Strategies for Using Antibiotics in Animals
WSAVA 2002 Congress
Mark G. Papich, DVM, MS, Diplomate ACVCP
Professor, College of Veterinary Medicine, North Carolina State University
Raleigh, North Carolina, USA

BACTERIAL SUSCEPTIBILITY

Most bacteria that cause infections in small animals come from the following list: Staphylococcus intermedius, (and occasionally other staphylococci) Escherichia coli, Klebsiella pneumoniae, Pasteurella multocida, beta-hemolytic streptococci, Pseudomonas aeruginosa, Proteus mirabilis (and occasionally indole-positive Proteus), Enterobacter spp and Enterococcus spp. If the bacteria are accurately identified, antibiotic selection is simplified because the susceptibility pattern of many organisms is predictable. For example, if the bacteria is likely to be Pasteurella, Streptococcus, or Actinomyces, susceptibility is expected to penicillin or an aminopenicillin such as ampicillin, amoxicillin, or amoxicillin-clavulanic acid (Clavamox).

Staphylococcus isolated from small animals is most likely to be S. intermedius rather than S. aureus. S. intermedius will usually have a predictable susceptibility to ß-lactamase resistant ß-lactam antibiotics such as amoxicillin combined with a ß-lactamase inhibitor such as clavulanate or sulbactam, or a first-generation cephalosporin such as cephalexin or cefadroxil. Staphylococcus also is susceptible to oxacillin and dicloxacillin but these are not used as commonly in small animal medicine. Reports of studies on S. intermedius have shown that, despite frequent use of the drugs listed above for small animals, the incidence of resistance has not increased (Lloyd, et al, 1996). This appears to be confirmed from the clinical experience of most veterinarians. Most staphylococci are also sensitive to fluoroquinolones, although resistance is possible (Ganière, et al 2001). The majority of staphylococci are sensitive to lincosamides (clindamycin, lincomycin), trimethoprim-sulfonamides, or erythromycin, but resistance can occur in as high as 25% of the cases.

If the bacteria is an anaerobe (for example, Clostridium, Fusobacterium, Prevotella, Actinomyces, or Porphyromonas) predictable results can be attained by administering a penicillin, chloramphenicol, metronidazole, clindamycin, amoxicillin-clavulanic acid, or one of the second-generation cephalosporins such as cefotetan or cefoxitin. Metronidazole is consistently highly active against anaerobes including B. fragilis. The activity of first-generation cephalosporins, trimethoprim-sulfonamides/ormetoprim-sulfonamides, or fluoroquinolones for an anaerobic infection is unpredictable. If the anaerobe is from the Bacteroides fragilis group, resistance may be more of a problem because they produce a beta-lactamase that may inactivate 1st generation cephalosporins and ampicillin/amoxicillin. Some of these Bacteroides may also be resistant to clindamycin. These resistant strains of Bacteroides may have increased in recent years (Jang et al 1997).

Problem, or Resistant Bacteria

If the organism is Pseudomonas aeruginosa, Enterobacter, Klebsiella, Escherichia coli, or Proteus, resistance to many common antibiotics is possible and a susceptibility test is advised. For example, a recent report showed that among nonenteric E. coli, only 23% were sensitive to a 1st generation cephalosporin, and less than half were sensitive to ampicillin. In that same study, 13%, and 23% were intermediate or resistant to enrofloxacin, and orbifloxacin, respectively (Oluoch, et al 2001). One report indicated that resistance to enrofloxacin among E. coli was 10-16% in 1997-1998 and that many of these bacteria also were resistant to other commonly used antibiotics (Cooke et al, 2002).

Based on these data as well as other studies, for initial therapy we may rely on initial treatment of infections caused by gram-negative enteric bacteria with fluoroquinolones and aminoglycosides. An extended-spectrum cephalosporin (second- or third-generation cephalosporin) usually is active against enteric-gram negative bacteria, but will not be active against Pseudomonas aeruginosa. If the organism is a Pseudomonas aeruginosa, inherent resistance to many drugs is common, but it may be susceptible to fluoroquinolones, aminoglycosides, or an extended-spectrum penicillin such as ticarcillin or piperacillin. When administering a fluoroquinolone to treat Pseudomonas aeruginosa the high-end of the dose range is suggested to reach adequate drug concentrations, but even with these high doses, resistance is common. Of the currently available fluoroquinolones, (human or veterinary drugs) ciprofloxacin is the most active against Pseudomonas aeruginosa.

PHARMACOKINETIC-PHARMACODYNAMIC (PK-PD) OPTIMIZATION

To achieve a cure, the drug concentration in plasma, serum, or tissue fluid should be maintained above the minimum inhibitory concentration (MIC), or some multiple of the MIC, for at least a portion of the dose interval. Antibacterial dosage regimens are based on this assumption, but drugs vary with respect to the peak concentration and the time above the MIC that is needed for a clinical cure. Pharmacokinetic-pharmacodynamic (PK-PD) relationships of antibiotics attempt to explain how these factors can correlate with clinical outcome (Nicolau et al. 1995, Hyatt et al. 1995). Shown on Figure 1 are some terms used to describe the shape of the plasma concentration vs time profile. The CMAX is simply the maximum plasma concentration attained during a dosing interval. The CMAX is related to the MIC by the CMAX:MIC ratio. The AUC is the total area-under-the-curve. The AUC for a 24 hour period is related to the MIC value by the AUC:MIC ratio. Also shown in Figure 1, is the relationship of time to MIC measured in hours (T > MIC).


 

Antibiotics can be time-dependent or concentration-dependent. Those that are bacteriostatic are usually time-dependent. For a drug that is bactericidal and concentration-dependent, the activity in animals can be predicted by the AUC:MIC ratio, or the CMAX:MIC ratio. When the CMAX: MIC or AUC:MIC ratio is the best predictor of efficacy, the dose should be high enough to achieve an optimum ratio. If the drug is time-dependent, the drug should be administered frequently enough to maximize the T > MIC. Examples of how these relationships affect drug regimens are described below:

Aminoglycosides

Aminoglycosides (e.g., gentamicin, or amikacin) are concentration-dependent bactericidal drugs, therefore the higher the drug concentration, the greater the bactericidal effect. An optimal bactericidal effect occurs if a high enough dose is administered to produce a peak of 8-10x the MIC. This can be accomplished by administering a single dose once daily. This regimen is at least as effective, and less nephrotoxic, than lower doses administered more frequently (Freeman et al, 1997). Our current regimens in small animals employ this strategy. The single daily dose is based on the drug's volume of distribution (calculated using the area method). A once daily dose for gentamicin is 5-8 mg/kg for cats, and 10-14 mg/kg for dogs, once daily. An appropriate dose for amikacin is 10-15 mg/kg for cats and 15-30 mg/kg for dogs once daily. The efficacy of these regimens has not been tested for conditions encountered in veterinary medicine, but the relationships are supported by experimental evidence.

Fluoroquinolones

For the fluoroquinolone antimicrobials, either the CMAX:MIC ratio, or the AUC:MIC may predict antibacterial success. As reviewed by Hyatt et al (1995), Dudley (1991), and recently by Wright et al (2000) and Papich & Riviere (2001) investigators have shown that either the peak plasma concentration above bacterial minimum inhibitory concentration (MIC), also known as the CMAX:MIC ratio, or the total AUC above the MIC (also known as the AUC:MIC ratio), may predict clinical cure in studies of laboratory animals, and in a limited number human clinical studies. There are no published studies involving dogs or cats that indicate which of these parameters is a predictor of clinical cure, or what the respective target ratios might be. However, it is the prevailing opinion based on other studies (Andes & Craig, 2002) is that that a CMAX:MIC of 8-10, or a AUC:MIC of greater than 100-125 have been associated with a cure. Investigators of some studies have shown that AUC:MIC ratios as low as 30-55 may result in a clinical cure, especially when the patient has a competent immune system (i.e., not neutropenic) (Wright 2000; Andes & Craig, 2002).

Beta-lactam antibiotics

ß-lactam antibiotics such as penicillins, potentiated-aminopenicillins, and cephalosporins are slowly bactericidal. Their concentration should be kept above the MIC throughout most of the dosing interval (long T>MIC) for the optimal bactericidal effect (Turnidge 1998). Dosage regimens for the ß-lactam antibiotics should consider these pharmacodynamic relationships. Therefore, for treating a gram-negative infection, especially a serious one, some regimens for penicillins and cephalosporins require administration 3 to 4 times per day.

Bacteriostatic drugs

The drugs such as tetracyclines, macrolides (erythromycin and derivatives), sulfonamides, lincosamides (lincomycin and clindamycin), and chloramphenicol derivatives act in a bacteriostatic manner against most bacteria. However, against susceptible gram-positive bacteria, the macrolides appear to be bactericidal and can demonstrate a post-antibiotic effect. Chloramphenicol also can produce a bactericidal effect if the organism is very susceptible.

These drugs are time-dependent and most effective when the drug concentrations are maintained above the MIC throughout the dosing interval. Many of the bacteriostatic drugs must be administered frequently to achieve this goal. However, a property of some of these drugs is that they persistent in tissues for a prolonged time, which allows infrequent dosing intervals.

REFERENCES

1.  Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 19: 261-268, 2002.

2.  Cooke CL, Singer RS, Jang SS, and Hirsh DC. Enrofloxacin resistance in Escherichia coli isolated from dogs with urinary tract infections. J Am Vet Med Assoc. 220: 190-192, 2002.

3.  Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH: Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 39: 677, 1997.

4.  Ganière J-P, Mèdaille C, Limet A, et al. Antimicrobial activity of enrofloxacin against Staphylococcus intermedius strains isolated from canine pyodermas. Vet Dermatol 12: 171-175, 2001.

5.  Hyatt JM, McKinnon PS, Zimmer GS, Schentag JJ: The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome. Clin Pharmacokinet 28: 143-160, 1995.

6.  Jang SS, Breher JE, Dabaco LA, & Hirsh DC (1997) Organisms isolated from dogs and cats with anaerobic infections and susceptibility to selected antimicrobial agents. J Am Vet Med Assoc 210: 1610-1614.

7.  Lloyd DH, Lamport AI, Feeney C: Sensitivity to antibiotics amongst cutaneous and mucosal isolates of canine pathogenic staphylococci in the UK, 1980-1996. Vet Derm 7: 171-175, 1996.

8.  Lode, H., Borner, K., Koeppe, P. Pharmacodynamics of Fluoroquinolones. Clinical Infectious Diseases. 1998; 27: 33-9.

9.  Lorian V: Antibiotics in Laboratory Medicine 4th Ed. Williams & Wilkins, 1996.

10. Nicolau DP, Quintiliani R, Nightingale CH: Antibiotic kinetics and dynamics for the clinician. Med Clinics North America 79: 477-495, 1995.

11. Oluoch AO, Kim C-H, Weisiger RM, et al. Nonenteric Escherichia coli isolates from dogs: 674 cases (1990-1998). J Am Vet Med Assoc 218: 381-384, 2001.

12. Papich MG, Riviere JE: Fluoroquinolones. In: Adams HR (editor) Veterinary Pharmacology and Therapeutics, 8th Edition, Iowa State University Press, Ames, Iowa, 2001.

13. Turnidge JD. The pharmacodynamics of ß-lactams. Clinical Infectious Diseases. 1998; 27: 10-22.

14. Wright DH, Brown GH, Peterson ML, Rotschafer JC. Application of fluoroquinolone pharmacodynamics. Journal of Antimicrobial Chemotherapy 46: 669-683, 2000.

Speaker Information
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Mark G. Papich, DVM, MS, Diplomate ACVCP
Professor, College of Veterinary Medicine
North Carolina State University
Raleigh, North Carolina, USA


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