ANTIBIOTIC USE IN GUINEA PIGS

ABSTRACT

Guinea pigs (Cavia porcellus) are very common rodent pets. They are considered “minor” species for which very few antimicrobials are approved by the Food and Drug Administration. Inappropriate antibiotic therapy will suppress the normal enteric bacterial flora and allow overgrowth of Clostridia spp. with subsequent enterocolitis, cecitis, enterotoxemia and death. Antibiotics with a predominantly gram-positive and narrow spectrum are associated with this syndrome and include penicillins (penicillin, amoxicillin, and ampicillin) and the macrolides (erythromycin, lincomycin, and streptomycin). Aminoglycosides are associated with nephrotoxicity and ototoxicity while tetracyclines are only potentially nephrotoxic. Fluoroquinolones cannot be administered to growing animals due to their ability to cause articular degeneration. Chloramphenicol, fluoroquinolones, trimethoprim-sulfa drugs, some aminoglycosides and metronidazole are considered to be safe and efficacious in rodent therapy. When the dosage and frequency of drug administration is unknown, allometric scaling can be used. Subcutaneous drug administration is easy, fast and associated with minimal tissue trauma. Antibiotic-induced enteritis and enterotoxemia should be treated aggressively as they can be life threatening. The treatment protocol should include fluids, supplemental nutrition, vitamin C and metronidazole.

INTRODUCTION

In recent years the interest in rodents as pets has dramatically increased. This has led to a rapid expansion in pet rodent medicine. Guinea pigs (Cavia porcellus) belong to Caviidae family and are hystricomorph rodents from South America (Quesenberry, 1996). They were first used by Incas for food and religious ceremonies and then brought to Europe about 400 years ago (Hillyer et al., 1997). Guinea pigs adapt poorly to environmental changes and get stressed easily (Quesenberry, 1996). In an adequately clean environment and with proper feeding these animals rarely become sick. The most common medical problems in guinea pigs are due to traumatic injuries, infectious diseases and aging. Few drugs used in veterinary practice are approved specifically by Food and Drug Administration for use in rodents, a consideration that presents both legal and therapeutic complications (Harkness and Wagner, 1995). This paper will review antibiotic toxicity, safe antibiotics, allometric scaling, routes of administration, and treatment of antibiotic-induced enteritis in guinea pigs. In addition, other factors may influence the effect of a particular drug such health and breeding status, metabolic rate, presence of pathogenic organisms among intestinal flora, nutritional level, concomitant administration of other drugs, and ambient temperature (Harkness and Wagner, 1995). In addition to these concerns, improper antibiotic treatment can change an active clinical infection to a chronic, subclinical, carrier state (Harkness and Wagner, 1995).

ANTIBIOTIC TOXICITY

Incorrect antibiotic therapy in guinea pig will suppress the normal enteric bacterial flora (Lactobacillus and Bacteroides spp.), allowing overgrowth of gram-negative and anaerobic which will change the pH, increase volatile fatty acid production, and lead to further suppression of normal bacteria (McKellar, 1989; Quesenberry, 1994). Toxins produced by Clostridium difficile are the primary cause of enterotoxemia and death, although Clostridium histolyticum and Clostridium spiroforme (iota toxins) also have been implicated (Quesenberry, 1994; Rosenthal, 1998). Gram-positive narrow spectrum antibiotics are associated with this syndrome and include penicillins (penicillin, amoxicillin, and ampicillin) and the macrolides (erythromycin, lincomycin, and streptomycin) (Lowe at al., 1980; Quesenberry, 1994).

Penicillins are fundamentally toxic to guinea pigs; all will potentially cause enterotoxemia (Harkness, 1995). As well, ampicillin has a very rapid rate of urinary and biliary clearance and thus it’s used only occasionally for Staphylococcus spp. (e.g., pododermatitis) and gram-negative infections, at a dose of 2-5 mg/kg every 8 hours parenterally, in well hydrated animals (Young et al., 1987; Harkness, 1995). Penicillin G at a dose of over 10,000 units, has been shown to induce hemorrhagic cecitis and colitis (Harkness, 1995). However, Botting suggests that this toxicity was not actually due to the penicillin itself but rather was due to the impure nature of the compound previously used (Botting, 1997). In other studies deaths due to toxic effects of procaine, at a dose of 0.40 mg/kg, have occurred in guinea pigs following treatment with procaine penicillin G (Burgman and Percy 1993; Harkness and Wagner, 1995).

Lincosamides are considered to be contraindicated for use in guinea pigs due to serious gastrointestinal effects, often followed by death. Clindamycin, a semisynthetic derivative of lincomycin, is a common lincosamide used in small animal practice (Plumb, 1999). In a 1980 study, cecal filtrated from guinea pigs inoculated with clindamycin contained Clostridium sordellii toxin or an antigenically related toxin which was lethal to guinea pigs when injected intraperitoneally (Rehg, 1980). In some cases gentamicin may counteract lincomycin-associated enterotoxemia (Harkness and Wagner, 1995).

Fluoroquinolones are potent, broad spectrum antimicrobial agents that include norfloxacin, enrofloxacin, ciprofloxacin, and orbifloxacin (Bendele et al., 1990; Allen et al., 1998). All quinolones have the capacity to cause articular degeneration of unknown pathogenesis in growing guinea pigs. This is characterized by blister formation and subsequent cartilage erosion with the lesions being most severe in the weight-bearing joints (Bendele et al., 1990). In addition, fluoroquinolones compete for gamma-aminobutyric acid (GABA) receptor sites in the central nervous system, and thus their use would be contraindicated in certain neurological conditions (Morris, 1995). Norfloxacin is an effective antibiotic in urinary and respiratory tract infections. However, it seems to impair protein metabolism in the liver, caussing reduced bile secretion leading to significant cholestasis (El-Ashmawy et al., 1994).

Aminoglycosides can cause an ascending flaccid paralysis with respiratory arrest, coma and death, especially in high dosages or under anesthesia, due to neuro-muscular blockade of skeletal muscle (aminoglycosides are thought to be calcium-channel blockers) (Harkness and Wagner, 1995). In addition, all aminoglycosides are considered ototoxic and nephrotoxic. Some studies show albino guinea pigs to he more susceptible to ototoxicity than pigmented animals (Conlee et al., 1989). It has been noted that the least nephrotoxic dosing schedule is once a day rather than dividing the daily dose into multiple intervals since the amount of aminoglycoside in the proximal renal tubules is directly related to duration of renal exposure to the drug (McClure and Rosin, 1998). This type of drug administration is also known as a pulse therapy and will be discussed later.

The tetracyclines, at doses over 50 mg/kg, are potentially nephrotoxic, which will be exacerbated by concurrent endotoxemia due to the synergistic effect (Harkness and Wagner, 1995).

One srudy demonstrated that high doses of cefazolin (100 mg/kg) will result in toxicity while lower doses have some toxicity, but minimal therapeutic effect (Fritz et al., 1987). The drug was distributed extensively in the extravascular tissue, but also eliminated very rapidly wilth a half-life less than 1 hour (Fritz et al., 1987).

Bacitracin, methicillin, spiramycin, tylosin and erythromycin (in most cases) have also been implicated in causing fatal antibiotic-related enterocolitis in guinea pigs (Fritz et al., 1987; Quesenberry, 1994; Harkness, 1997).

SAFE ANTIBIOTICS

The ideal antibiotic for use in guinea pigs would one which is easily administered, bactericidal, does not cause gastrointestinal disease, or any major side effects.

Chloramphenicol, a bacteriostatic broad spectrum antibiotic, is considered generally safe and useful in weaned and non-pregnant guinea pigs. It is given parenterally at a dose of 20-50 mg/kg every 6 to 12 hours (Harkness, 1995). Medication of the drinking water can be difficult due to the drug’s bitter taste (Allen et al., 1998). Owners should be warned to avoid contact with this drug due to possibly acquiring chloramphenicol-induced aplastic anemia.

Fluoroquinolones are safe, bactericidal, broad spectrum, and orally active agents with a little cross-resistance to other classes of antibiotics (Morris, 1995). These antimicrobials are effective against Pasteurella spp. and other gram-negative infections (Rosenthal, 1998). Enrofloxacin is given (at a dosage of 10 to 20 mg/kg) intramuscularly, subcutaneously or orally every 12 hours (Rosenthal, 1998). Irritation at injection site may occur (Harkness, 1995). This antibiotic is recommended for the treatment of Bordetella bronchiseptica and Streptococcus infections (Dorrestein, 1992). Ciprofloxacin, is an agent active against gram positive (Staphylococcus, Streptococcus and Enterococcus spp.) and gram negative (Pseudomonas, Serratia, Klebsiella, Pasteurella spp.) ocular pathogens. It doesn’t interfere with re-epithelization of corneal ulcers and is used at a dose of 2-3 drops twice a day (Rosenthal, 1995). Ciprofloxacin is also given per os in well hydrated animal at 7-20 mg/kg every 12 hours to defeat gram-negatives, Staphylococcus and Mycoplasma spp. infections (Harkness, 1997).

Trimethoprim-sulfa drugs appear to be safe and useful for treating bacterial infections at a dose of 30 mg/kg per os every 12 hours. Trimethoprim-sulfamethoxazole, in the oral pleasant-flavored suspension, is inexpensive and easy to administer at a dose of 15 mg/kg twice a day (Tynes, 1998).

Aminoglycosides in guinea pigs therapy should be administered concurrently with fluids, particularly if the animal is older or even mildly dehydrated (Burgmann and Percy, 1993). The recommended dosage for gentamicin is 2-4 mg/kg every 8-24 hours subcutaneously or intramuscularly (Harkness, 1995). Amikacin sometimes is indicated for bacterial infections caused by E.coli, Klebsiella, Proteus, and Pseudomonas spp at a dose of 8 to 16 mg/kg intramuscular or intravenously every 24 hours (Allen, 1998; Rosenthal, 1998).

Metronidazole is used to control anaerobic infections at a dose of 20 mg/kg per os every 12-24 hours (Rosenthal, 1998).

ALLOMETRIC SCALING

Drug dosage estimation on the basis of body weight is not always acceptable in treating smaller mammals due to a difference in metabolic rates. At present, allometric scaling is used to establish dose and frequency of administration when such information is not available. It involves mathematical calculations from one species of animal to another by multiplying an exponential function of lean body weight by a constant K (marsupials=49, placental mammals=70) (Allen et al., 1998). The main limitation of this method is an assumption that all animals absorb, distribute, and metabolize a given drug in the same manner which is not always the truth due to diverse physiology in different species (Allen et al., 1998).

Another reason why it is difficult to establish the exact dose needed at the infected site is the tendency for rodents to form caseous pus and thick-walled abscesses; for many drugs both are difficult to penetrate. In these cases the abscesses will be best treated by combining antibiotic therapy with wound debridement and daily flushing (Rosenthal, 1998).

ROUTES OF ADMINISTRATION

There are various routes that can be employed for drug delivery to the animal.

Administration via water is one of the easiest and inexpensive methods; many animals can be treated simultaneously with minimal stress. However, disadvantages of this method are, unknown exact dosage for an individual animal and too many factors (body weight, water palatability, disease status, dehydration, obesity, age, and sex) which may influence water intake (Burgmann and Percy, 1993). Also, medication of the drinking water rarely allows drug to reach effective serum concentrations (Porter et al., 1985; Percy and Black, 1988). Antibiotic preparations should be water soluble and stable, palatable and well absorbed from the gastrointestinal tract (Burgmann and Percy, 1993).

Direct drug administration is preferable since the amount administered can be accurately determined based on the needs of an individual and the drug can be easily hidden in a piece of feed with no stress of handling. For this method to work, palatability is essential. If the drug is administered directly per os, proper restraint techniques are necessary to prevent regurgitation, exhalation, or aspiration (Burgmann and Percy, 1993).

Parenteral therapy is indicated for antibiotics that are not very well absorbed from the gastrointestinal tract, or if rapid effect is required. Most commercial drugs are too concentrated, and accordingly require dilution before use (Burgmann and Percy, 1993).

Subcutaneous administration minimizes tissue damage to muscles and large volumes of drug can be injected. Some drugs, such as sulfonamides are irritating to tissues, especially if dissolved in a propylene glycol base and require dilution before use (Allen et al, 1998).

Intramuscular route is rarely used for an extended period of time in small mammals due to their size, small muscle mass and potential for sciatic nerve damage (Rosenthal, 1998).

Intravenous and intraosseous routes are the most challenging and reserved for severe cases of bacterial disease (Rosenthal, 1998).

Topical drug preparations have limited use in rodents due to their fastidious grooming habits; therefore, caution should be employed if the topical antibiotic ingredient has the potential to cause dysbiosis (Rosenthal, 1998). In addition, because of the small size, surface area to volume ratio is greater, which result in higher susceptibility of rodents to the toxic side effects of topical drugs, particularly those containing steroids or organophosphates (Allen et al., 1998).

Nebulization of antibiotics for respiratory tract infections is very helpful in all species and can be used as an adjunct to oral or parenteral therapy (Burgmann and Percy, 1993). Pulse therapy is a new concept in drug administration and involves once-a-day drug administration rather than multiple, daily dosing. Drugs known to be effective in pulse therapy usually have a “postantibiotic effect” which means that they are still effective even after decrease in concentrations. In addition, these drugs have their best effect at a high dose for a limited time which is opposed to the classes of drugs that are more effective a steady state (Rosenthal, 1998). For example, penicillins are more effective at a steady-state concentrations, while fluoroquinolones and aminoglycosides, are more effective and safe in pulse therapy.

TREATMENT OF ANTIBIOTIC-INDUCED ENTERITIS

Antibiotic-induced enteritis and enterotoxemia are life threatening and should be treated aggressively with the offending drug should be discontinued immediately. Use of metronidazole at 20 mg/kg every 12 hours to decrease the amount of Clostridia spp. is recommended. Intravenous or subcutaneous fluids should be given to replace lost fluids, plus maintenance at 10ml/100g of body weight (Messonnier, 1998). Use of cholestyramine, to bind iota toxins, at a dose of 2 g per 20 ml of water every 24 hours by gavage is controversial (Rosenthal, 1998). Sick guinea pigs must daily supplementation with vitamin C at high doses (30-100 mg/kg) (Quesenberry, 1996). And nutritional support with high-fiber diets. This can be accomplished by syringe-feeding a blenderized form of the patient’s regular diet or oral administration of feces from a healthy animal of the same species. The later is useful to help re-establish normal gut flora, although it is unknown whether the microbes survive the stomach’s extreme acidity (Harrenstien, 1994). Ill animals should be kept warm at all times, but the environmental temperature should not exceed 80° F in order to avoid hyperthermia (Messonnier, 1998).

Oral lactobacillus supplements have been used routinely to protect guinea pigs from the adverse effects of antibiotics, but the effectiveness of this measure is debatable (Tynes, 1998).
SUMMARY

In summary, fluoroquinolones show promise as effective, safe and broad spectrum agents. Due to small muscle size in guinea pigs and ability to inject relatively large volumes, the subcutaneous route may be the most effective for drug delivery in these species. A consideration of the basic principles of veterinary pharmacology and the factors discussed above will help rationalize the use of antibiotics in guinea pigs.

Before treating a guinea pig or any other pet rodent a practitioner should notify the extralabel medication use if applicable.

Client education is also essential. Owners have to realize the importance of monitoring their pets closely, discontinuing medications at the first sign of side effects, and notifying their veterinarian of any problem.

The lack of clinical trials on antibiotic therapeutics in guinea pigs, together with extrapolation from available information, means that many “doses” are based on clinical response and absence of side-effects. As small mammals become more popular as pets, specific products, with dosage information based on scientific data, will become available. One however, has to bear in mind that it is impossible to label each product for every specie. Use of allometric scaling should be practiced where necessary to extrapolate dosages from other species for more realistic dose regimens.

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