Bacterial Resistance and Its Management in the 21st Century
World Small Animal Veterinary Association World Congress Proceedings, 2007
Mark G. Papich, DVM, MS, DACVCP
Professor of Clinical Pharmacology, North Carolina State University
Raleigh, NC, USA

Introduction

Bacterial resistance to antibiotics is an increasing concern among veterinarians. Although new drugs have become available, the expense and inconvenience of administration (many of the new human drugs are injectable only), presents a problem for pet owners. Resistance problems are most common with gram-negative bacilli, especially those of the Enterobacteriaceae (for example, E. coli, Klebsiella pneumoniae, Proteus spp., and Enterobacter spp.). Pseudomonas aeruginosaalso presents a problem in wounds, ears, dermal folds, and the urinary tract. Recently, gram-positive cocci have emerged as a more common problem in veterinary patients with resistance seen with Staphylococcus intermedius, S. aureus, and Enterococcus species.

Resistant Gram-negative Bacteria

The most common bacteria to develop resistance in veterinary small animal medicine are the gram-negative bacilli, especially the enteric isolates. If the organism is Pseudomonas aeruginosa, Enterobacter, Klebsiella, Escherichia coli, or Proteus, resistance to many antibiotics is possible and a susceptibility test is advised.

After a susceptibility report is available, one may find that the only drugs to which a gram-negative bacilli is sensitive are extended-spectrum cephalosporins and carbapenems. The injectable cephalosporins most often used are cefotaxime and ceftazidime, although individual veterinary hospitals have utilized others in this group. These drugs are expensive, injectable, and must be administered frequently. There are oral third-generation cephalosporins used in human medicine. One of these is also registered for use in veterinary medicine: cefpodoxime proxetil (Simplicef). Although the MIC values for cefpodoxime are lower than first-generation drugs such as cephalexin, it is not as active as cefotaxime or ceftazidime against resistant strains. The breakpoint for susceptibility also is lower for cefpodoxime vs other third-generation cephalosporins (2 µg/mL vs 8 µg/mL).

The carbapenems have been valuable for treatment of resistant gram-negative bacteria. These drugs include imipenem, meropenem, and ertapenem. All three have activity against the enteric gram-negative bacilli.

Some disadvantages of imipenem are the inconvenience of administration, short shelf-life after reconstitution, and high cost. It must be diluted in fluids prior to administration. One of the adverse effects caused from imipenem therapy is seizures. Meropenem, one of the newest of the carbapenem class of drugs has antibacterial activity approximately equal to, or greater than imipenem. Other characteristics are similar to imipenem. Its advantage over imipenem is that it is more soluble and can be administered in less fluid volume and more rapidly. For example, small volumes can be administered subcutaneously with almost complete absorption. There also is a lower incidence of adverse effects to the central nervous system, such as seizures. Based on pharmacokinetic experiments in our laboratory (Bidgood & Papich 2002), the recommended dose for Enterobacteriaceae and other sensitive organisms is 8.5 mg/kg SC every 12hr, or 24 mg/kg IV every 12 hr. In our experience, these doses have been well-tolerated.

Pseudomonas aeruginosa

Of the 8-lactam antibiotics, a few are designated as anti-Pseudomonas antibiotics. Those with activity against this organism include the ureidopenicillins (mezlocillin, azlocillin, piperacillin) and the carboxylic derivatives of penicillin (carbenicillin, ticarcillin). Ticarcillin is more active than carbenicillin against gram-negative bacteria, but whether this relates to clinical differences is not clear. These derivatives are available as sodium salts for injection; there are no orally-effective formulations in this class, except indanyl carbenicillin (Geocillin, Geopen) which is poorly absorbed and not useful for systemic infections in small animals. These drugs are more expensive than the more-commonly used penicillins, and must be administered frequently (for example, at least 4 times daily) to be effective. Ticarcillin is available in combination with the beta-lactamase inhibitor clavulanic acid (Timentin). Ticarcillin also has been used in compounded topical formulations applied to the ear canal for treatment of otitis externa caused by Pseudomonas. Because these drugs degrade quickly after reconstitution, observe the storage recommendations on the package insert to preserve the drug's potency.

Of the cephalosporins, only the 3rd-generation cephalosporins, ceftazidime (Fortaz, Tazidime), cefoperazone (Cefobid), or cefepime (Maxipime), a 4th-generation cephalosporin, have predictable activity against Pseudomonas aeruginosa. Ceftazidime has greater activity than cefoperazone and is the one used most often in veterinary medicine. These drugs must all be injected, and are usually given IV, although subcutaneous, and IM routes have been used. As with the penicillins, frequent administration is necessary.

The 8-lactam antibiotics with greatest activity against Pseudomonas aeruginosa are the carbapenems. The drugs in this class are imipenem-cilastatin, and meropenem. Ertapenem is a new addition to the class of carbapenems but it does not have anti-Pseudomonas activity.

Aminoglycosides include gentamicin, amikacin, and tobramycin. They are active against most Pseudomonas aeruginosa strains. Amikacin and tobramycin are more active than gentamicin, and resistance is less likely to these drugs (Petersen et al, 2002). The aminoglycosides are limited to topical and injectable administration. They have been administered once-daily for systemic infections IV, IM, or SC. There are two important disadvantages to systemic use of aminoglycosides: 1) Treatment usually must extend for at least two weeks or longer. Risk of nephrotoxicosis is greater with longer duration of treatment. 2) Activity of aminoglycosides is diminished in the presence of pus and cellular debris. This may decrease their usefulness for the treatment of wound and ear infections caused by Pseudomonas aeruginosa.

Fluoroquinolones are active against Pseudomonas aeruginosa, but usually MIC values are higher than against other gram-negative organisms. Subsequently, when administering a fluoroquinolone to treat Pseudomonas aeruginosa the high-end of the dose range is suggested. Of the currently available fluoroquinolones, (human or veterinary drugs) ciprofloxacin is the most active against Pseudomonas aeruginosa (Riddle et al, 2000).

Resistant Gram-positive Bacteria

Resistant Staphylococcus

Staphylococcal resistance can be caused by altered penicillin-binding proteins and the resistance may be carried by the gene mecA. These are known as methicillin-resistant staphylococci or MRSA when resistance occurs with S. aureus and MRSI with S. intermedius (Gortel et al, 1999, Jones et al, 2007). Oxacillin is now used more commonly than methicillin as the marker for this type of resistance, and resistance to oxacillin is equivalent to methicillin-resistance. This resistance has been historically uncommon among veterinary isolates (Petersen et al, 2002; Normand et al, 2000; Prescott et al, 2002), but increases have been documented recently. If staphylococci are resistant to oxacillin or methicillin, they should be considered resistant to all other β-lactams, including cephalosporins and amoxicillin-clavulanate (e.g., Clavamox), regardless of the susceptibility test result. Adding a β-lactamase inhibitor will not overcome methicillin resistance. Unfortunately, these strains often carry a co-resistance to macrolides, lincosamides, and fluoroquinolones.

These strains should be tested for susceptibility to clindamycin or a fluoroquinolone. In some instances the only drug that is active for treatment will be a glycopeptide such as vancomycin (Vancocin). There are new drugs used in human medicine for MRSA such as a tigecycline (Tygacil), the oxazolidinone linezolid (Zyvox), the streptogramin compounds (marketed in a combination of 30:70 quinupristin: dalfopristin called Synercid) or the cyclic lipopeptide daptomycin (Cubicin). However, these drugs have not been evaluated for infections in small animals. The only oral drug of this list is linezolid (Zyvox); all the others are injectable. All are quite expensive. There has been some limited anecdotal experience with oral linezolid for MRSA and MRSI infections in dogs and cats.

Resistant Enterococcus

Enterococci are gram-positive cocci that have emerged as important causes of infections, especially those that are nosocomial. The most common species identified are Enterococcus faecalis and E. faecium. Enterococcus faecalis is more common, but E. faecium is usually the more resistant. Wild-strain enterococci may still be sensitive to penicillin G and ampicillin, or amoxicillin. However, the enterococci have an inherent resistance to cephalosporins and fluoroquinolones. These strains also are usually resistant to trimethoprim-sulfonamide combinations, clindamycin, and erythromycin. Susceptibility test results for cephalosporins, beta-lactamase resistant penicillins (e.g., oxacillin), trimethoprim-sulfonamide combinations, and clindamycin can give misleading results. Even if isolates are shown to be susceptible to a fluoroquinolone, this class of drugs may not be a good alternative for treatment.

In human medicine frequent use of fluoroquinolones and cephalosporins (both of which have poor activity against enterococci), has been attributed to emergence of a higher rate of enterococcal infections. Evidence to document this trend is limited in veterinary medicine, but one study from a veterinary teaching hospital indicated increased rate of enterococcal urinary tract infections (Prescott, et al, 2002).

Treatment of Enterococcus is frustrating because there are so few drug choices. If the Enterococcus isolated is sensitive to penicillins, administer amoxicillin or ampicillin at the high-end of the dose range. When possible, combine an aminoglycoside with a beta-lactam antibiotic for treating serious infections. Each drug alone is poorly bactericidal against enterococci when used alone. Occasionally, one of the carbapenems (imipenem-cilastatin) or an extended-spectrum penicillin (e.g., piperacillin) can be considered for treatment of E. faecalis (but not E. faecium). When enterococci are present in wound infections, peritoneal infections, and body cavity infections (e.g., peritonitis), the organism may exist with other bacteria such as gram-negative bacilli, or anaerobic bacteria. In these cases, there is evidence that treatment should be aimed at the anaerobe, and/or gram-negative bacilli and not directed at the enterococcus. Treatment cures are possible if the other organisms are eliminated without specific therapy for Enterococcus.

Often, the only effective drug will be a glycopeptide. Of the glycopeptides, vancomycin is the only one used in veterinary medicine. Vancomycin (Vancocin) has been given as an IV infusion administered over 30 to 60 minutes. It is not absorbed orally and is too painful when injected IM. The dose to maintain concentrations within the therapeutic range, and avoid toxicity is 15 mg/kg, q6h, IV. For successful therapy of serious infections, an aminoglycoside such as gentamicin or amikacin should be administered with vancomycin.

References

1.  Bidgood T, Papich MG. Meropenem pharmacokinetics in dogs. Am J Vet Res 2002;63(12):1622-1628.

2.  Gortel K, Campbell KL, Kakoma I, Whittem T, Schaeffer DJ, Weisiger RM. Methicillin resistance among staphylococci isolated from dogs. Am J Vet Res 60: 1526-1530, 1999.

3.  Jones RD, Kania SA, rohrbach BW, Frank LA, & Bemis DA. Prevalence of oxacillin- and multidrug-resistant staphylococci in clinical samples from dogs: 1,772 samples (2001-2005). J Am Vet Med Assoc 2007; 230: 221-227.

4.  Normand EH, Gibson NR, Taylor DJ, et al. Trends of antimicrobial resistance in bacterial isolates from a small animal referral hospital. Vet Rec 146: 151-155, 2000.

5.  Petersen AD, Walker RD, Bowman MM, Schott HC, Rosser EJ. Frequency of isolation and antimicrobial susceptibility patterns of Staphylococcus intermedius and Pseudomonas aeruginosa isolates from canine skin and ear samples over a 6 year period (1992-1997). J Am Anim Hosp Assoc 38: 407-413, 2002.

6.  Prescott JF, Hanna WJB, Reid-Smith R, and Drost K. Antimicrobial drug use and resistance in dogs. Canadian Veterinary Journal 43: 107-116, 2002.

7.  Riddle C, Lemons CL, Papich MG, and Altier C. Evaluation of ciprofloxacin as a representative of veterinary fluoroquinolones in susceptibility testing. J Clin Microbiol 2000; 38: 1636-1637.

8.  Tomlin J, Pead MJ, Lloyd DH, Howell S, et al. Methicillin-resistant Staphylococcus aureus infections in 11 dogs. Vet Rec 144: 60-64, 1999.

Speaker Information
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Mark G. Papich, DVM, MS, DACVCP
North Carolina State University
North Carolina, USA


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