Managing Resistant Infections
ACVIM 2008
Mark G. Papich, DVM, MS, DACVCP
Raleigh, NC, USA

Introduction

Treatment of common infections in small animals has been reported to provide guidelines and established regimens. Drug manufacturers have produced several important drugs to treat the most common infections encountered in small animals. However, the drugs and approaches to therapy are more limited when the infection is more refractory, resistant, or is associated with another complicating factor. Susceptibility of the most common isolates has been documented well enough to make sound judgments and empirical antimicrobial drug choices. However, when the patient has a refractory and/or resistant infection, or is seriously ill with an infection, other strategies and drugs may be necessary. As with many new treatments, there are few veterinary clinical studies to support a recommended use and dose and many of these details have been extrapolated from human medicine.

Treating Resistant Gram-Negative Bacteria

The most common resistant gram-negative bacteria in veterinary small animal medicine are the gram-negative bacilli, especially the enteric isolates. The most common resistant gram-negative bacilli that we encounter in small animal medicine is Escherichia coli. In some hospitals, there have been outbreaks of Klebsiella pneumoniae, Enterobacter, and indole-positive Proteus, but E. coli remains as the most common. Wild-type strains of E. coli should respond to third-generation cephalosporins, fluoroquinolones, and aminoglycosides. Many are susceptible to amoxicillin-clavulanate (Clavamox), or ampicillin-sulbactam (Unasyn) combinations. Drugs that are not expected to have good activity against the wild type strains are first-generation cephalosporins, ampicillin/amoxicillin, or macrolides.

After a susceptibility report is available, one may find that the only drugs to which some gram-negative bacilli are sensitive are extended-spectrum cephalosporins, penems (carbapenems), or amikacin. 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 (except for the oral exception discussed below), and must be administered frequently. The activity of the oral third-generation cephalosporin, cefpodoxime proxetil (Simplicef) is variable among gram-negative bacteria. To treat the indications for which it is registered in dogs (skin infections), it can be given once a day orally at a dose of 5-10 mg/kg. Its absorption from oral administration is good (63%) compared to other oral third generation cephalosporins and it is excreted mostly in the urine with a half-life of 5.6-6 hours. Cefpodoxime is more active than 1st-generation cephalosporins against gram-negative bacteria, but not as active as the injectable drugs in this class. It is not active against Pseudomonas aeruginosa, Enterococcus, or methicillin-resistant Staphylococcus. One should be aware that the break-point for susceptibility is lower than for other third-generations cephalosporins. Therefore, it is possible for a bacterial isolate to be sensitive to cefotaxime or ceftazidime (breakpoint 8 µg/mL) but resistant to cefpodoxime (breakpoint 2 µg/mL) (CLSI 2008). If cefpodoxime is not included on a routine panel, specific disks or E-tests are suggested for testing bacterial isolates, rather than relying on the results from other cephalosporins. The new injectable 3rd-generation cephalosporin, cefovecin (Convenia) has greater activity than 1st-generation cephalosporins (Stegemann et al, 2007), but comparisons to other 3rd-generation cephalosporins are not available. The first 4th generation cephalosporin is cefepime (Maxipime). It is unique from other cephalosporins because of its broad spectrum of activity that includes gram-positive cocci, enteric gram-negative bacilli, and Pseudomonas. It even has activity against some extended-spectrum β-lactamase (ESBL) producing strains of Klebsiella and E. coli that have become resistant to many other β-lactam drugs and fluoroquinolones. Except for one investigation in dogs, adult horses, and foals, the use of cefepime has been limited in veterinary medicine (Gardner, et al. 2001), and there has been recent concern about the mortality associated with its use in human medicine (Yahav, et al, 2007).

The carbapenems have been valuable for treatment of resistant gram-negative bacteria. The carbapenems are β-lactam antibiotics that include imipenem-cilastatin sodium (Primaxin), meropenem (Merrem), and most recently, ertapenem (Invanz). All three have activity against the enteric gram-negative bacilli. Resistance (carbapenemases) among veterinary isolates has been very rare. Imipenem is administered with cilastatin to decrease renal tubular metabolism. Imipenem has become a valuable antibiotic because it has a broad spectrum that includes many bacteria resistant to other drugs (Edwards & Betts, 2000). Imipenem is not active against methicillin-resistant staphylococci or resistant strains of Enterococcus faecium. The high activity of imipenem is attributed to its stability against most of the β-lactamases (including ESBL) and ability to penetrate porin channels that usually exclude other drugs (Livermore 2001). The carbapenems are more rapidly bactericidal than the cephalosporins and less likely to induce release of endotoxin in an animal from gram-negative sepsis.

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. Meropenem, one of the newest of the carbapenem class of drugs (some experts consider it a 2nd-generation penem) and has antibacterial activity greater than imipenem against some isolates. One important 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 (Edwards & Betts, 2000). 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. For infections caused by Pseudomonas aeruginosa, or other similar organisms that may have MIC values as high as 1.0 mcg/mL: 12 mg/kg q8h, SC, or 25 mg/kg q8h, IV. For sensitive organisms in the urinary tract, 8 mg/kg, SC, every 12 hours can be used. In our experience, these doses have been well-tolerated except for slight hair loss over some of the SC dosing sites.

Aminoglycosides are still valuable for treating gram-negative bacilli that are resistant to other drugs. They are rapidly bactericidal, less expensive than injectable drugs listed above, and can be administered once-daily. Among these, amikacin is the most active. Therefore, it is often the first choice in small animal medicine. It has 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 (Konig et al 1998). This may decrease their usefulness for the treatment of wound and ear infections caused by Pseudomonas aeruginosa. To decrease the risk of drug-induced nephrotoxicosis, therapeutic drug monitoring and careful evaluation of renal function during its use is recommended.

Infections caused by Pseudomonas aeruginosa present a special problem because so few drugs are active against this organism. Of the β-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 (carbencillin, ticarcillin). 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. These drugs are more expensive than the more-commonly used penicillins, and must be administered frequently (e.g., at least 4 times daily) to be effective. Ticarcillin is available in combination with the β-lactamase inhibitor clavulanic acid (Timentin). 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 SC, and IM routes have been used. As with the penicillins, frequent administration is necessary. As mentioned previously, the β-lactam antibiotics with greatest activity against Pseudomonas aeruginosa are the carbapenems. Ertapenem is a new addition to the class of carbapenems but it does not have anti-Pseudomonas activity. Aminoglycosides are active against most wild-type strains of Pseudomonas aeruginosa. Against resistant isolates, amikacin and tobramycin are more active than gentamicin, and resistance is less likely to these drugs (Petersen et al, 2002). Of the currently available fluoroquinolones, (human or veterinary drugs) ciprofloxacin is the most active against Pseudomonas aeruginosa.

Treatment of Resistant Gram-Positive Bacteria

Resistant Staphylococcus

Staphylococcal resistance can be caused by altered penicillin-binding proteins (for example the resistance carried by the gene mecA). These are known as methicillin-resistant staphylococci--MRSA or MRSI, depending on whether it is S. aureus or S. intermedius (Gortel et al, 1999; Deresinski 2005). Other Staphylococcus species also have been identified among veterinary isolates, such as coagulase-negative Staphylococcus. 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. The mecA gene and methicillin resistance appears to be increasing in veterinary medicine based on the number of reports in the last several years. 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 bacteria often carry co-resistance to many other non-β-lactam drugs, including clindamycin, fluoroquinolones, macrolides, tetracyclines, and trimethoprim-sulfonamides. Use of fluoroquinolones and cephalosporins has been linked to emergence of resistance of methicillin-resistant staphylococci (Dancer, 2008). Because susceptibility to non-β-lactam antibiotics is unpredictable, a susceptibility test is needed to identify which drug to use for these infections. In some instances the only drug that is active for treatment will be a glycopeptide such as vancomycin (Vancocin) or the oxazolidinone, linezolid (Zyvox). Vancomycin can only be administered by intravenous infusion. Linezolid is the first in the class of oxazolidinones to be used in medicine and it is used in people to treat resistant gram-positive infections caused by enterococci and streptococci. It can be administered IV or orally and has excellent absorption, but is extremely expensive. Nevertheless, veterinary patients have been treated with this medication with good success.

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, β-lactamase resistant penicillins (e.g., oxacillin), trimethoprim-sulfonamide combinations, and clindamycin can give misleading results (CLSI, 2008). 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, one should administer amoxicillin or ampicillin at the high-end of the dose range. When possible, combine an aminoglycoside with a β-lactam antibiotic for treating serious infections. 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, lower urinary tract, 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 (Bartlett et al 1978). As mentioned above for resistant Staphylococcus, sometimes the only active drug will be a glycopeptide or the oxazolidinone linezolid. Disadvantages of these drugs were discussed above.

Resistant / Refractory Urinary Tract Infections

Urinary tract infections that are refractory, recurrent, and/or caused by resistant bacteria can be frustrating cases in veterinary medicine. Some of these patients are immunocompromised, diabetic, receiving corticosteroids, or have underlying neurological disease. The secondary UTI associated with diabetes and other underlying problems often are often occult (McGuire, et al, 2002; Torres et al, 2005). Clinical signs may be minimal or may be attributed to underlying disease or drug therapy, and white blood cells (WBC) and bacteria may be found in very minimal concentration in dilute urine. Treatment of complicated UTI must be based on urine culture and sensitivity, and even with this information it can be very difficult to eradicate infection (Sequin et al, 2003). After initiating antimicrobial therapy, follow-up urine culture should be obtained after approximately one week to be sure of antimicrobial efficacy in vivo. Culture should be repeated approximately one week after antibiotics are discontinued, and again several weeks later if immunocompromise continues. The antibiotics already discussed above can have an important role in treating these difficult-to-treat urinary tract infections. In some cases, antibiotics alone are not sufficient and urinary antiseptics are used.

Use of Urinary Antiseptics

For frequent recurrent UTI, once acute infection is resolved urinary antiseptics or daily antimicrobial administration may be useful to prevent re-infection. However, the ideal urinary antiseptic has not been identified in veterinary medicine (Sequin et al 2003). Drugs used for this purpose include nitrofurantoin (Macrodantin) and methenamine (methenamine hippurate or methenamine mandelate). Nitrofurantoin has caused adverse gastrointestinal effects in animals. Methenamine is converted to formaldehyde--which is naturally antibacterial--in acidic urine. However, for the conversion to be effective the urine pH must be low, in the range of 5 to 6. Depending on the animal's diet and other medications, urinary pH consistently in this range may not occur in all animals. Drugs or natural compounds that decrease the virulence of uropathogens, such as fosfomycin tromethamine (Monural), or cranberry juice also have been used in dogs with recurrent, or refractory, urinary tract infections. Cranberry juice (or its extract) contains a proanthocyanidin that inhibits the attachment of bacteria to the urinary mucosa (Howell et al, 2007). Its efficacy has not been reported in animals. Veterinarians and pet owners should be warned that products marketed as cranberry juice, or its extract, are highly variable in content. Cranberry may help to prevent but not treat urinary tract infections in women. Veterinarians may wish to refer interested pet owners to the web site at the National Center for Complimentary and Alternative Medicine (NCCAM), http://nccam.nih.gov/health/cranberry/). Fosfomycin tromethamine can be antibacterial and also decrease virulence of uropathogens. In people it is used as a one-time administration for uncomplicated urinary tract infections in women (Monural 3-gram packet taken once with water). The efficacy has not been evaluated in animals.

References

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18. Torres SM, Diaz SF, Nogueira SA, et al. Frequency of urinary tract infection among dogs with pruritic disorders receiving long-term glucocorticoid treatment. J Am Vet Med Assoc. 2005;227:239-243.

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Speaker Information
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Mark Papich, DVM, MS, DACVCP
North Carolina State University
Raleigh, NC


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