that develop diarrhea dur- into account the high likelihood that penicillinase- ing a course of antimicrobial therapy. Antimicro- producing Staphylococcus sp are involved and the bial treatment is generally not indicated for the fact that the condition can progress rapidly and lead treatment of undifferentiated colitis, except in to serious complications including laminitis, skin horses with profound neutropenia, persistent high slough and death. fever, or other evidence of severe compromise to the integrity of the bowel wall. In these instances, the First choice: cephalothin or cefazolin ϩ antibiotic of choice is gentamicin (6.6 mg/kg SID) amikacin administered IV for a short (3 to 5 day) course, Alternate choices: enrofloxacin; penicillin or am- provided renal function is adequate and fluid deficits picillin ϩ amikacin; cephalothin or cefazolin are addressed by IV fluid therapy. When C. diffi- (preferably with gentamicin); oxacillin ϩ ami- cile or C. perfringens are the suspected or confirmed kacin or gentamicin; rifampin ϩ gentamicin etiologic agents, oral administration of metronidazole (15 mg/kg PO TID) is the treatment of choice. Treatment protocols for cellulitis in association Whereas a high proportion of C. difficile isolates are with septic myositis secondary to IM injections susceptible to metronidazole in most geographic ar- should include antimicrobials with activity against eas, a substantial number of those isolated at UC Clostridium sp. Davis have proven to be resistant to metronidazole,25 necessitating carefully controlled use of other antimicrobials such as vancomycin under these spe- First choice: penicillin or ampicillin ϩ gentami- cial circumstances. Administration of oxytetracy- cin ϩ metronidazole. Fasciotomy, drainage of cline (6.6 mg/kg IV SID) is the treatment of choice abscesses, and debridement of necrotic tissue when E. risticii is the suspected or confirmed cause are also important therapeutic measures. of colitis. Mastitis 7. Activity and Properties of Selected Antimicrobials Mastitis occurs sporadically in lactating, non-lactating, and nulliparous mares and fillies.21 S. zooepi- Penicillin G4 demicus is the most common etiologic agent, being involved in approximately 40% of cases. Gram- Spectrum of Activity and Mode of Action negative enteric bacteria (E. coli, Klebsiella Penicillin G, like other penicillins and cephalo- pneumoniae, Enterobacter sp) are isolated from ap- sporins, exerts a bactericidal effect by inhibiting proximately 20% of cases, Gram-negative non-en- penicillin-binding proteins (PBPs) and therefore teric bacteria (Actinobacillus sp or Pasteurella sp) synthesis and incorporation of peptidoglycan into from 15%, and Staphylococcus sp from about 10%.21 the cell wall of susceptible bacteria.4 The antimi-

AAEP PROCEEDINGS ր Vol. 47 ր 2001 81

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS crobial spectrum of penicillin G includes most Gram- 4. Procaine has been detected in urine for 425 positive aerobes with the exception of about 50% of hours after administration of multiple doses of coagulase-positive Staphylococcus sp, alpha-Strepto- PPG;34 thus administration of PPG to perfor- coccus sp, and Rhodococcus equi.5,26 Most isolates mance horses has the potential to result in a of Actinobacillus sp and Pasteurella sp from horses positive procaine blood test for at least 14 are also susceptible. Enterobacteriaceae are gener- days. ally resistant. Gram-positive anaerobes and many Bacteroides sp isolates (Gram-negative anaerobes), Adverse Effects but not Bacteroides fragilis, are susceptible.5 1. Penicillin allergy is rare in horses but can Dosage and Pharmacokinetics cause serious anaphylactic reactions leading to respiratory difficulty and/or diarrhea. Sodium or potassium salts of penicillin G: 10,000 2. Reactions lasting up to 5 minutes and charac- to 40,000 IU/kg q 4–6 h IV or IM terized by excitement, seizure activity, and sometimes death have been observed during Procaine penicillin G (PPG): 22,000 IU/kg q 35 12–24 h IM or shortly after IM injection of PPG. These Benzathine penicillin G: not recommended be- reactions are more common after several days cause of low plasma concentrations achieved of therapy, particularly if one injection site is used repeatedly. These reactions may reflect accidental IV administration of PPG, or a re- The polar nature of penicillin G and other penicil- action to free procaine. The concentration of lins gives them a volume of distribution similar to free procaine in bottles of PPG increase follow- the extracellular fluid volume and results in low ing exposure to heat such as would occur with lipid solubility and poor tissue penetration unless bottles kept in a car or truck during the high doses are used to achieve a high serum to tissue 36 4 summer. concentration gradient. The soluble dosage forms 3. Many horses develop muscle soreness and fo- have a short serum elimination half-life of less than cal myositis during prolonged courses of IM 27,28 ␤ 1 hour, and because -lactams do not exert a treatment with PPG. significant inhibitory post-antibiotic effect on sus- 4. Many horses develop measurable levels of ceptible bacteria, frequent dosing or constant anti-penicillin antibodies of the IgM class of infusion is necessary to maintain concentrations limited significance following treatment with above the MIC of susceptible bacteria (so called 29,30 penicillin. Some horses also elaborate IgG “time-dependent” killing). Complexing of pen- antibodies that become bound to the surface of icillin G with procaine for IM administration erythrocytes and will develop a Coombs’ test maintains detectable serum concentrations for at positive immune-mediated hemolytic anemia least 24 hours but peak serum concentrations are 31 which may be severe and life-threatening but low. This limits the antimicrobial spectrum and usually resolves when penicillin treatment is penetration into tissue sites of infection. Penicil- discontinued.37–39 lins are excreted by active renal tubular secretion 5. Reactions to potassium penicillin G are fre- and therefore achieve high concentrations of active 4 quently observed when this formulation is in- drug in the urine. For this reason, they are useful jected IV, particularly when administration is for treating urinary tract infections caused by or- rapid. Reactions seen during or after admin- ganisms that may not otherwise be considered istration include head shaking/rubbing, lip susceptible. smacking, teeth grinding, salivation, lacrimation, increased borborygmus, mild colic/agita- Limitations tion, and passage of soft/liquid feces. Signs often recur with subsequent doses but can 1. Parenteral administration is necessary for all usually be eliminated by administration of the dosage forms of penicillin G. The bioavail- drug by infusion over at least 30 minutes. ability of penicillin V administered intragas- Similar reactions have not been reported with tically to horses is less than 10%.32,33 rapid IV administration of sodium penicillin G 2. The soluble sodium and potassium salts are or sodium ampicillin. unstable in solution and reconstitution of fresh drug is necessary before dosing. Ampicillin and Amoxicillin4 3. The activity of penicillins is reduced in acid Ampicillin and amoxicillin are aminobenzyl penicil- environments such as occur in abscesses and lins which, when first introduced onto the market, sites of tissue necrosis. Penicillin G is inac- had a substantially broader spectrum of activity tivated by ␤-lactamase enzymes elaborated by than penicillin G against Gram-negative bacteria many Staphylococcus sp, most Gram-negative including E. coli, Proteus mirabilis, and Salmonella enteric organisms, and many Bacteroides sp, sp, by virtue of their improved ability to penetrate including B. fragilis. the outer membrane of Gram-negative bacteria.

82 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS Both ampicillin and amoxicillin are susceptible to In addition, acute renal failure has been observed inactivation by ␤-lactamases and are slightly less in dogs given nafcillin perioperatively at our active than penicillin G against susceptible Gram- clinic. Nafcillin sodium is labeled for slow IV infu- positive bacteria.4 The progressive increase in sion in humans. It should be diluted to at least one plasmid-mediated resistance, which induces produc- liter and administered slowly over at least 30 min- tion of ␤-lactamases by Gram-negative bacteria, has utes when used in horses in the event that oxacillin reduced the activity of ampicillin and amoxicillin to is unavailable. the point where they now show only a slight advantage over penicillin G in terms of spectrum of activ- Beta-Lactamase Inhibitors and Anti-Pseudomonal ity. Rapid IV injection of ampicillin sodium is well Penicillins4 tolerated, a clear advantage over potassium penicil- Clavulanic acid (clavulanate) and sulbactam are lin G. Ampicillin sodium administered IV has an ␤-lactam antibiotics that have a low level of antimi- elimination half-life of less than 1 hour,40 thus doses crobial activity but a very high afﬁnity for many, but of 10 to 40 mg/kgq6to8harerecommended, not all, ␤-lactamases.4 When ␤-lactamase inhibi- depending on the susceptibility of the infecting or- tors are administered concurrently with susceptible ganism. The trihydrate formulations of ampicillin ␤-lactam antibiotics, time-dependent binding of and amoxicillin are designed for IM injection and ␤-lactamases by the inhibitor protects susceptible give a depot effect similar to that seen with procaine penicillins from inactivation resulting in restoration penicillin G. However, the low serum concentra- of their spectrum of activity. Antibiotic formulations achieved limits the spectrum of activity. tions containing amoxicillin/clavulanic acid, ticarcil- Amoxicillin trihydrate is irritant and stings when lin/clavulanic acid, and ampicillin/sulbactam are injected IM.41 For these reasons, procaine penicil- marketed for veterinary use in North America and lin G or ceftiofur are preferred when IM administra- have proven to be useful for the treatment of infection of a ␤-lactam antibiotic is indicated. tions caused by penicillinase-producing Staphylo- coccus sp, many Enterobacteriaceae and Bacteroides Isoxazolyl (Penicillinase-Resistant) Penicillins4 sp in several species. Since ampicillin, amoxicillin, Beta-lactamase enzymes (penicillinases and cepha- and ticarcillin possess good activity against Gram- losporinases) are a heterogeneous group of com- positive bacteria, combinations of these antibiotics pounds elaborated by many coagulase-positive with ␤-lactamase inhibitors can be used to provide staphylococci, Gram-negative bacteria, and some broad-spectrum antibiotic activity.42-45 anaerobic bacteria. They inactivate ␤-lactam anti- Ticarcillin is an anti-pseudomonal carboxypeni- biotics by cleaving the ␤-lactam ring. Two ap- cillin that is active against many isolates of Pseudo- proaches have been taken to overcome this problem, monas aeruginosa and several other Gram-negative namely co-administration of ␤-lactamase inhibitors bacteria, with the exception of Klebsiella sp, En- with a penicillinase susceptible penicillin or the use terobacter sp, Citrobacter sp, and Serratia sp. of a penicillinase-resistant penicillin. Isoxazolyl Whereas approximately 50% of P. aeruginosa iso- penicillins include oxacillin, cloxacillin, diclox- lates are resistant to ticarcillin by virtue of produc- acillin, methicillin, and nafcillin.4 By virtue of tion of ␤-lactamases, most of the ␤-lactamases their chemical structure, these compounds resist produced by this organism are not inactivated by cleavage by many ␤-lactamases, including almost all clavulanic acid. Therefore, P. aeruginosa isolates of those elaborated by coagulase-positive Staphylo- that are resistant to ticarcillin are usually also re- coccus sp. Their spectrum of activity is largely resistant to ticarcillin/clavulanic acid.42 Conversely, stricted to Gram-positive aerobic bacteria but their a number of isolates of Klebsiella pneumoniae and potency against penicillin-sensitive bacteria is lower some other Enterobacteriaceae are made susceptible than that of penicillin G. While nafcillin has to ticarcillin by co-administration of clavulanic greater in vitro activity than oxacillin and cloxacil- acid.46 Since the ticarcillin/clavulanic acid combi- lin, and all have higher activity than methicillin, nation is expensive, indications for its use in the differences in protein binding result in similar in horse are limited and include systemic or uterine vivo activity. The major indication for the use of infections with P. aeruginosa or penicillinase-pro- isoxazolyl penicillins in horses is the treatment of ducing Staphylococcus sp, and neonatal septicemia systemic or local infections with penicillin-resistant involving aminoglycoside-resistant Gram-negative Staphylococcus sp, the most important of which is bacteria or patients with physiologic or toxic condi- limb cellulitis, particularly in racehorses. Oxacil- tions that preclude aminoglycoside use.42-44 lin is the drug most often chosen and is used at a dose of 20 to 40 mg/kg IVq6to8h,usually in Oral Penicillins combination with an aminoglycoside antibiotic to Absorption of penicillin V, ampicillin, and extend the spectrum of activity. Oxacillin is con- amoxicillin after oral administration to horses is sidered to be a relatively safe drug in horses. In poor, except in neonatal foals. The bioavailability contrast, nafcillin administered by bolus IV injection of penicillin V is Ͻ5%, that of ampicillin is Ͻ10%, at the same dose as oxacillin, appears to be highly and that of amoxicillin is variable, but ranges from irritant and may induce severe thrombophlebitis. 5% to 20%.32,33,41,47-50 In addition, feeding further

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Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS reduces absorption. Absorption and elimination of enteric bacteria such as E. coli is usually in the the bioavailable fraction is rapid and the half-life of range of 0.25 to 1.0 ␮g/ml. elimination is about 1 hour. It would be necessary to administer very high doses (50 to 100 mg/kg) of 1. The label dose for the label indication is 2.2 to these antibiotics at frequent intervals to achieve 4.4 mg/kg q 24 h IM. therapeutic serum concentrations. Unabsorbed 2. Doses of 5–10 mg/kg q 12 h IV or IM have been drug remaining in the GI tract would likely cause used successfully to treat foals with septice- disturbances in the colonic flora and may initiate 33 mia caused by Gram-negative bacteria. fatal pseudomembranous colitis. For this reason, 3. IV or IM administration has been used in the oral administration of available penicillins in adult clinical setting, although the kinetic profile of horses is not recommended. ceftiofur is slightly better when the drug is Several esters of ampicillin, including pivampi- administered IM rather than IV. This may cillin, bacampicillin, and talampicillin have reflect the fact that administered ceftiofur so- been developed for oral administration to other spe- dium is rapidly hydrolyzed to the equally ac- cies. These esters are resistant to degradation by tive compound, desfuroylceftiofur, which is gastric acid and pass to the small intestine as inac- then highly bound to plasma proteins that tive pro-drugs that become hydrolyzed to active am- protect it from rapid renal elimination. picillin during absorption from the GI tract. For Ceftiofur shows good penetration into body this reason, the bioavailability (30% to 40%) is much fluids, joints, and pulmonary tissue sites of higher than that achieved by ampicillin and the infection, but does not enter the cerebral spi- majority of unabsorbed drug remaining in the GI nal fluid in effective concentrations in the ab- lumen is probably inactive and less likely than am- 47-52 sence of meningeal inflammation. picillin to disrupt the colonic flora. Of interest 4. The pharmacokinetics of ceftiofur are highly is the finding that the absorption of pivampicillin in 48 complex, and results of studies are further horses is improved by feeding. Further develop- influenced by the assay methods used to mea- ment of pivampicillin or bacampicillin as oral dosage sure concentrations in plasma. A more pro- forms for horses would prove very useful to equine longed elimination half-life is found when an clinicians but these drugs are not yet available in HPLC assay which measures free and protein the US. bound ceftiofur and metabolites is used rather Ceftiofur than a microbiologic assay that measures mi- crobially active concentrations of free ceftiofur Ceftiofur is a third-generation cephalosporin antibi- and its active desfuroylceftiofur metabolite. otic approved for use in horses and food-producing 5. Despite a label claim that includes only infec- animals.4,53-57 tions caused by ␤-hemolytic Streptococcus sp, Spectrum of Activity the high susceptibility of this organism to penicillin G and the relatively low cost of procaine Ceftiofur has a broad antimicrobial spectrum that penicillin G make it the drug of choice in most includes Gram-positive and Gram-negative aerobes, instances. Third-generation cephalosporins including Enterobacteriaceae, and many anaero- such as ceftiofur are best reserved for treat- bes, including Clostridium sp and Fusobacterium ment of infections caused by organisms resis- sp.9,58,59 Pasteurella sp are highly susceptible tant to penicillin G, potentiated sulfonamides, and generally have a lower MIC than Enterobacte- or aminoglycosides. However, the IM route riaceae. Resistant bacteria include Bacteroides sp, of administration of this drug, lack of risk of Enterococcus sp, Rhodococcus equi, and Pseudomo- “penicillin reactions” and positive procaine nas aeruginosa. drug tests, and its broad spectrum of activity Dosage and Pharmacokinetics which includes Enterobacteriaceae make ceftiofur very useful for treating neonatal sepsis The efficacy of ceftiofur has been demonstrated in an and polymicrobic infections such as bacterial equine “shipping fever” model and in several field pneumonia in adult horses. trials with naturally occurring equine respiratory disease, in which it was shown to be equal or superior to ampicillin and potentiated sulfonamide Limitations and Adverse Effects preparations.53 The approved label claim in the USA includes only respiratory tract infections 1. Ceftiofur sodium is unstable in solution and caused by ␤-hemolytic Streptococcus sp. Like Pas- must be reconstituted before dosing. Once teurella sp isolated from cattle, ␤-hemolytic Strepto- reconstituted, it should be used within 12 coccus sp isolated from horses are highly susceptible hours if kept at room temperature but can be to ceftiofur (MIC usually Ͻ0.25 ␮g/ml). This is, in maintained for up to 7 days if refrigerated or part, the reason why the label dose is so much lower up to 8 weeks if frozen. than that routinely recommended for other third- 2. Diarrhea and pseudomembranous colitis have generation cephalosporins. The MIC of susceptible been observed in horses treated with higher

84 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS than label doses of ceftiofur, although routinely tration in urine and accounts for the high utility recommended doses are reasonably safe.54 of aminoglycosides for treating urinary tract 3. Minor injection site discomfort and irritation infections.4,65 Unlike penicillins and cephalospo- occur with repeated administration.54 rins, aminoglycosides exert a significant post-antibiotic effect.66 Killing of susceptible bacteria by Aminoglycosides4 aminoglycosides is “concentration-dependent” and correlates more closely with the peak concentration Spectrum of Activity achieved, the area under the plasma concentration- Aminoglycosides exert a bactericidal effect on sus- time curve, and the ratio of the peak concentration ceptible bacteria by interfering with ribosomal pro- of the drug to the MIC of the infecting organism, tein synthesis.4 To exert this effect, the drug must than with the length of time during the dosage in- first be transported into the bacterial cell, in part by terval that aminoglycoside concentrations remain diffusion and in part by an active transport mecha- above MIC.67 Aminoglycosides are concentrated in nism that is inhibited in anaerobic conditions but renal tubular epithelium through a saturable trans- which is facilitated by damage to the bacterial cell port mechanism during therapy. Nephrotoxicity wall created by other antibiotics. This is the mech- depends on persistence of the drug in renal tubular anism underlying synergy between aminoglycosides epithelium and is governed by the amount of time and ␤-lactam antibiotics. Extensive resistance to during the dosage interval that serum concentra- kanamycin and streptomycin has rendered these tions remain above a putative nephrotoxic threshold drugs much less useful than gentamicin and amika- concentration. In recent years it has been docu- cin, which are consequently the most commonly mented that administration of the total daily dose used aminoglycosides in horses and have indications of an aminoglycoside once daily is safer and more for treating a variety of Gram-negative infections in effective in humans than administration of the many body systems. Amikacin and gentamicin same total daily dose divided into 3 equal doses at 8- both show excellent activity against Gram-negative hour intervals as in traditional dosage regimens.68,69 aerobes, including Enterobacteriaceae.5,26 Some Once-daily dosage regimens for amikacin (21 mg/kg) Mycobacterium sp and Mycoplasma sp are also sus- and gentamicin (7 mg/kg) IV or IM are now routinely ceptible. Activity against Gram-positive aerobes is used at our clinic and elsewhere and have proven to be generally poor, although many coagulase-positive safe and effective.61,62,70 Staphylococcus sp are susceptible to amikacin and, to a slightly lesser extent, gentamicin.5,26 Obligate Limitations anaerobes and facultative anaerobes under anaerobic conditions are resistant to aminoglycosides. In 1. The need for parenteral dosing. terms of potency, spectrum of activity, and stability 2. Amikacin and gentamicin cause irritation to enzymes involved in plasmid-mediated resis- when administered IM; therefore, IV dosing is tance, the order of activity of aminoglycosides is preferred. amikacin Ͼ tobramycin Ն gentamicin Ͼ kanamy- 3. Use by routes other than intrauterine consti- cin ϭ neomycin Ն streptomycin.4 Bacteria resis- tutes extra-label drug use. tant to an aminoglycoside higher in the order are 4. Lack of activity against anaerobic bacteria generally also resistant to all aminoglycosides that and Streptococcus sp. appear lower in the order. One exception is the finding that gentamicin is inherently more active Adverse Effects than amikacin against non-enteric organisms such All aminoglycoside antibiotics have the potential to as Actinobacillus sp and Pasteurella sp.5 Whereas induce nephrotoxicity (acute tubular nephrosis), amikacin has a broader spectrum of activity against neuromuscular blockade, and ototoxicity (vestibular Enterobacteriaceae, the MIC of organisms that and cochlear damage), although ototoxicity is recog- are susceptible to gentamicin is often 2- to 4-fold nized infrequently in horses.71-73 The general or- lower than amikacin, indicating that gentamicin is der of nephrotoxicity is neomycin Ͼ gentamicin Ͼ inherently more potent than amikacin.5,26 The rec- kanamycin and amikacin Ͼ streptomycin and tobra- ommended dose of gentamicin is, therefore, about mycin. With the exception of neomycin, therapy one-third of that used for amikacin. with aminoglycosides is usually well tolerated unless treatment is prolonged or risk factors are Dosage and Pharmacokinetics present. Prevention of aminoglycoside toxicity Aminoglycosides are not absorbed after oral admin- involves using recommended dosage regimens, istration and must therefore be administered paren- minimizing the duration of therapy, maintaining terally by IV or IM injection. These polar organic hydration and optimal renal perfusion, minimiz- bases are restricted in their distribution to a volume ing concurrent use of other nephrotoxic drugs equivalent to the extracellular fluid volume,60–64 such as NSAIDs, and seeking alternative drugs thus penetration into cells and tissues is generally in patients with pre-existing renal tubular dis- poor.4 Elimination is by glomerular filtration of ease. Dosage adjustment based on measured peak active drug, which therefore appears in high concen- and trough plasma antibiotic concentrations, along

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Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS with periodic urinalysis and monitoring of serum in higher than optimal ratio’s of the drugs in infec- concentrations of blood urea nitrogen (BUN) and tion sites.74 For this reason, potentiated sulfon- creatinine are recommended. Aminoglycoside use amides should be administered at least twice daily is contraindicated in patients with botulism. in horses. Absorption of TMP and sulfonamides from the GI tract of horses is good, although the Trimethoprim-Sulfonamide Combinations (Potentiated absorption of TMP is reduced substantially by feed- Sulfonamides)4,74 ing and the absorption of sulfonamides is delayed by feeding.74,77 Elimination of trimethoprim and sul- Spectrum of Activity fonamides involves both renal excretion of active Potentiated sulfonamides are considered bacteri- drug and hepatic metabolism followed by elimina- cidal by virtue of inhibition of sequential steps in tion of metabolites in the urine. Sufficient concen- the synthesis of folate and, therefore, DNA. Tri- trations of active drug appear in urine to make methoprim and other diaminopyrimidines such potentiated sulfonamide preparations useful for as ormetoprim and pyrimethamine inhibit the treating urinary tract infections.74,76 dihydrofolate reductase enzyme and exert a synergistic action with sulfonamides which competi- Limitations tively inhibit incorporation of PABA into folic 4,74 1. Lack of clinical activity against anaerobic acid. Potentiated sulfonamides have a broad- bacteria. spectrum activity against many Gram-positive and ␤ 5,26,74,75 2. Some -Streptococcus sp appear to be resis- Gram-negative aerobes. However, Pseudo- tant despite susceptibility results to the monas sp, Mycoplasma sp, and many isolates of contrary. Klebsiella sp are resistant. The in vivo activity of potentiated sulfonamides against anaerobic bacteria Adverse Effects is poor despite susceptibility test results to the contrary.5 This may result from the high levels of 1. Reversible neutropenia without a left shift folate present in sites of anaerobic infection second- has been noted during prolonged courses of ary to cell death. Sulfadiazine or sulfamethoxazole treatment. This likely results from suppres- are commonly used in combination with pyri- sion of folate synthesis and resolves following methamine to treat equine protozoal myelitis caused termination of therapy. Supplementation by Sarcocystis neurona. with folinic acid in the form of Brewer’s yeast may further speed resolution. Dosage and Pharmacokinetics 2. TMP/sulfonamide combinations are generally thought to minimally disturb the gastrointes- 79 1. A dose of 15–24 mg/kg q 8–12 h IV is recom- tinal flora of horses. Therefore antibiotic- mended in those countries in which aqueous associated colitis and diarrhea are not injectable solutions are available. Similar commonly encountered. However, serious doses are used for the TMP/sulfadiazine aque- pseudomembranous colitis and death have ous suspension (Tribrissen® 48%) that was been observed on occasion. Geographic, di- recently reintroduced for IV use in horses in etary, and other factors such as prior treat- the USA. This formulation should be admin- ment with other antibiotics or surgical stress, istered slowly. may influence colonic flora (particularly Clos- 2. Oral tablets, paste, or powders containing tridium difficile) and predispose horses to the TMP with sulfadiazine or sulfamethoxazole in development of pseudomembranous colitis. a 1:5 ratio are used at doses of 20 to 30 mg/kg 3. Tremors, excitement, ataxia, collapse, and of drug combination BID. rare deaths have been encountered during or shortly after intravenous administration of The pharmacokinetic and antimicrobial profile both the approved aqueous solution and aque- of sulfadiazine is superior to that of sulfamethox- ous suspension formulations of trimethoprim/ sulfadiazine, particularly when the rate of azole, although generic formulations of TMP/sulfa- 74 methoxazole are commonly used in horses in an administration is rapid. Thus, a slow rate extra-label manner. Trimethoprim and, to a lesser of administration is recommended when TMS extent, sulfadiazine and sulfamethoxazole, are is used IV. well distributed in the body due to their high 4. Concurrent use of detomidine and intrave- lipid solubility.74,76,77 They achieve high intracel- nous TMS formulations should be avoided because this combination has been associated lular concentrations and cross the blood–brain 74 barrier.78 Widespread distribution is reflected in a with dysrhythmias, hypotension, and death. volume of distribution for TMP that exceeds 1 Rifampin4 l/kg.74,76 The pharmacokinetics of TMP and sulfonamides are well matched in humans but, in horses, Spectrum of Activity the rapid elimination of trimethoprim leads to more Rifampin exerts a bactericidal action on susceptible prolonged persistence of the sulfonamide, resulting bacteria by inhibiting RNA polymerase, the enzyme

86 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS that catalyses transcription of RNA to DNA.4 Since Adverse Effects Gram-negative bacteria are relatively impervious to this enzyme, most are resistant.80 Thus the narrow 1. Causes rusty orange staining of urine, mucous antimicrobial spectrum of rifampin includes Gram- membranes, secretions, and clothing. positive aerobes, most Gram-positive and Gram-nega- 2. Suspensions constituted from oral capsules tive anaerobes, and some Gram-negative non-enteric taste bad, even when mixed with molasses or aerobes.80 Rifampin is one of the most active known corn syrup. Horses may be reluctant to swal- antimicrobials against Staphylococcus aureus and low the administered dose. The bad taste of shows excellent activity against Rhodococcus equi, My- rifampin remaining in the mouth may cause cobacterium sp, Corynebacterium sp, and Streptococ- horses to become anorectic during ther- cus sp.80 The major indications for the use of apy. It is therefore important to administer rifampin in horses are treatment of R. equi pneumo- the drug far back on the tongue and make nia, internal abscesses caused by Corynebacterium sp, sure the horse swallows. Rinsing the mouth and Streptococcus sp, and infections caused by penicil- before feeding reduces this negative effect on linase producing Staphylococcus sp. appetite, as with other orally administered medications in horses. Dosage and Pharmacokinetics 3. Many horses develop slight softening of the feces while on treatment with rifampin. This 1. Oral doses of 2.5 to 7.5 mg/kg PO q 12 h are is not usually a major concern. However, recommended and have a bioavailability of explosive diarrhea with rapid loss of so- about 70%, although substantial inter-indi- dium, potassium, and chloride occurs on occa- vidual variation exists.80-83 Doses of 5.0–7.5 sion and can be life threatening, especially mg/kg q 12 h are usually used initially in during hot weather. This problem has been combination with erythromycin to treat R. observed in foals and adult horses when ri- equi pneumonia. The dose can be reduced fampin is used in combination with erythro- after a good initial response to therapy has mycin, penicillin G, or TMP/sulfonamide. been observed. 4. Rifampin may cause a false elevation in con- 2. Wide distribution and excellent penetration of centrations of some liver enzymes measured tissues and cell membranes facilitate killing on automated chemistry analyzers and can of bacteria at sites of infection. Rifampin potentially affect elimination of other drugs penetrates phagocytic cells, is active intracel- metabolized by the liver.

lularly, and retains antimicrobial activity at 4 acid pH, allowing sterilization of abscesses. Erythromycin 3. Rifampin is synergistic with erythromycin, Mechanism of Action and Spectrum of Activity the drug most often administered concurrently, and can be used with penicillins and Erythromycin, like other macrolide antibiotics, has with potentiated sulfonamides.84 Slight an- a macrocytic lactone ring structure attached to two tagonism of antimicrobial effect has been or more sugar moieties. Killing of susceptible bac- noted in vitro with gentamicin but this is teria is mediated through binding to subunits of the likely of minor clinical importance.84 Ri- 50S ribosome resulting in inhibition of translocation fampin has been used successfully in combi- and protein synthesis. Erythromycin is usually nation with gentamicin in our clinic to treat R. considered to be bacteriostatic but may be bacteri- equi pneumonia in foals. cidal at high concentration. Erythromycin is active against Gram-positive aerobes (R. equi is highly susceptible); some Actinobacillus sp and Pasteurella sp; Limitations some anaerobic bacteria including Clostridium sp, Bacteroides sp (except B. fragilis), and some 1. No approved, easily administered oral dosage Fusobacterium sp.26 Intermediate susceptibility is forms are available for horses. Capsules for shown by Ehrlichia sp and Bordetella sp. Resis- human use are expensive, unpalatable, and tant organisms include Enterobacteriaceae, Myco- not easily prepared into a suitable oral paste. bacterium sp, Mycoplasma sp, and Chlamydia 2. Poor solubility in aqueous media limits the sp.26 The major indication for use of erythromycin availability of injectable dosage forms. is the treatment of R. equi pneumonia. 3. Narrow spectrum of antimicrobial activity. 4. Bacteria may rapidly gain resistance to ri- Dosage and Pharmacokinetics fampin during therapy; therefore the drug should only be used in combination with other 1. Oral doses of 20 to 25 mg/kgq8harerecom- antimicrobial agents that will kill resistant mended. A 12-hour dosing interval may mutants. be appropriate for erythromycin estolate 5. Feeding reduces absorption of rifampin from after several days of dosing at an 8-hour the gastrointestinal tract. interval.85 Erythromycin stearate or esters

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Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS (estolate or ethylsuccinate) are the preferred Adverse Effects oral dosage forms in humans because they are less susceptible than erythromycin base and 1. Like other macrolide antibiotics, erythromy- salts to degradation by gastric acid. Eryth- cin can cause gastrointestinal disturbances, romycin stearate undergoes hydrolysis in the diarrhea, and fatal pseudomembranous coli- intestine to form erythromycin base, while the tis.90-92 The poor absorption of orally ad- erythromycin esters are absorbed intact and ministered drug, and excretion of active are then hydrolyzed to active erythromycin erythromycin and metabolites in bile, likely base after absorption.85 Oral administration result in substantial concentrations of active of the less expensive free base or phosphate erythromycin reaching the colon to initiate salt of erythromycin has proven to be effective disturbances in flora. For this reason, eryth- for treating foals with R. equi pneumonia, romycin use by the oral route in adult horses either when used alone or in combination should be avoided if possible. Fatal colitis with rifampin, despite the finding that bio- has been reported in mares while their foals availability ranges from 10–40%.85-87 Simi- are being treated orally with erythromycin, larly, erythromycin ethylsuccinate is poorly presumably due to ingestion of small amounts absorbed in foals. Feeding prior to adminis- of active drug during coprophagic activity, or tration reduces bioavailability of all dosage from contamination of feeders or water buck- 86 ets with drug remaining on the foals’ forms evaluated. Bioavailability in adult 91,92 horses is probably even lower than in foals, muzzle. 2. The motilin-like activity of erythromycin although differences in experimental design stimulates gastrointestinal motility.93 This in published studies preclude definitive effect has been exploited clinically for the conclusions.85-88 The bioavailability of mi- treatment of adynamic ileus, particularly that croencapsulated erythromycin base and seen in post-operative colic patients, by using erythromycin estolate in foals is higher than low-dose (2 mg/kg) IV infusions of erythromy- that of other dosage forms, making these the cin lactobionate. This effect may also be re- two recommended formulations for treating R. 85,86,89 sponsible for signs of mild colic and diarrhea equi pneumonia. in some horses treated orally with erythromy- 2. In the unusual event that parenteral dosing of cin. Rapid IV administration of antimicro- erythromycin is necessary, the lactobionate bial doses of erythromycin lactobionate (5–10 salt is used at a dose of 5 to 10 mg/kg q 8–12 mg/kg) causes severe reactions characterized hbyslow intravenous infusion. by excitement, disorientation, ataxia, tachy- 3. High lipid solubility of erythromycin and cardia, diarrhea, lacrimation, sweating, other macrolides ensures wide distribution in urination, and other signs of autonomic stim- the body and excellent penetration of cells and ulation, including collapse.85-87 Therefore, tissues. Intracellular concentrations of ac- erythromycin lactobionate should be adminis- tive erythromycin in phagocytes greatly ex- tered slowly as an IV infusion. ceed serum concentrations and persist for a 3. Fever/hyperthermia and severe, often fatal, longer duration. respiratory distress have been observed in 4. Erythromycin is active intracellularly and at foals treated with erythromycin during hot acid pH, and is synergistic with rifampin. weather.90 The mechanism underlying this reaction is unknown, but it likely results from Limitations derangement of the hypothalamic temperature “set-point” and may be predisposed by pre-existing lung disease. This reaction is of 1. The acid susceptibility of erythromycin base, acute or peracute onset and is generally seen phosphate and some esters limits absorption between the second and fourth day of treat- of active drug and may predispose to side ment, although it can occur at any time (even effects. Serum concentrations of the mi- shortly after treatment is discontinued) if ad- crobially inactive anhydroerythromycin acid verse environmental conditions of high ambi- breakdown product are higher than concen- ent temperature prevail.90 Tachypnea and trations of active erythromycin base after ad- hyperthermia (up to 110°F) are observed early ministration of the base and phosphate in the course of condition. If the core body formulations.85–87 Anhydroerythromycin temperature can be brought down quickly us- may be responsible for some of the observed ing cold water/alcohol baths, fans, and cold side effects. water enemas, affected foals may recover 2. Frequent dosing is necessary. rapidly and fully. Otherwise, an acute res- 3. Intravenous formulations (lactobionate and piratory distress syndrome with underlying gluceptate) are expensive and poorly bronchointerstitial pneumonia and systemic tolerated. signs of heat stroke develops and frequently

88 2001 ր Vol. 47 ր AAEP PROCEEDINGS

Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS proves fatal. Extreme care should therefore (Baytril, Bayer Corp.) is approved for use in small be taken when erythromycin is used to treat animals and cattle in the US and is occasionally foals during hot weather. Close observation used in an extra-label manner to treat infections in and provision of shade are essential. Foals horses using the IV or oral routes. The cattle for- on erythromycin treatment should not be left mulation (Baytril 100, Bayer Corp), an aqueous so- outside on hot sunny days, and good ventila- lution in L-arginine designed for IM injection, has tion, fans, or air conditioning should be used been shown to be effective and generally well toler- to control indoor temperatures.90 ated when administered IV or IM to horses, al- 4. Erythromycin has been shown to inhibit che- though some horses experience pain and swelling at motaxis and migration of neutrophils into in- the injection site.b flammatory sites in pulmonary airways and perhaps other sites.94 This effect can prove Spectrum of Activity highly beneficial in the treatment of neutro- Fluoroquinolones show excellent activity against phil-mediated hyperreactive airway disease, Gram-negative aerobes, including Enterobacteri- such as occurs commonly in foals with chronic aceae and Pseudomonas aeruginosa, and against bacterial pneumonia. However, this effect Mycoplasma sp, Rickettsia sp, and Ehrlichia may predispose to superinfection of the lung sp.4,95 These antimicrobials are generally less with resistant Enterobacteriaceae, Pneumo- active against Gram-positive aerobes, although cystis carinii, and perhaps other pathogens many isolates of Staphylococcus sp are sus- that may play a role in induction of an acute ceptible.95 Most isolates of R. equi and anaero- respiratory distress syndrome. bic bacteria are resistant.4 Fluoroquinolones are 5. Hepatobiliary toxicity, interference with elim- active against intracellular organisms. After ad- ination of other drugs metabolized by the ministration to horses about 20–25% of the ab- liver, and interference with liver enzyme as- sorbed dose is de-ethylated to ciprofloxacin, which says are reported to be considerations with has slightly higher antimicrobial activity than erythromycin use but are rarely of clinical enrofloxacin.96 significance. 6. Erythromycin formulations approved for IM Dosage and Pharmacokinetics use in ruminants and pigs are generally non- aqueous, buffered, alcohol or propylene glycol- 1. An IV dose of 5.0–5.5 mg/kg SID (Baytril® based preparations which cause severe local 100 or Baytril®, Bayer Corp.) and an oral dose pain and tissue reactions when administered of 7.5 mg/kg SID or 4.0 mg/kg BID (Baytril® IM to horses and can prove fatal when admin- tablets or Baytril® 3.23% Concentrate Anti- istered IV. Use of these formulations in bacterial Solution, Bayer Corp.) are recom- horses is, therefore, contraindicated. mended based on results of pharmacokinetic studies.96,97 IM injection of Baytril inject- Other Macrolide Antibiotics able is not recommended because it causes Azithromycin, roxithromycin, clarithromycin, di- unacceptable tissue reactions,96 whereas Bay- rithromycin, flurithromycin, and other new macro- tril 100 appears to be tolerated better when lides which show enhanced absorption from the GI administered IM. tract, longer elimination half-life, more persistent tissue concentration, and broader antimicrobial The elimination half-life of enrofloxacin after IV spectrum have been developed for use in humans injection to horses is reported to be 4.5 to 6 hours and show great promise for use in animals, includ- and after IM injection to be about 12–15 hours.95–97 ing horses.4 Unpublished observations indicate The difference reflects slow absorption after IM in- that the absorption of azithromycin in foals is supe- jection. Mean bioavailability after oral administra- rior to that of erythromycina and that an oral dose of tion of crushed Baytril tablets is approximately 60%, 10 mg/kg SID for 5 days followed by the same dose although absorption is erratic and there is consider- every other day until lesions resolve has proven to be able inter-individual variation.97,98 Bioavailability successful for the treatment of R. equi pneumonia and after intragastric administration of Baytril 3.23% pneumonia caused by other susceptible pathogens.b Concentrate Antibacterial Solution (Bayer Corp.) is almost 80%.95 Volume of distribution after IV use Fluoroquinolone Antibiotics4 exceeds 2 l/kg, indicating widespread distribution in Antibiotics of the fluoroquinolone class include the body.96 Concentrations of bioactive enrofloxa- enrofloxacin, ciprofloxacin, orbifloxacin, marbo- cin and metabolites in liver, spleen, and kidney are floxacin, norfloxacin, danofloxacin, and several 5 to 10 times higher than those in serum after re- others.4 These antimicrobials are bactericidal peated oral dosing.99 Concentrations in brain, vit- DNA gyrase inhibitors that were developed as oral reous, and aqueous humor are only 10–20% of or parenteral dosage forms for use in humans and serum concentrations, whereas concentrations in certain domestic species. Nalidixic acid, the first of skin, muscle, heart, stomach, intestine, uterus, the quinolones, is now rarely used. Enrofloxacin mammary gland, bone, and bladder are similar to

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Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS those in serum.99 After oral administration, con- Metronidazole4 centrations of active enrofloxacin in feces are much higher than those in serum, reflecting incomplete Spectrum of Activity absorption as well as biliary secretion of parent drug Metronidazole, like other nitroimidazoles, acts by and active metabolites.99 Concentrations in urine causing extensive breakage in DNA strands and inhi- are several hundred fold higher than those in serum, bition of the DNA repair enzyme, DNAase 1.4 The indicating renal elimination of a large fraction of the narrow spectrum of activity includes almost all anaer- dose and suggesting utility for treating urinary tract obic bacteria and many protozoa.4 The major indica- infections.97 tion for use of metronidazole in horses is the treatment of infections caused by anaerobic bacteria or, in com- Limitations/Adverse Effects bination with other antibiotics, treatment of polymicrobic infections such as pleuropneumonia that may involve anaerobic bacteria.8,103 Oral use for treating 1. Suboptimal activity against Gram-positive pseudomembranous colitis caused by Clostridium aerobes, except Staphylococcus sp limits indi- sp,104 and topical use to treat thrush and canker are cations for use in horses. additional indications. 2. Ataxia and other neurologic signs have been noted during or following rapid IV bolus ad- Dosage and Pharmacokinetics ministration of high doses (15 mg/kg or more) 100 of Baytril 100. Similar signs have been 1. Oral doses of 20–25 mg/kg q 8–12 h or 15 observed in debilitated post surgical cases mg/kgq6harerecommended.105,106 Ab- given the same formulation at the 5 mg/kg sorption is rapid and bioavailability is dose. Thus, a slow rate of IV administration high.105–108 An oral dose of 15 mg/kgq8his of enrofloxacin formulations is recommended. used to treat Clostridial colitis. 3. Rapid onset of non-inflammatory arthropathy 2. The parenteral dose is 20 mg/kg q 8–12 h. when used in immature animals limits fluoro- 3. Good absorption of metronidazole after intra- 101 quinolone use in foals. This effect is inde- rectal administration has been documented pendent of dose but is dependent on age, in horses and offers an alternate route when species, and joint stress. Signs include joint oral or esophageal lesions preclude oral swelling and lameness and reflect disruption administration.107,109 of the extracellular matrix of collagen and de- 4. Metronidazole is widely distributed in the pletion of collagen that results in erosions/ body and penetrates tissues well.105-108 blisters on weight-bearing surfaces of articular 5. Metronidazole is compatible with penicillins cartilage. Foals appear to be highly suscep- and aminoglycosides when used to treat tible to these adverse articular effects, partic- polymicrobic infections. ularly when they are weight bearing and active.101 No clinical signs or histopathologic Limitations lesions indicative of articular cartilage damage were observed in adult horses treated 1. The narrow antibacterial spectrum usually with high doses of enrofloxacin daily for 21 necessitates use in combination with other days but 2 horses did develop clinical evidence antibiotics. of mild plantar desmitis or superficial digital 2. No oral dosage forms are approved for use in flexor tendinitis.100 horses in the USA, although palatable paste 4. Weakening and rupture of tendons, particu- formulations designed for horses are available larly the Achilles tendon, has been reported in in Britain and some other countries. humans during treatment with fluoroquino- 3. The parenteral dosage form (a 5% solution) is lones. Cases have been observed as early as expensive and, because of poor solubility of the second day of therapy but most occurred metronidazole in aqueous media, requires a during chronic treatment of older people, par- large administration volume. ticularly when corticosteroids were administered concurrently.102 This adverse effect Adverse Effects likely has a mechanism similar to that involved in fluoroquinolone-induced arthropa- 1. Metronidazole is considered to be a safe drug thy. for use in horses.103 Gastrointestinal upsets 4. Since the potential long-term toxic effects of and diarrhea are encountered on occasion. fluoroquinolones in adult performance horses 2. Neurologic side effects characterized by de- have not been assessed, enrofloxacin should pression, weakness, ataxia, vestibular signs, be reserved for treating Gram-negative or seizures, and peripheral neuropathy have staphylococcal infections resistant to other been observed on occasion in horses treated antibiotics and its use in foals should be concurrently with metronidazole and other avoided, except under special circumstances. drugs. Attempts to reproduce these signs

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Proceedings of the Annual Convention of the AAEP 2001 Reprinted in the IVIS website with the permission of AAEP Close window to return to IVIS IN DEPTH: CURRENT CONCEPTS IN SELECTION AND USE OF ANTIMICROBIALS with high doses of metronidazole (50 mg/kg 21. McCue PM, Wilson WD. Equine mastitis—a review of 28 PO q 8 h) were not successful in spite of the cases. Equine Vet J 1989;21:351–353. 22. Donaldson MT, Palmer JE. Prevalence of Clostridium per- very high serum concentrations of metronida- fringens enterotoxin and Clostridium difficile toxin A in zole achieved. feces of horses with diarrhea and colic. J Am Vet Med Assoc 1999;215:358–361. References and Footnotes 23. Jones RL. Clostridial enterocolitis. Vet Clin North Am [Equine Pract] 2000;16:471–485. 1. Brumbaugh GW, Langston VC. Principles of antimicrobial therapy. In: Smith BP, ed. Large animal internal 24. House JK, Mainar-Jaime RC, Smith BP, et al. Risk factors medicine, 2nd ed. St. Louis: Mosby, 1996;1587–1613. for nosocomial Salmonella infection among hospitalized 2. Baggot JD, Prescott JF. Antimicrobial selection and dos- horses. J Am Vet Med Assoc 1999;214:1511–1516. age in the treatment of equine bacterial infections. Equine 25. Jang SS, Hansen LM, Breher JE, et al. Antimicrobial sus- Vet J 1987;19:92–96. ceptibilities of equine isolates of Clostridium difficile and 3. Hirsh DC, Ruehl WW. A rational approach to the selection molecular characterization of metronidazole-resistant of an antimicrobial agent. J Am Vet Med Assoc 1984;185: strains. Clin Infect Dis 1997;25(Suppl 2):S266–S267. 1058–1061. 26. Adamson PJ, Wilson WD, Hirsh DC, et al. Susceptibility of 4. Prescott JF, Baggot JD, Walker RD. Antimicrobial therapy equine bacterial isolates to antimicrobial agents. Am J Vet in veterinary medicine, 3rd ed. Ames, IA: Iowa State Uni- Res 1985;46:447–450. versity Press, 2000;796. 27. Durr A. Comparison of the pharmacokinetics of penicillin 5. Hirsh DC, Jang SS. Antimicrobic susceptibility of bacterial G and ampicillin in the horse. Res Vet Sci 1976;20:24–29. pathogens from horses. Vet Clin North Am [Equine Pract] 28. Horspool LJI, McKellar QA. Disposition of penicillin G 1987;3:181–190. sodium following intravenous and oral administration to 6. Wilson WD, Madigan JE. Comparison of bacteriologic cul- Equidae. Br Vet J 1995;151:401–412. ture of blood and necropsy specimens for determining the 29. Koritz GD, Bevill RF. Role of pharmacokinetics in the out- cause of foal septicemia: 47 cases (1978–1987) [published come of treatment of infections. Acta Vet Scand Suppl erratum appears in J Am Vet Med Assoc 1990 Feb 1;196(3): 1991;87:18–27. 438]. J Am Vet Med Assoc 1989;195:1759–1763. 30. Drusano GL. Role of pharmacokinetics in the outcome of 7. Mair TS, Yeo SP. Equine pleuropneumonia: the impor- infections. Antimicrob Agents Chemother 1988;32:289– tance of anaerobic bacteria and the potential value of met- 297. ronidazole in treatment. Vet Rec 1987;121:109–110. 31. Uboh CE, Soma LR, Luo Y, et al. Pharmacokinetics of 8. Sweeney CR, Holcombe SJ, Barningham SC, et al. Aerobic penicillin G procaine versus penicillin G potassium and pro- and anaerobic bacterial isolates from horses with pneumo- caine hydrochloride in horses. Am J Vet Res 2000;61:811– nia or pleuropneumonia and antimicrobial susceptibility 815. patterns of the aerobes. J Am Vet Med Assoc 1991;198: 32. Ducharme NG, Dill SG, Shin SJ, et al. Phenoxymethyl 839–842. penicillin in the horse: an alternative to parenteral admin- 9. Samitz EM, Jang SS, Hirsh DC. In vitro susceptibilities of istration of penicillin. Can J Comp Med 1983;47:436–439. selected obligate anaerobic bacteria obtained from bovine 33. Baggot JD, Love DN, Love RJ, et al. Oral dosage of peni- and equine sources to ceftiofur. J Vet Diagn Invest 1996;8: cillin V in adult horses and foals. Equine Vet J 1990;22: 121–123. 290–291. 10. Hoffman AM, Baird JD, Kloeze HJ, et al. Mycoplasma felis 34. Stevenson AJ, Weber MP, Todi F, et al. Plasma elimina- pleuritis in two show-jumper horses. Cornell Vet 1992;82: tion and urinary excretion of procaine after administration 155–162. of different products to Standardbred mares. Equine Vet J 11. Aleman M, Spier SJ, Wilson WD, et al. Corynebacterium 1992;24:118–124. pseudotuberculosis infection in horses: 538 cases (1982– 35. Nielsen IL, Jacobs KA, Huntington PJ, et al. Adverse re- 1993). J Am Vet Med Assoc 1996;209:804–809. action to procaine penicillin G in horses. Aust Vet J 1988; 12. Rumbaugh GE, Smith BP, Carlson GP. Internal abdomi- 65:181–185. nal abscesses in the horse: a study of 25 cases. JAmVet 36. Chapman CB, Courage P, Nielsen IL, et al. The role of Med Assoc 1978;172:304–309. procaine in adverse reactions to procaine penicillin in horses 13. Schneider RK, Bramlage LR, Moore RM, et al. A retrospec- [published erratum appears in Aust Vet J 1992 Aug;69(8): tive study of 192 horses affected with septic arthritis/teno- 193]. Aust Vet J 1992;69:129–133. synovitis. Equine Vet J 1992;24:436–442. 37. Blue JT, Dinsmore RP, Anderson KL. Immune-mediated 14. Schneider RK, Bramlage LR, Mecklenburg LM, et al. Open hemolytic anemia induced by penicillin in horses. Cornell drainage, intra-articular and systemic antibiotics in Vet 1987;77:263–276. the treatment of septic arthritis/tenosynovitis in 38. McConnico RS, Roberts MC, Tompkins M. Penicillin- horses. Equine Vet J 1992;24:443–449. induced immune-mediated hemolytic anemia in a 15. Murphey ED, Santschi EM, Papich MG. Regional intrave- horse. J Am Vet Med Assoc 1992;201:1402–1403. nous perfusion of the distal limb of horses with amikacin 39. Wilkerson MJ, Davis E, Shuman W, et al. Isotype-specific sulfate. J Vet Pharmacol Ther 1999;22:68–71. antibodies in horses and dogs with immune-mediated hemo- 16. Whitehair KJ, Bowersock TL, Blevins WE, et al. Regional lytic anemia. J Vet Intern Med 2000;14:190–196. limb perfusion for antibiotic treatment of experimentally 40. Horspool LJI, Sarasola P, McKellar QA. Disposition of am- induced septic arthritis. Vet Surg 1992;21:367–373. picillin sodium in horses, ponies and donkeys after intrave- 17. Butson RJ, Schramme MC, Garlick MH, et al. Treat- nous administration. Equine Vet J 1992;24:59–61. ment of intrasynovial infection with gentamicin-impreg- 41. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacoki- nated polymethylmethacrylate beads. Vet Rec 1996;138: netics and estimated bioavailability of amoxicillin in mares 460–464. after intravenous, intramuscular, and oral administration. 18. Summerhays GES. Treatment of traumatically induced Am J Vet Res 1988;49:1688–1694. synovial sepsis in horses with gentamicin-impregnated col- 42. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacoki- lagen sponges. Vet Rec 2000;147:184–188. netics and bioavailability of ticarcillin and clavulanate in 19. Snyder JR, Pascoe JR, Hirsh DC. Antimicrobial suscepti- foals after intravenous and intramuscular administra- bility of microorganisms isolated from equine orthopedic tion. J Vet Pharmacol Ther 1991;14:78–89. patients. Vet Surg 1987;16:197–201. 43. Sweeney RW, Beech J, Simmons RD, et al. Pharmacoki- 20. Markel MD, Wheat JD, Jang SS. Cellulitis associated with netics of ticarcillin and clavulanic acid given in combination coagulase-positive staphylococci in racehorses: nine cases to adult horses by intravenous and intramuscular (1975–1984). J Am Vet Med Assoc 1986;189:1600–1603. routes. J Vet Pharmacol Ther 1988;11:103–108.

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44. Sweeney RW, Beech J, Simmons RD. Pharmacokinetics of centrations after single dose intramuscular administra- intravenously and intramuscularly administered ticarcillin tion. J Vet Pharmacol Ther 1982;5:119–122. and clavulanic acid in foals. Am J Vet Res 1988;49:23–26. 66. Karlowsky JA, Zhanel GG, Davidson RJ, et al. Postantibi- 45. Hoffman AM, Viel L, Muckle CA, et al. Evaluation of sul- otic effect in Pseudomonas aeruginosa following single and bactam plus ampicillin for treatment of experimentally in- multiple aminoglycoside exposures in vitro. J Antimicrob duced Klebsiella pneumoniae lung infection in foals. Am J Chemother 1994;33:937–947. Vet Res 1992;53:1059–1067. 67. Moore RD, Lietman PS, Smith CR. Clinical response to 46. Sparks SE, Jones RL, Kilgore WR. In vitro susceptibility of aminoglycoside therapy: importance of the ratio of peak bacteria to a ticarcillin-clavulanic acid combination. Am J concentration to minimal inhibitory concentration. J Infect Vet Res 1988;49:2038–2040. Dis 1987;155:93–99. 47. Sarasola P, McKellar QA. Ampicillin and its congener pro- 68. Deamer RL, Dial LK. The evolution of aminoglycoside drugs in the horse. Br Vet J 1994;150:173–187. therapy: a single daily dose [see comments]. Am Fam 48. Ensink JM, Klein WR, Mevius DJ, et al. Bioavailability of Phys 1996;53:1782–1786. oral penicillins in the horse: a comparison of pivampicillin 69. Zhanel GG, Ariano RE. Once daily aminoglycoside dosing: and amoxicillin. J Vet Pharmacol Ther 1992;15:221–230. maintained efficacy with reduced nephrotoxicity? Renal 49. Ensink JM, Vulto AG, van Miert AS, et al. Oral bioavail- Fail 1992;14:1–9. ability and in vitro stability of pivampicillin, bacampicillin, 70. Godber LM, Walker RD, Stein GE, et al. Pharmacokinet- talampicillin, and ampicillin in horses. Am J Vet Res 1996; ics, nephrotoxicosis, and in vitro antibacterial activity asso- 57:1021–1024. ciated with single versus multiple (three times) daily 50. Ensink JM, Mol A, Vulto AG, et al. Bioavailability of piv- gentamicin treatments in horses. Am J Vet Res 1995;56: ampicillin and ampicillin trihydrate administered as an oral 613–618. paste in horses. Vet Quarterly 1996;18:S117–S120. 71. Riviere JE, Coppoc GL. Selected aspects of aminoglycoside 51. Ensink JM, Santen EV, Tukker JJ, et al. Pivampicillin antibiotic nephrotoxicosis. J Am Vet Med Assoc 1981;178: granules: a new formulation of pivampicillin for horses, in 508–509. Proceedings. 7th Eur Assoc Vet Pharmacol Toxicol Inter- 72. Riviere JE, Coppoc GL, Hinsman EJ, et al. Species depen- natl Cong. 1997;20–38. dent gentamicin pharmacokinetics and nephrotoxicity in the 52. Sarasola P, McKellar QA. Pharmacokinetics of bacampicil- young horse. Fundam Appl Toxicol 1983;3:448–457. lin in equids. Am J Vet Res 1995;56:1486–1492. 73. Nostrandt AC, Pedersoli WM, Marshall AE, et al. Ototoxic 53. Folz SD, Hanson BJ, Griffin AK, et al. Treatment of respi- potential of gentamicin in ponies. Am J Vet Res 1991;52: ratory infections in horses with ceftiofur sodium [published 494–498. erratum appears in Equine Vet J 1992 Sep;24(5):366] [see 74. Van Duijkeren E, Vulto AG, Van Miert AS. Trimethoprim/ comments]. Equine Vet J 1992;24:300–304. sulfonamide combinations in the horse: a review. J Vet 54. Mahrt CR. Safety of ceftiofur sodium administered intra- Pharmacol Ther 1994;17:64–73. muscularly in horses. Am J Vet Res 1992;53:2201–2205. 75. Amyes SG, Smith JT. Trimethoprim-sensitivity testing 55. Jaglan PS, Roof RD, Yein FS, et al. Concentration of cef- and thymineless mutants. J Med Microbiol 1974;7:143– tiofur metabolites in the plasma and lungs of horses follow- 153. ing intramuscular treatment. J Vet Pharmacol Ther 1994; 76. Brown MP, Gronwall R, Castro L. Pharmacokinetics and 17:24–30. body fluid and endometrial concentrations of trimethoprim- 56. Meyer JC, Brown MP, Gronwall RR, et al. Pharmacokinet- sulfamethoxazole in mares. Am J Vet Res 1988;49:918– ics of ceftiofur sodium in neonatal foals after intramuscular 922. injection. Equine Vet J 1992;24:485–486. 77. Bogan JA, Galbraith A, Baxter P, et al. Effect of feeding on 57. Cervantes CC, Brown MP, Gronwall R, et al. Pharmacoki- the fate of orally administered phenylbutazone, tri- netics and concentrations of ceftiofur sodium in body fluids methoprim and sulphadiazine in the horse. Vet Rec 1984; and endometrium after repeated intramuscular injections in 115:599–600. mares. Am J Vet Res 1993;54:573–575. 78. Green SL, Mayhew IG, Brown MP, et al. Concentrations of 58. Salmon SA, Watts JL, Yancey RJ, Jr. In vitro activity of trimethoprim and sulfamethoxazole in cerebrospinal fluid ceftiofur and its primary metabolite, desfuroylceftiofur, and serum in mares with and without a dimethyl sulfoxide against organisms of veterinary importance. J Vet Diagn pretreatment. J Vet Pharmacol Ther 1992;15:309–313. Invest 1996;8:332–336. 79. White G, Prior SD. Comparative effects of oral administra- 59. Yancey RJ Jr, Kinney ML, Roberts BJ, et al. Ceftiofur tion of trimethoprim/sulphadiazine or oxytetracycline on the sodium, a broad-spectrum cephalosporin: evaluation in faecal flora of horses. Vet Rec 1982;111:316–318. vitro and in vivo in mice. Am J Vet Res 1987;48:1050– 80. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacoki- 1053. netics, bioavailability, and in vitro antibacterial activity of 60. Jones SL, Wilson WD, Milhalyi JE. Pharmacokinetics of rifampin in the horse. Am J Vet Res 1988;49:2041–2046. gentamicin in healthy adult horses during intravenous fluid 81. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin administration. J Vet Pharmacol Ther 1998;21:247–249. disposition in the horse: effects of age and method of oral 61. Magdesian KG, Hogan PM, Cohen ND, et al. Pharmacoki- administration. J Vet Pharmacol Ther 1992;15:124–132. netics of a high dose of gentamicin administered intrave- 82. Burrows GE, MacAllister CG, Beckstrom DA, et al. Ri- nously or intramuscularly to horses. J Am Vet Med Assoc fampin in the horse: comparison of intravenous, intramus- 1998;213:1007–1011. cular, and oral administrations. Am J Vet Res 1985;46: 62. Magdesian KG, Wilson WD, Mihalyi J. Pharmacokinetics 442–446. and nephrotoxicity of high dose, once daily administered 83. Kohn CW, Sams R, Kowalski JJ, et al. Pharmacokinetics amikacin in neonatal foals, in Proceedings. 43rd Ann Conv of single intravenous and single and multiple dose oral ad- Am Assoc Equine Practnr 1997;396–397. ministration of rifampin in mares. J Vet Pharmacol Ther 63. Golenz MR, Wilson WD, Carlson GP, et al. Effect of route 1993;16:119–131. of administration and age on the pharmacokinetics of ami- 84. Prescott JF. The susceptibility of isolates of Corynebacte- kacin administered by the intravenous and intraosseous rium equi to antimicrobial drugs. J Vet Pharmacol Ther routes to 3 and 5-day-old foals. 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Proceedings of the Annual Convention of the AAEP 2001