Antibiotics in the Treatment of Wounds

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Wound Management

Antibiotics in the Treatment of Wounds

Shauna L. Spurlock, DVM, MS,* and Elizabeth A. Hanie, DVMt

The use of antibiotics in the treatment of wounds is but one aspect of patient management. Debridement of the wound, surgical reconstruction, and tetanus prophylaxis should all be considered. 22 • 49 • 51 With a spectrum of clinical situations, the first step in selecting an appropriate antibiotic for a patient with a wound is discovering factors that influence the establishment of an infection. Certain characteristics of a wound or of the patient increase the likelihood of infection, prompting the rational inclusion of antibiotics in the treatment regimen. 92 Wound Factors Tissue devascularized by necrosis, trauma, or crushing has decreased delivery of immunoglobulins and white blood cells to the site. 47 These physiologic factors , combined with the exact number of a specific bacteria, determine whether a suppurative lesion will develop. Despite the variety of both aerobic and anaerobic bacteria that are present in the environment and may be introduced when the integrity of the skin is interrupted, it has been suggested that it is not the specific bacteria but rather the number of bacteria in the wound that is the most important factor. 47 • 51 As an infectious process becomes established, further reduction of blood flow may occur. As an example, traumatically induced osteomyelitis is usually associated with some degree of damage to the periosteum and surrounding soft tissue. The resulting environment favors bacterial growth , since the blood supply to the osseous tissue is anatomically limited and often damaged during a traumatic episode. Local necrosis in the traumatized area follows, preventFrom the Marion duPont Scott Equine Medical Center, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Leesburg, Virginia *Assistant Professor, Medicine tResident, Surgery The Veterinary Clinics of North America: Equine Practice-Vol. 5, No. 3, Decem ber 1989

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ing the animal's immune defenses from gaining access to the area. This prevents resorption of necrotic tissue and limits antibiotic penetration.

Patient Factors The status of the patient's immune system may also play a role in the development of infection. 49 Malnutrition, underlying renal or liver disease, treatment with immunosuppressive drugs such as steroids, and the presence of other systemic diseases may have a negative impact on the animal's immune function. If any of these conditions are present, then the animal may require antimicrobial therapy to help contain the infection until such a time that the immune system can effectively respond. Antibiotics must work in concert with a competent immune system to effect a cure. Antibiotics will not and cannot take the place of the host's immune response.

ANTIBIOTIC SELECTION To be effective, an antibiotic must reach levels at the site of the infection that kill or retard the growth of the pathogen. This entails selection of an antibiotic to which the pathogen is sensitive and delivery of an appropriate dose for an adequate period of time. 16• 63 Once sepsis is suspected, every attempt should be made to identify the organisms involved and their susceptibility. Samples for culture and susceptibility testing should be taken prior to initiating antibiotic therapy. Initial Gram stain examination to determine if gram-positive and/or gram-negative organisms are present should also be performed. The results of the Gram stain combined with the knowledge of likely organisms involved should aid in the initial selection of antibiotics, as initiation of such therapy may be necessary prior to availability of culture results. 72 Streptococcus spp are the most frequently isolated bacteria from wounds in a variety of locations, but any number of gram-positive and gram-negative aerobic and anaerobic organisms may gain entry through a wound . 63 The presence of anaerobic organisms in soft tissue infections appears to be higher than previously thought, 34 and anaerobes have been shown to be capable of producing osteomyelitis single-handedly, especially when metallic implants are placed. 22 The role of anaerobes should be considered when culture results are negative, and especially in cases of osteomyelitis, abscess formation, or in the presence of draining tracts. With a wide variety of pathogens that may be encountered, both aerobic and anaerobic cultures should be submitted. Negative culture results may be encountered, owing to prior antibiotic administration or flaws in sampling or laboratory techniques, or the pathogenic bacteria may not be represented in the sample obtained. 25 To minimize the chance of erroneous results, a reputable laboratory should be used, along with steps taken to deliver the best possible sample. The aerobic culture should be placed in thioglycolate or infusion broth after streaking on blood agar. If antibiotics were given prior to obtaining samples for cultures, an antibiotic removal device may be appropriate. Anaerobic

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cultures should be placed in a commercial anaerobic transport medium, not shipped on swabs, as drying and exposure to oxygen may occur. As an alternative, 2 ml of fluid may be shipped in a small, tightly capped tube for anaerobic culturing. 33 Isolation of invading organisms may be more difficult in specific situations. Identification of pathogens within a joint can be particularly difficult, owing to the fact that the bacteria may not be present in the joint fluid. 22 • 41 • 43 If culture results for synovial fluid are negative, synovial biopsy and culture may provide more reliable information. Draining tracts frequently accompany osteomyelitis. Since all major pathogens can colonize these tracts, culture results will not correctly identify organisms growing within the bone. 87 Although nearly two thirds of infected skeletal samples yield only one organism from surgical bone biopsy cultures, sinus tract cultures over the same lesion commonly reveal mixed growth with contaminants. 33 In a study of draining tracts in human patients, only 44 per cent of the sinus tract cultures contained the organism recovered from the corresponding surgical bone biopsy culture. Only in the case of Staphylococcus aureus was there a good correlation between sinus tract cultures and actual infected bone culture. Obtaining fine-needle aspirates of the affected area is a valuable technique if a lytic lesion is present, using a direct path to the area under local anesthesia. 35 If surgical debridement of the area is undertaken, a culture of the infected bone should always be submitted. In vitro culture and sensitivity testings are invaluable in identifying antimicrobial agents to which the pathogen is sensitive 00 • 87 ; however, there are limitations to the use of these techniques. Results of the Kirby-Bauer disk diffusion test, which has become an integral part of human and veterinary medicine, relate to the susceptibility pattern of aerobic bacteria. This method fails to take into account species' variations in achievable blood levels or tissue concentrations that may be above or below blood levels. The information obtained from the Kirby-Bauer disk diffusion test must be evaluated in light of the site of infection and specific characteristics of the antimicrobial agents that may aid or limit penetration to the site of infection. Pharmacokinetic data provide some information on distribution of the drug as well as concentrations found in serm. Since organisms causing soft tissue infection are most likely found in the extracellular fluid, serum levels should be reasonable predictors of levels at the site of infection. 67 Technical problems exist in determining the antibiotic concentration in bone 58 • 66 or other tissue such as muscle, 67 making specific dosing recommendations more difficult. Environmental factors may also influence antimicrobial activity at the site of infection. An acidic pH and the presence of purulent material have a profound inhibitory effect on a number of antimicrobial agents. Local factors may either limit or enhance penetration of an antibiotic. Fibrin or blood clots have been shown to limit antibiotic penetration, but inflammation may enhance penetration. The dosing interval and route of administration may also impact on penetration of an antibiotic. 42 Intermittent dosing resulting in fluctuating blood levels from very high to low allows a diffusion gradient to be established. 38 This has been shown to enhance penetration of antibiotics. 9

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These fluctuations in blood levels are from well above minimum inhibitory concentration (MIC) of the pathogen to levels below the MIC. This creates another controversy as to whether or not the blood levels should be kept in excess of the MIC for the particular pathogen . Subinhibitory levels of antibiotics may better cooperate with host defense mechanisms through several means . 15• 38 The expression of antiphagocytic material seems to be impaired by subinhibitory levels of antibiotics , favoring phagocytosis and killing by macrophages. Adhesion of bacteria to mucosa! surfaces through alteration of their cell surface may also occur with subinhibitory levels of antibiotics. 3 This postantibiotic effect lasts for a period of several hours after complete removal of the drug, during which time there is no growth of the target organism. 15• 50 This effect has been demonstratred for a number of organism and antibiotic combinations. Marked differences among drugs do exist, and the duration of postantibiotic effect and the drug concentration required to produce them can vary with different bacteria. While much remains unknown about the clinical application of pulse dosing, the idea of intermittent drug administration resulting in higher serum concentrations and better tissue penetration can certainly be used in the clinical approach to cases. Duration of Therapy

The optimum duration of antibiotic therapy remains unclear. 85 Recommendations have been based on clinical laboratory parameters such as white blood cell count (WBC) and fibrinogen concentration as well as clinical evidence of improvement. The type of tissue involved in the trauma also plays a role in determining the necessary length of antimicrobial therapy. It is generally accepted that infections involving bone and joints require long-term antibiotic therapy, as bacteria can survive for long periods of time in the bone and physeal cartilage. Premature discontinuation of the antibiotics may result in recurrence of the infection, and it has been suggested that treatment for 2 to 3 months may be necessary. 49 A shorter duration of treatment in cases of osteomyelitis or joint infection has been advocated by some investigators, provided initial clinical response has been good. In cases of osteomyelitis and osteoarthritis occurring in human patients, intravenous antibiotics were maintained for a minimum of 3 weeks, followed by oral administration of effective antibiotics. 22 • 85 The recommended duration of oral antibiotics was two to three times that used for minor infections .85 As an alternative in cases of gram-negative osteomyelitis, long-term intravenous therapy has been suggested. Work conducted in human patients demonstrated that the use of long-term intravenous catheters provided a means of antibiotic delivery for up to 3 months on an outpatient basis. 94 The same rationale has been applied to equine patients that require long-term venous access through the use of catheters made of softer material, such as Silastic or polyurethane. In determining the duration of antibiotic therapy for a particular wound, the structures involved and soft tissue compromise should be considered. If antibiotics are deemed appropriate , a minimum course of therapy would be 3 to 5 days. The more compromised the tissue, the more

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prolonged the therapy should be. Wounds involving tissues with a poor blood supply require a more prolonged course of antibiotic therapy. 49

Route of Administration Oral, intramuscular, and intravenous delivery routes are most commonly utilized in veterinary medicine. Oral administration is often preferred, owing to considerations of owner compliance as well as patient compliance . Antibiotics that are routinely delivered orally include trimethoprim/sulfa combination, rifampin, metronidazole , and erythromycin. Although these antibiotics are effective against a variety of pathogens, it may not be possible to use them in the face of some gram-negative infections. Additional drawbacks to the oral administration of antibiotics is the potential for variability in gastrointestinal absorption. In humans , this is a major cause for concern and has led to recommendations of therapeutic monitoring of patients on oral antimicrobial therapy to assure that appropriate absorption has occurred. Parenteral administration of antibiotics may be more difficult for clients to perform. The intramuscular route of administration does allow for longer dosage intervals in many cases, owing to the prolonged absorption from the site of administration. But the specific site of delivery may also influence the rate of uptake, with deposition between fascia! planes resulting in more prolonged absorption as opposed to uptake from muscle itself. The intravenous route of administration may be technically more difficult, but placement of an intravenous catheter can facilitate intermittent drug administration . This route of administration has the advantage of bypassing absorption and results in predictably high circulating blood levels. More fluctuation in blood levels is encountered, but this may facilitate diffusion. One of the major disadvantages of this route of administration is the need for more frequent dosing.

PENICILLINS The penicillins are the oldest family of antibiotics and are still effective and widely used. The 13-lactam ring is the structural entity that distinguishes the family. The bactericidal effect is a result of interference with cell wall development, and elimination is primarily by the kidneys . With the exception of Bacteroides fragilis, the penicillins are generally effective against anaerobic organisms, making this family of antibiotics important in the treatment of wounds, osteomyelitis, abscesses, or draining tracts, all of which may harbor anaerobic organisms. In general, the penicillins are distributed well to the extracellular fluid. 24 • 78 • 95 Levels in synovial fluid are approximately 60 to 70 per cent of the serum level, whereas penetration into bone is more variable for the different members of the penicillin family. 20 · 58 The family is remarkably nontoxic, but all members have the potential for hypersensitivity reactions . Understanding the structure of penicillin and its relationship to therapeutic weaknesses , including destruction of penicillin by acid and 13-lactamase enzymes and a low activity against

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gram-negative bacteria, has allowed for modification to combat these shortcomings. Modifications in the chemical structure of penicillin results in maintenance of the low potential for toxicity and permits the selection of the route of administration and antibacterial spectrum. 27 The most appropriate member of the family should be chosen, with the dose and interval of treatment tailored to the recipient. Penicillins may be classified, based on their structure and activity, into four groups. The benzylpenicillin or penicillin G is perhaps the most widely used form of penicillin, followed by the extended-spectrum penicillins. Oral delivery of an acid-resistant penicillin such as phenoxymethylpenicillin (penicillin V) results in low blood levels, limiting its usefulness to the treatment of highly sensitive organisms such as Streptococcus. 71 · 75 Penicillinase-resistant penicillins have been reported to have decreased antibacterial activity, making maintenance of full-dosage schedules imperative in their use. The kinetics data on oxacillin, one of the penicillinase-resistant penicillins, suggest that 25 mg/kg be given intravenously or intramuscularly every 8 to 12 hours. 39 · 77 Available forms of benzylpenicillin or penicillin G include procaine penicillin, benzathine penicillin, and the sodium or potassium salts. These have, primarily, a gram-positive spectrum and are inactivated in acid environments by [3-lactamases. Although the half-life for penicillin G is less than 1 hour, the magnitude and duration of blood levels depend on the solubility of the particular salt or ester. 75 The sodium and potassium salts may be given intramuscularly, intravenously, or subcutaneously. Both forms are highly soluble, resulting in rapid absorption. The penicillin in the blood is rapidly eliminated, necessitating frequent administration (every 4 to 6 hours) to maintain therapeutic blood levels. 75 All soluble penicillin salts share a problem with stability, necessitating reconstitution just prior to administration and a very limited shelf life , even with refrigeration. Procaine penicillin differs from the potassium and sodium salts in that absorption from the intramuscular sites is slower; this allows for prolonged maintenance but lower blood levels of penicillin. 80 The obvious advantage is decreased frequency of administration; however, lower blood and tissue levels require a relatively more sensitive pathogen. The dosage recommendation on the package insert is 3,000 IU/lb (6,600 IU/kg). This is substantially less than the 15,000 to 50,000 IU/kg dose that is recommended to produce effective blood levels. 45 • 46 · 91 An additional consideration on the administration of procaine penicillin is the potential for positive blood tests for procaine up to 2 weeks after administration. Central nervous system (CNS) signs may also be attributed to procaine, as horses are reportedly 20 times more sensitive to this substance than are humans. As for benzathine penicillin, low blood and tissue concentrations limit its value to highly sensitive streptococcal organisms . 45 Most penicillins are limited in their ability to penetrate gram-negative cell walls. This is caused by the molecular structure of penicillin and the difficulty in penetrating the lipopolysaccharide layer of gram-negative organisms external to the peptidoglycan network. Modification of the penicillin molecule has resulted in a group of extended-spectrum penicillins .

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It is important to point out that members of this group are, as a rule, more expensive, generally less potent for gram-positive organisms, and may alter normal flora and allow overgrowth of resistant organisms 95 ; therefore, selection of extended-spectrum antibiotics should be based on sound clinical judgment and laboratory evidence that a particular organism is resistant to benzylpenicillin. Ampicillin was the first of the extended-spectrum penicillins. 26 · 61 Two preparations of ampicillin are available for use: ampicillin trihydrate and sodium ampicillin. Like the sodium salt of penicillin G, sodium ampicillin may be given intramuscularly, intravenously or subcutaneously. It is well absorbed, produces high blood levels, and is eliminated by the kidneys. In contrast to sodium penicillin, the half-life of sodium ampicillin is about 90 minutes. It is less protein-bound, and its spectrum includes a number of gram-negative organisms in addition to gram-positive, penicillin-sensitive organisms. 23 · 37 · 91 It is important to recognize that the term "sensitive" must be interpreted in light of the pathogen. For example, sensitive grampositive organisms may have a minimum inhibitory concentration of less than 0.5 mcg/ml, whereas a sensitive gram-negative organism may have a MIC of up to 5 mcg/ml. 90 This points out the need to give ampicillin at higher doses and/or shorter dosing intervals to achieve a therapeutic success with most gram-negative pathogens. The trihydrate form of ampicillin closely resembles intramuscular procaine penicillin, in that lower blood levels are maintained for longer periods of time. 8 · 23 · 90 Oral administration of ampicillin trihydrate has been evaluated in foals. Although the blood levels obtained paralleled levels after intramuscular administration, the rate of clearance increased as the foals became older. 14 The more rapid elimination resulted in a more rapid decline in blood levels. Given the relative insensitivity of equine pathogens, administration of ampicillin trihydrate by either route is likely to be effective only in the face of highly sensitive gram-positive infections. Amoxicillin and ampicillin are very similar in structure, with essentially the same spectrum of activity; however, amoxicillin differs in that a larger percentage is absorbed after oral administration, and it has a more rapid bactericidal effect. 75 · 98 Oral dosage regimens have been described for the foal, but these should be used with the same precautions as for penicillin V. Relatively low blood levels can be anticipated, which limits therapeutic efficacy to highly sensitive organisms. 4 · 46 The greatest interest recently has been focused on the development and clinical application of penicillins with an enhanced gram-negative spectrum, including Pseudomonas. While the MIC of a number of equine pathogens, including Pseudomonas , is relatively high, the low toxicity of these antimicrobials allows for the administration of a dose sufficiently large to reach and exceed the inhibitory level. Distribution of these drugs may differ somewhat from other ~-lactams. Although distribution within the extracellular fluid remains good, the antipseudomonal penicillins penetrate bone more effectively, with about 20 per cent of the serum level achieved in the bone. Ticarcillin has been evaluated in the horse . 76 · 81 The information available regarding achievable blood levels, combined with the MIC of the

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pathogen, allow for the selection of an appropriate dose. For example, ticarcillin given at the dose of 7 mg/lb results in peak blood levels of 14. 7 mcg/ml 30 minutes after injection, with a decline to less than 4 mcg/ml by 6 hours. 81 These levels may be adequate when dealing with a 13-hemolytic streptococcal organism, for which the MIC may be 0.5 mcg/ml; however, to achieve blood levels greater than 25 mcg/ml, the MIC of Pseudomonas, it would require an intramuscular dose of 20 mg/lb, repeated approximately every 6 hours. Since penicillin G, penicillinase-resistant penicillins, or ampicillin are preferred for gram-positive organisms, ticarcillin should be reserved from gram-negative organisms. Situations in which its use is justified usually require administration of the higher dose rates. Further, the temptation to control cost by decreasing the dose must be avoided. Despite the wide spectrum of activity, use of ticarcillin alone has been questioned. Rapid development of R factor mediated resistance has been noted in human pathogens when ticarcillin is the sole antimicrobial agent. 20 Such resistance has not been a problem when an aminoglycoside or appropriate cephalosporin is included in the treatment regimen. An additional advantage of incorporating an aminoglycoside in the treatment regimen is the synergistic activity that has been demonstrated. 84 • 93 In vitro, the MIC of each antibiotic may be reduced by a factor of four or more. 75 Recently, a fixed combination of ticarcillin and clavulanic acid has become available. Pharmacokinetic data generated in the horse suggest that 50 mg/kg ticarcillin and 1. 7 mg/kg clavulanic acid given intravenously every 6 hours should achieve a therapeutic serum concentration. 82 Specific tissue concentrations have yet to be determined. This combination is designed to prevent inactivation of the ticarcillin by 13-lactamases and, thereby, enhance antibacterial activity. 36 · 73 Clavulanic acid has a special affinity for such plasmid-mediated 13-lactamases as might be produced by S. aureus or by some gram-negative bacteria36 ; however, it is relatively ineffective against non-plasmid-mediated 13-lactamases produced by other gram-negative bacilli. As with ticarcillin alone, combining ticarcillin/clavulanic acid with an appropriate aminoglycoside should decrease the chance of developing resistance . 36 · 97

CEPHALOSPORINS Cephalosporins share with penicillin the 13-lactam ring; however, differences in the adjoining ring (five-mem her ring for penicillin, sixmember ring for cephalosporin) result in antibiotic agents that are more resistant to hydrolysis by many bacterial 13-lactamases and are able to penetrate the outer envelope of gram-negative organisms. 30· 57 · 86 They also are effective against anaerobic organisms, with the exception of B. fragilis. Like other 13-lactam antibiotics , cephalosporins are bactericidal agents that interfere with the cell-wall synthesis and are quickly eliminated by the kidneys. In addition and in contrast to penicillins, biotransformation in the liver may take place with some members of this group. 69 · 86 In general, the cephalosporins are expensive antimicrobials, and the cost escalates with each succeeding generation. As with penicillin, the cephalosporins are

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associated with a low incidence of adverse reaction .57 • 86 In general, they are well distributed in the extracellular fluid. Synovial fluid levels are excellent, and antibiotics do enter the bone. For these reasons, cephalosporins are widely used for prophylaxis in long orthopedic procedures, especially those involving implants. 28 · 53 Cephalosporin antibiotics have been classified in te rms of gene ration, with membe rs of a given gene ration possessing similar in vitro antibacterial potency and spectrum activity. The first-generation cephalosporins have good activity against most gram-positive bacteria, including a number of penicillinase-producing strains of Streptococcus and some gram-negative organisms. It is this group of cephalosporins that have been evaluated most extensively in the horse: cephalothin, cefadroxil, cephapirin, and cefazolin are first-ge ne ration cephalosporins for which kinetic information has bee n generated in the horse . Although studies have shown a large number of equine pathogens to be sensitive to these antimicrobial agents, there are drawbacks to the ir use. Cephalothin is quickly metabolized by esterases in the kidney, liver , small intestine, and stomach. 65• 69 The resulting metabolite has greatly reduced antimicrobial activity, and its concentration exceeds that of the parent drug 15 minutes after administration. 65 This rapid metabolism limits the clinical usefulness of the drug. Cefadroxil had the potential advantage of a wide distribution as the result of a relatively greater degree of lipid solubility, while maintaining good water solubility. 30· 86 However, kine tic information shows that frequent intravenous dosing would be necessary to maintain blood levels in excess of the MIC for most pathogens, and oral administration resulted in poor and inconsistent absorption.97 Cepharin shares many of cefazolin's properties including the need for parenteral administration. 86 Kinetic data suggest that a dose of 20 mg/kg of cepharin given intramuscularly at 8-hour intervals might be useful in treating infections caused by S. aureus. 12 Cefazolin is a first-generation cephalosporin that had been advocated as the drug of choice for human orthopedic procedures. The MIC for many equine pathogens has been determined to be le ss than 2 mcg/ml. 69 · 70 This concentration can be achieved with the administration of 11 mg/ kg of cefazolin , given intramuscularly or intravenously. However, the 2 mcg/ml leve l is exceeded only for a 2- to 4-hour pe riod. 70 D espite this limitation, cefazolin has been used in horses when susceptible organisms are present or as a prophylactic age nt in equine orthoped ic procedures. This rapid elimination requires frequent dosing to maintain blood above the MIC. Second-generation cephalosporins are the product of various substitutions on the ring structure. These are antimicrobial age nts effective against a greater numbe r of gram-negative organisms, but they possess less activity against gram-positive organisms. Cefoxitin is a second-ge neration cephalosporin that has been evaluated in a limited number of horses. 11 This drug seems to penetrate a variety of tissues, with therapeutic levels achieved in a number of body fluids , including synovial fluid. Intravenous injection of sodium cefoxitin demonstrated a half-life of 0.82 hours, with elimination occurring primarily via the kidneys. Intramuscular administration of 20 mg/ kg every 8 hours should maintain body fluid levels above 2.4 mcg/ml. In a

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study evaluating repeated intramuscular administration of this drug to six mares, one horse developed acute laminitis. The role that cefoxitin played in the development of this condition is unknown at this time. 11 Third-generation cephalosporins show a further decrease in efficacy against gram-positive organisms but are very resistant to gram-negative 13lactamases, and several are effective against Pseudomonas aeruginosa. The clinical use of both second- and third-generation cephalosporins is limited, owing to lack of kinetic data, expense, and the availability ofother antibiotics that are equally effective against equine pathogens.

AMINOGLYCOSIDES Aminoglycosides as a group are effective against a variety of gramnegative aerobic organisms through inhibition of protein synthesis. When aminoglycosides are used, toxic side effects must be considered, particularly nephrotoxicity. 62 • 64 Disease conditions that decrease renal perfusion, including hypovolemia and endotoxemia, have been associated with an increased risk of aminoglycoside-induced nephrotoxocity. Use of this family of antibiotics in young animals has also been reported to be associated with increases in nephrotoxicity, in spite of the comparatively larger extracellular fluid compartment in these animals. To monitor for any adverse effects on renal function, periodic dete rmination of blood urea nitrogen (BUN), creatinine, and urinalysis (presence of blood, protein, or casts) is recommended. A more sensitive indicator of tubular damage would be an elevation of the ratio of urinary -y-glutamyl transpeptidase to urine creatinine. Early detection of nephrotoxicity is important, so that the dose may be reduced or the aminoglycoside discontinued. Although not routinely performed in a clinical setting, therapeutic monitoring or aminoglycoside blood levels does allow for appropriate alterations in the dosage schedule, thereby minimizing the chance of nephrotoxicity. Peak levels may also be important in determining the clinical response. With aminoglycoside therapy, a positive clinical response has been correlated with the peak concentrations.52 More specifically, high peak concentrations relative to the MIC for the infecting organism has been shown to be a major determinant of clinical response to aminoglycoside therapy. This suggests that route of administration as well as frequency of administration may be important in determining the clinical outcome. Administration via the intral'enous route results in higher peak levels than does the same dose given intramuscularly. This same rationale has led to intraarticular administration of gentamicin when treating infectious arthritis. This route is used to achieve a higher synovial fluid concentration . Both human and veterinary medical literature have questioned this practice because of the synovial irritation that may develop, presumably owing to the acidity of the gentamicin solution. 19· 2 1. 22· 48 Recent work evaluating the synovial fluid and histologic changes suggests that a mild transient synovitis, evidenced b y increases in red blood cells, white blood cells, and protein, does ensue. 9 From this

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work as well as a study evaluating intraarticular administration of buffered gentamicin in normal joints, it appears that factors other than acidity may be responsible for the synovitis . H 79 The synovial changes that occurred after intraarticular administration of gentamicin were mild; however, specific recommendations for this route of administration in the treatment of septic arthritis are needed, and the level of antibiotic achieved and maintained in both the syovial fluid and surrounding tissue should be evaluated and compared with levels achieved and maintained after parenteral administration. Distribution to various body fluids and tissues is good with the exception of CSF and vitreous humor. The presence of inflammation may increase the concentration of antibiotic reaching the site. This has been shown with experimentally induced synovial inflammation. Systemically administered kanamycin apparently entered inflamed joints more easily, 29 resulting in highe r concentrations than in normal joints. These higher concentrations may be of little help if local factors are not favorable . An acidic pH and the presence of purulent exudate greatly decrease the effectiveness of aminoglycosides. To minimize the impact of these local factors , surgical debridement or flushing of areas may be important. Of this family of antibiotics, kanamycin, gentamicin, and amikacin are the three most commonly used . Ove r the past few years, development of bacterial resistance has been reported with kanamycin, and this has resulted in decreased use in particular geographic areas. There is no doubt that resistance problems also exist with gentamicin in particular areas; and with indiscriminate use , this is likely to increase. With clinically important strains of bacteria possessing transferable R factor resistance, antibiotic use should be limited to those cases in which culture and sensitivity determinations indicate that their use is warranted, or when the disease is of a lifethreatening nature , necessitating the delivery of broad-spectrum antibiotics prior to the availability of results of specific cultures. To provide broadspectrum antibiotic coverage, aminoglycosides are frequently given in combination with a ~-lactam antibiotic. Such combinations have been shown to be synergistic. 84 · 93 Gentamicin remains the most commonly used aminoglycoside. 7· J.,. 35 · 59 Dosage recommendations vary from 2.2 mg/kg to 4.4 mg/kg, with total doses of less than 9 mg/kg divided BID or QID most often reported . The goal is to achieve serum concentration of 3 to 10 mcg/ ml, which has been suggested as being efficacious in treating gram-negative infections in various sites. 32 · 59 Pharmacokinetic studies have demonstrated that 3 to 5 mg/kg of gentamicin given intramuscularly every 8 hours should produce average steady-state serum concentrations of 7 mcg/ml , with minimum and maximum level of 1.1 and 16.8 mcg/ml, respectively. Such calculations have been performed in healthy animals, and it should be noted that this level of drug administration has been associated with nephrotoxicity. Recognizing that a disease state may alter the volume of distribution and also the rate of elimination, the narrow therapeutic index of gentamicin suggests that therapeutic monitoring may be warranted. Peak serum concentrations consistently greater than 12 to 15 mcg/ml and trough levels consistently

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greater than 2 mcg/ml have been associated with increased nephrotoxicity in people. 52 Amikacin is a derivative of kanamycin, to which most gram-negative organisms are sensitive. In order to prevent further development of drug resistance it has been suggested that the use of amikacin be limited to those cases in which culture and sensitivity determinations indicate that its use is warranted. Combining pharmacokinetic data with information available on MICs for various equine pathogens, it has been suggested that the therapeutic dose of amikacin would be between 4.4 and 6.6 mg/kg twice daily. 31 • 56 For more serious infections, increasing the frequency to three times per day has been suggested. The nephrotoxic effects of amikacin are reported to be less frequently encountered than with gentamicin; still, monitoring for nephrotoxicity should be considered, especially as the dose and frequency of administration are increased. Healthy horses have been dosed with 4.5 mg/kg twice per day for 14 days without evidence of renal pathology. 56

POTENTIATED SULFAS The combination of trimethoprim and sulfonamides has a synergistic effect on folate metabolism in the bacterial cell. The result is a marked improvement in the in vitro effects of both drugs against common pathogens. The broad spectrum of activity includes most gram-positive organisms as well as a number of gram-negative organisms and obligate anaerobes. 68 Trimethoprim in combination with sulfadiazine or sulfamethoxazole has been evaluated in the horse . Equal doses of sulfadiazine or sulfamethoxazole have been shown to result in similar serum concentrations. Likewise, results of in vitro susceptibility testing with trimethoprim and sulfadiazine or trimethoprim and sulfamethoxazole are similar. Both combinations result in good distribution of the drug, with trimethoprim tissue levels exceeding serum levels, and with sulfa levels, in most cases, approximating serum concentrations. A parenteral product is also available for intravenous administration. As a suspension, rapid delivery is contraindicated. The major advantage of these combination products is the availability of an oral preparation. While adequate blood levels of trimethoprim and sulfa can occur following oral administration, gastrointestinal absorption may be variable, and feed intake has been shown to reduce the absorption of trimethoprim, with no consistent effect on sulfadiazine absorption in the horse. IO . 74 Age may also have an effect on gastrointestinal absorption. The area under the plasma concentration time curves for trimethoprim and sulfadiazine have been shown to be greater in 1-day-old foals and to decline with increasing age. The dosage range of trimethoprim and sulfa varies with the pathogen and clinical response. Delivery of 15 mg/kg to 35 mg/kg (total of trimethoprim and sulfa) once per day or twice per day has been recommended. IO, 74 The lower dose given twice per day should be adequate for treating infections caused by Corynebacterium pseudotuberculosis, S. aureus, S. zooepidemicus, and obligate anaerobes. Higher doses may be necessary for

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successful treatment of infections caused by other less susceptible organisms. In addition, the higher levels have been shown to be more effective in producing microbiologic cures in experimentally induced S. aureus septic arthritis in the horse.

Miscellaneous Antibiotics Obligate anaerobes have been demonstrated to be important contributing agents of pyonecrotic processes in domestic animals. 22 • 34 Studies from different species indicate that from 25 to 40 per cent of positive culture samples obtained from animals may contain obligate anaerobes. Although penicillin is effective against a wide variety of anaerobes, B. fragilis, a 13lactamase secreting obligate anaerobe, may be resistant. Improved culturing technique s in veterinary laboratories have been credited with more frequent identification of B. fragilis as well as other obligate anaerobes in samples obtained from animal species. This has increased concern about the involvement of anaerobes that may be resistant to penicillin or other 13-lactam antibiotics. Me tronidazole is highly active against obligate anaerobes, particularly B. fragilis . Whereas prohibitively expensive in the intravenous form, metronidazole may be given orally, as it is well absorbed in the stomach and duodenum . 83 Bioavailability has been reported to be 75 to 85 per cent, but the rate of absorption does vary among individual horses. 5 · 83 The half-life of the drug has been reported to be 2. 9 to 3. 9 hours. Dosage recommendations must be based on pharmacokinetic characteristics and also bacterial susceptibility. One study demonstrated the in vitro susceptibility to metronidazole of gram-negative anaerobes to be 2 mcg/ml and of Clostridia sp to be 4 mcg/ ml. Anothe r study evaluating the susceptibility of B. fragilis showed 88 per cent of the isolates susceptible to a metronidazole concentration of 3.1 mcg/ ml and 94 per cent susceptible to 12.5 mcg/ml. Keeping these levels in mind, dosage recommendations range from 20 mg/kg at 6-hour intervals, the higher dosages and more frequent intervals being necessary for more resistant anaerobic pathogens. Side effects noted in humans receiving this medication include diarrhea, depression, weakness, and pruritus . Similar symptoms have been observed in horses receiving metronidazole , but a clear causal relationship has not been proven. If these symptoms are observed, discontinuation of the medication is advised . Rifampin is a unique antibiotic both in structure and activity. It is a complex macrocyclic antibiotic that inhibits RNA synthesis by inhabitation of bacterial DNA-depende nt RNA polymers; the result is a bactericidal effect. What makes rifampin particularly unique is its high lipid solubility and effectiveness in acid environments . This antibiotic readily penetrates macrophages and neutrophils, whe re it can exe rt its antibacterial effects. Owing to rifampin's capacity to penetrate biologic membranes, blood-totissue ratios of greater than one have been demonstrated in many tissues, including lung, spleen , skin, muscle, intestinal wall , kidney, mammary tissue, and milk. Because emergence of resistance can happen quite quickly, it is

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recommended that rifampin not be used alone but in combination with another antibiotic. The treatment regimen of rifampin along with erythromycin for treating Rhodococcus equi pneumonia in foals has been very successful. Rifampin has been shown to have synergistic activity with se veral other antibiotics and to have additive effects with penicillin G and ampicillin. It may be important to recognize that some controversy exists ove r combining rifampin with trimethoprim . One study looking at the treatment of experimental staphylococcal osteomyelitis showed that rifampin plus trimethoprim was more effective than either drug alone 54 ; however, othe r work has shown that the syne rgism that exists be tween the drugs occurred in a relatively small proportion of bacterial strains, and antagonism occurs about as freque ntly. 2 • 55 Further, the combination of these drugs delayed but did not prevent the emergence of resistance. Rifampin is absorbed fairly we ll from the gastrointestinal tract, with a bioavailability of 50 to 70 per cent. Although the exact mechanisms involved in elimination have not been determined , it is known that metabolism by the live r is involved . The resulting half-life of the drug is 6 to 7 hours in adults.17 The elimination half-life in foals has been shown to be 17.5 hours , suggesting slower hepatic metabolism. Based on in vitro susceptibility testing of equine pathogens and plasma levels of rifampin after oral administration , a dose of 10 to 20 mg/kg/day has been suggested for treating infections cause d by coagulase -positive staphylococcus, 13-hemolytic streptococcus , R. equi , C. pseudotuberculosis and some strains of gram-negative none nte ric bacte ria. The dose may be given once a day or divided into two doses , which would result in less fluctuation in blood levels.

SUMMARY In selecting an antibiotic, conside rations include the sensitivity of the pathoge n , drug distribution to th e site of infection, bacteriostatic or bactericidal action unde r the existing tissue conditions, safety, and cost. Ideally, in vitro susceptibility of the pathogen can be obtained. In addition, cytologic evaluation , including a Gram stain, may be helpful in directing the initial course of therapy. Antibiotic sensitivity does not by itself guarantee satisfactory results . The terms "sensitive " and "resistant" are relative terms based on achievable blood levels of antimicrobial age nts. The term "sensitive" implie s that the level necessary to inhibit bacte rial growth is achieved when an adequate dose is give n at appropriate intervals. The distribution of the drug and , in turn, the le vel achieved at the site of infection depends on a number of factors , including molecular size, protein binding, and lipid solubility. Because, in most cases, specific tissue concentrations are not known , se rum concentrations are used to re prese nt the levels in the extracellular fluid space, which is the site of most bacterial infections. The local e nvironm e nt can furth e r e nhance or hinde r antimicrobial pene tration and activity . The antibiotic conce ntration achieved in the blood affects the concentration at the site of infection because simple passive diffusion appears to be the method of transport for most antibiotics. The antibiotic activity afte r reaching the site of infection is influenced by

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environmental conditions. Local production of enzymes, purulent and fibrinous exudate, and pH changes can adversely affect drug action. With many of these variables being difficult to predict, knowledge of etiologic agents is the corne rstone of rational use of the antimicrobial drugs. A reasonable suspicion based on clinical signs and knowledge of likely pathogens can guide the initial choice of antimicrobial therapy. Since both aerobic and anaerobic organisms may be involved in wound infections, and because antibiotic sensitivity of many of these pathogens is unpredictable, broad-spectrum antimicrobial therapy is often warranted initially.

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48. Marsh DC, Mathew EB, Perse llin RH: Transport of gentamicin into synovial fluid. J Am Med Assoc 228:607, 1974 49. Martens RJ, Auer JA, Carter K: Equine pediatrics: septic arthritis and osteomyelitis. J Am Vet Med Assoc 188:582, 1986 50. McDonald PJ, Wetherall BL, Pruul H: Postantibiotic leukocyte enhancement: Increased susceptibility of bacteria pretreated with antibiotics to activity of leukocytes. Rev Infect Dis 3:38, 1981 51. Mcllwraith CW: Antibiotic use in musculoskeletal disease. Proceedings AAEP Nashville, TN 241, 1986 52. Moore RD, Lietman PS, Smith CH: Clinical response to aminoglycoside therapy: Importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 155:93, 1987 53. Neu HC: Cephalosporin antibiotics as applied in surgery of bones and joints. Clin Orthop 190:50, 1984 54. Norden CW: Prevention of bone and joint infections. Am J Med 78:229, 1985 55. Norden CW, Ke leti E: Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim alone and in combination. Antimicrob Agents Chemother 17:591, 1980 56. Orsini JA, Soma LR, Rourke JE, et al: Pharmacokinetics of amikacin in the horse following intravenous and intramuscular administration. J Vet Pharmacol Ther 8:194, 1985 57. Papich MG: Clinical pharmacology of cephalosporin antibiotics. J Am Vet Med Assoc 184:344, 1984 58. Parsons RL: Antibiotics in bone. J Antimicrob Chemother 2:228, 1976 59. Pedersoli WM, Belmonte AA, Purohit RC, e t al: Pharmacokinetics of gentamicin in the horse. Am J Vet Res 41:351, 1980 60. Prescott JF, Baggot JD: Antimicrobial susceptibility testing and antimicrobial drug dosage . J Am Vet Med Assoc 187:363, 1985 61. Reynolds WA: Ampicillin for treatment of bacterial respiratory infections in horses. Proc Am Assoc Equine Practnr 19:91, 1973 62. Riviere JE. Coppoc CL: Selected aspects of aminoglycoside antibiotic nephrotoxicosis. J Am Ve t Med Assoc 178:508, 1981 63. Riviere JE , Kaufman GM, Bright RM : Prophylactic use of systemic antimicrobial drugs in surgery. Comp Contin Educ 3:345, 1981 64. Riviere JE , Traver DS, Coppoc CL: Gentamicin toxic nephropathy in horses with disseminated bacterial infection. J Am Vet Med Assoc 180:648, 1982 65. Ruoff WW, Sams RA: Pharmacokinetics and bioavailability of cephalothin in horse mares. Am J Vet Res 46:2085, 1985 66. Rosdahl VT, Sorensen TS, Colding H: Determination of antibiotic concentrations in bone. J Antimicrob Agents Chemother 5:275, 1979 67. Ryan DM, Cars 0 : Antibiotic assays in muscle : Are conventional tissue levels misleading as indicators of antibacterial activity? Scand J Infect Dis 12:307, 1980 68. Salter AJ: Trimethoprim-sulfamethoxazole in treatment of severe infections. Rev Infect Dis 4:338, 1982 69. Sams RA, Ruoff WW: Pharmacology of cephalosporins in veterinary medicine. Powers JD, Powers TE (eds): Proc 3rd Symp Am Acad Vet Pharm and Ther, 1982 70. Sams RA, Ruoff WW: Pharmacokinetics and bioavailability of cefazolin in horses. Am J Vet Res 46:348, 1985 71. Schwart WS , Ducharne NG, Shen SJ, et al: Absorption and distribution patterns of oral phenoxymethylpenicillin (penicillin V) in the horse. Cornell Vet 73:314, 1983 72. Scoles PV, Aronaff SC: Antimicrobial therapy of childhood skeletal infections. J Bone Joint Surg 66-A:1487, 1984 73. Siebert WT, Kopp PE: Ticarcillin plus clavulanic acid versus moxalactam therapy of osteomyelitis, septic arthritis and skin and soft tissue infections. Am J Med 79(suppl)5B:141, 1985 74. Sigel CW, Byars TD, Divers TJ, et al: Serum concentrations of trimethoprim and sulfadiazine following oral paste administration to the horse. Am J Vet Res 42:2002, 1981 75. Simmons RD, Keefe TJ: Penicillins: An expanding spectrum. Part I. Mod Vet Pract 63:949, 1982 76. Spensley MS, Baggot JD, Wilson WD, et al: Pharmacokinetics and endometrial tissue

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Marion duPont Scott Equine Medical Center Virginia-Maryland Regional College of Veterinary Medicine Virginia Polytechnic Institute and State University P.O. Box 1938 Leesburg, VA 22075