Antimicrobial use in puppies and kittens

Introduction

It is well understood that puppies and kittens are not just smaller versions of dogs and cats, respectively, but beyond this, puppy- and kitten-hood encompasses a highly dynamic period of life, where there are substantial changes in various factors that influence the pharmacokinetics of drugs and the risks of adverse events. The variable and rapidly changing physiology in early life can impact both efficacy and safety of antimicrobial therapy, and there is limited species- and drug-specific information available for this critical neonatal period. Clinical trials regarding optimal antimicrobial regimens, and even data on whether antimicrobials are beneficial, are largely non-existent for young puppies and kittens. These factors complicate development of evidence-based treatment plans that maximize the potential therapeutic benefits while minimizing the risks. Furthermore, the scope of potential risks is also poorly understood, and even where the risks are known, our comprehension is often limited, with restricted information about incidence and long-term impact in clinically relevant situations.

The neonatal period is also highly variable and changeable microbiologically, as the individual develops its critical and complex commensal microbiota. Consideration of “adverse effects” has typically focused on drug-patient interactions, with limited thought as to drug-microbiota interactions. The impact of antimicrobials on the commensal microbiota is an area that is of increasing interest and attention, but one where objective data are very sparse. Proper cost-benefit assessment and use of evidence-based treatment regimens is therefore a challenge in the management of neonatal infectious disease.

Antimicrobial pharmacokinetics in neonates

Pharmacokinetics involves what the body does to a drug after administration, something that is a function of absorption, distribution, metabolism and elimination. All of these factors can be different in neonates when compared to adults, and are also changeable throughout the neonatal period. The impact on pharmacokinetic properties (e.g., half-life, bioavailability, volume of distribution) can impact the potential for efficacy, as well as adverse event risks.

After administration, antimicrobials must be absorbed into the circulation, and this may be unpredictable or different in neonates. Oral absorption in particular can be impacted by age (Figure 1). In the first 24 hours of life, absorption may be very high, resulting in unexpected and possibly unwanted bioavailability. Potentially toxic drugs that are not meant to be highly absorbed (e.g., neomycin) should therefore be avoided in very young individuals. Nursing can also impact the absorption of some drugs, either because a drug binds to milk components, or because it makes it impossible to administer a drug on an empty stomach (Figure 2). Slower gastric emptying can be a factor, as this can delay absorption but also potentially ultimately increase bioavailability from longer mucosal contact 1. A higher gastric pH than adults – a common situation in nursing individuals – can decrease absorption of drugs that are weak acids (e.g., fluoroquinolones); one study reports failure of oral administration of enrofloxacin to produce therapeutic drug levels in nursing 6-8-week-old kittens, which highlights potential issues 2. So while there is little information about commonly used drugs in puppies and kittens, there are competing factors that may increase or decrease oral bioavailability in this age of animal.

Other routes of administration may also be used. Administration by gastric tube may be required in puppies and kittens that cannot be effectively treated per os but are deemed adequately stable and to have good gastrointestinal motility. Subcutaneous administration likely results in similar drug levels to intravenous and oral administration, but may be affected by inadequate hydration and perfusion, something that can be of greater likelihood in compromised neonates. Intra-osseus administration is also an option for some drugs.

After absorption, antimicrobials distribute through serum to tissues. Neonates have a larger fraction of extracellular fluid, up to twice as large as adults, along with less adipose tissue and muscle, resulting in increased distribution of water-soluble drugs (e.g., penicillins, cephalosporins, aminoglycosides) and correspondingly lower tissue levels. Lower serum protein concentrations and lower affinity of protein binding in neonates may increase free (active) drug levels of highly protein-bound compounds such as cefovecin, and this also increases the rate of elimination. The free antimicrobial at the affected site is the factor that will influence potential antibacterial efficacy, so the clinician should be aware that a dosage may need to be increased or decreased depending on the drug and individual patient.

Metabolism may also be impacted by lower levels of enzymes involved in hepatic drug metabolism, particularly in the first four weeks of life. The kidneys are the site of elimination of many drugs, and renal excretion is impacted by glomerular filtration rate and renal tubular transport mechanisms, both of which change over time. This is mainly relevant very early in life, as renal and hepatic function are likely at near-adult levels by 4-6 weeks of age. Before that timepoint there may be increased risk of toxicity, particularly from drugs such as chloramphenicol that have narrower margins of safety and rely on hepatic metabolism. The half-live of enrofloxacin in 2-, 6- and 8-week-old puppies has been shown to be significantly shorter than in adults because of a greater rate of elimination, resulting in lower peak drug concentrations 2.

Dosing adjustments for neonates

A lack of data creates challenges in tailoring treatments for neonates. It is apparent from the above that there may be factors which can lead a need for higher doses (e.g., larger volume of distribution) or, conversely, lower doses or prolonged dosing intervals (e.g., delayed clearance). Given that metabolism and excretion can be unpredictable in young individuals and will vary greatly by age in the first month of life, and between individuals, predicting the pharmacokinetics at the patient level is difficult, and there are no evidence-based recommendations for puppies and kittens. For highly water-soluble drugs with wide margins of safety (e.g., beta-lactams) dosing at the high end of the adult dose with the adult dosing interval is reasonable, particularly in individuals that are four weeks of age or older. Historic literature recommendations that may advise reduced adult doses (sometimes substantially) are unsubstantiated and should be avoided. Table 1 identifies common antimicrobials and suggests likely dosages for use in young animals. Once puppies and kittens have reached 6 weeks of age, normal adult doses can probably be comfortably used for most antimicrobials.

Table 1. Potential dosing approaches for young puppies and kittens.

Drug-specific issues

Aminoglycosides

Aminoglycosides have excellent activity against Gram negative bacteria (including most multidrug resistant bacteria and Pseudomonas spp.) and good staphylococcal activity, with limited efficacy against other Gram positives and no activity against anaerobes. They must be administered parenterally and can be associated with nephrotoxicity and ototoxicity; the risks are lower with amikacin compared to gentamicin. Nephrotoxicity risks are greatest with dehydration or poor perfusion, but the incidence of toxicity is unknown. While it is common to see statements that aminoglycosides should be avoided in puppies and kittens, there are no actual data supporting such a recommendation, and this class of drug is used, when needed, in neonates of various other species, including humans. In fact, gentamicin has been reported as being the second most commonly used antimicrobial in human neonatal intensive care units (NICUs) after ampicillin 1. While not recommended for routine use, aminoglycosides may be useful for culture-directed treatment of many multidrug resistant bacteria, and as an empirical choice for Gram negative coverage in particularly high-risk patients (e.g., sepsis), where the risk of toxicity is outweighed by the risk of imminent death from infection. Ensuring good perfusion and hydration will reduce risks. An important point to note is that early signs of toxicity seen in adults (the development of granular casts) are not as consistently noted in neonates, complicating the monitoring for such cases.

Little is known about dosing of this drug class in young puppies and kittens. Neonates will have wider distribution of the drug but reduced renal elimination. In foals, higher doses are used compared to adult horses (e.g., amikacin 20-25 mg/kg q 24h vs. 10-15 mg/kg q 24h), but in neonatal babies the drug dosage tends to be similar to adults, although with an extended dosing interval – for babies of normal birthweight less than one week of age, q 30-36h administration has been recommended 1, but drug monitoring typically guides both dose and frequency. In theory at least, assessment of peak and trough drug levels can allow for better tailoring of doses for the individual, which could require a higher dose (because of greater distribution) but longer dosing interval (because of decreased renal elimination).

Doxycycline

Doxycycline is a broad-spectrum antimicrobial with activity against a range of Gram positive, Gram negative, vector borne and atypical bacterial pathogens. While tetracycline use can result in tooth staining if used in growing individuals 3, those risks are not present with doxycycline, as it does not have the same affinity for binding to calcium as tetracycline. It is therefore not contraindicated in young children *, and there is no need to avoid its use in puppies and kittens because of concerns about tooth staining or development. Earlier concerns about tooth staining in children likely contributed to minimal investigation of using doxycycline in neonates, as little information is available. No significant differences in pharmacokinetics have been identified in 2 to 8 years of age vs. older children 4, but data for younger children are lacking. Since it is generally regarded as safe – dosing is not altered in human patients with renal compromise – adult doses are reasonable for kittens and puppies.

* https://www.cdc.gov/rmsf/doxycycline/index.html

Cephalosporins

Cephalosporins are generally safe and effective options in young animals. Cephalexin is commonly used and provides excellent Gram-positive coverage (e.g., against Staphylococcus and Streptococcus spp.) with rather limited Gram-negative effects. Given orally and with a wide safety margin, it is a good option for situations where the focus is on Gram positive pathogens.

Third generation cephalosporins such as cefotaxime and ceftiofur are good, extra-label options for situations where broad-spectrum coverage is needed. This drug class provides excellent activity against Gram negatives while retaining good activity against Gram positives, but has no activity against enterococci, and most are ineffective against Pseudomonas spp. (except anti-pseudomonal cephalosporins such as ceftazidime). These antibiotics are good options for culture-directed treatment and for empirical treatment of seriously ill patients where reliable broad-spectrum coverage is needed. Cefotaxime is also commonly used when central nervous system (CNS) infection is suspected, because of reasonable blood-brain barrier penetration and the ability to administer high doses safely. Oral cefpodoxime can also be used.

As with other beta-lactams, renal elimination is reduced in early life, although the wide safety margin means that this may be of limited concern. However, human neonates are given higher doses and longer dosing intervals (50 mg/kg q 12h for 0-7 days of age and q 8h for 7-28 days of age) compared to the recommendations for babies older than 28 days of age (37.5 mg/kg q 6h) 1.

Cefovecin is not recommended for routine use; as a highly protein-bound drug, its pharmacokinetic properties may be quite different in neonates. It is also a poor choice for E. coli, apart from lower urinary tract infections. Since this drug is best positioned for treatment of superficial folliculitis and bacterial cystitis in patients where administration is problematic, there is limited indication in puppies and kittens.

Clindamycin

Clindamycin is another oral option with excellent activity against Gram positive and anaerobic bacteria. In humans, daily doses of 15-20 mg/kg are recommended for babies less than 28 days of age, compared to 20-40 mg/kg in older babies (in both cases, divided over 3-4 doses), although 9 mg/kg q 8h has been suggested for all infants of normal birth weight 5. No data are available for dogs and cats, and similar dosing regimens to those used in adults are probably reasonable. The lower end of the dosing range could be considered for very young individuals, as a result of presumed slower clearance.

Fluoroquinolones

Fluoroquinolones are excellent Gram-negative drugs, with less Gram-positive activity and no (apart from pradofloxacin) activity against anaerobes. The most recognized concern with administration of fluoroquinolones to growing animals is development of cartilage defects. Toxic effects of enrofloxacin on canine chondrocytes and tendon cells have been identified in vitro 6,7 and the US product insert for enrofloxacin indicates that microscopic changes in articular cartilage developed in older puppies with 30 days dosage at 5-25 mg/kg. However, clinical abnormalities were not reported in 2-week- or 29-34-week-old puppies given 25 mg/kg/daily for 30 days. Two recent studies in foals have not identified cartilage lesions after treatment of mares during late pregnancy 8,9, but severe cartilage erosions were identified in 2/2 foals treated postnatally using standard doses 9. This is consistent with an earlier report (only published as an abstract), which noted articular cartilage damage in 4/4 treated neonatal foals 10. The limited number and size of studies complicates safety assessment, as does the complete absence of field studies using clinically applicable doses over a range of ages. There may also be concerns about tendon rupture (based on canine cell culture study 7), but the incidence of this in human adolescents is very low 11 and nothing is known about the risks in dogs and cats.

Retinopathy is also recognized with this class of drug, reported as a dose-dependent problem in cats treated with enrofloxacin 12. Lower doses (5 mg/kg q 24h) have been recommended to reduce the risk; however, this may not be adequate for young animals with potentially decreased renal clearance. Lower doses are also undesirable for a concentration-dependent drug where high peak drug levels and AUC:MIC ratios * are important for bactericidal activity.

* AUC- area under curve; MIC = minimum inhibitory concentration

Overall, the risks posed by short duration use of clinically relevant doses in puppies and kittens are unclear, although they are probably higher in very young individuals. However, there are few indications for fluoroquinolone use in puppies and kittens, as other safer drugs that provide a similar antimicrobial spectrum (e.g., 3^rd generation cephalosporins) are available. Their use could be considered, ideally for a short duration, in limited situations where other routine antimicrobials are not indicated for bacterial or patient factors, as the benefits may outweigh the risks. Lower doses might reduce the risk but also may be undesirable from a bactericidal efficacy standpoint, so the focus is probably best on minimizing duration of treatment rather than reducing the dose.

Penicillins

Antibiotics in this category, including potentiated penicillins, are widely used in neonates, particularly oral amoxicillin and clavulanic acid, and parenteral ampicillin. They are also widely used in neonates of other species, with ampicillin being the most commonly used drug in human NICUs 1. There may be greater distribution and slower elimination in neonates, something that has been shown in puppies with ampicillin, with a corresponding dosing recommendation of 50 mg/kg IV q 4-6h for 6-week-old puppies 13. Higher doses could be considered for younger puppies. In humans, a neonatal dose of up to 200 mg/kg q 6h is used, compared to 20-40 mg/kg q 4-6h for adults. Ampicillin can also be administered intra-osseously to puppies and kittens at the same dose as for IV use, when venous access is not available 13,14.

A similar approach can be taken with amoxicillin, a drug that is largely analogous to ampicillin but with excellent oral bioavailability. Given the larger volume of distribution and safety, higher doses have been recommended in human neonates (50 mg/kg PO q 12h) 15. Since the half life is short, more frequent (q 8h) dosing should be considered in older puppies and kittens (e.g., >1 month). Amoxicillin-clavulanic acid is a very commonly used drug in neonates and can be obtained in an easy-to-use oral suspension. Amoxicillin pharmacokinetic issues are as described above, but little is known about clavulanic acid, so as a result, use of the high end of normal dosing ranges would be reasonable.

Antimicrobials and the commensal microbiota

The body contains a vast microbial population (the microbiota) and its complement of genes (the microbiome). While there have been tremendous advances in our ability to study these complex microbial populations that are present in the gut, respiratory tract, skin and other sites, understanding how these populations interact with the host, and the impact to and from the microbiota, remain unclear. Yet it is undeniable that the microbiota (particularly the intestinal fraction) has profound and complex interactions with the body, both locally within the gut and beyond.

At the time of birth, a puppy or kitten is inundated with microbial exposures, from the moment of delivery (if not before) and continuing throughout life. Neonates are exposed to the dam’s microbiota from her vagina, skin, milk, respiratory tract and intestinal tract, as well as the microbia from the environment, human handlers and any other contacts (Figure 3). These early exposures shape the development of the microbiota, and some can have long-lasting impacts. For example, human babies born by caesarean section develop a microbiota that is different from those born vaginally, and these changes can persist for months 16. However, probably the most profound influencer of the microbiota is antimicrobial exposure, as gut microbiota can be significantly impacted by antimicrobial therapy 17,18,19. These impacts can persist well beyond the time of treatment, and such therapy could disrupt the important development of the commensal microbiota and influence its complex interactions with the body. 

A key aspect of immunological development is tolerance, where the body learns how to regulate the immune response and not respond (or over-respond) to the massive commensal antigenic burden. For example, antibiotic usage in infants has been associated with increased risk of asthma, linked to changes in the gut microbiota 20. Other studies have also reported associations between antimicrobial use in children and subsequent risk of allergic disorders, including asthma, atopy and food allergy 21,22,23. While this has not been studied in dogs and cats, it is reasonable to suspect that changes in the gut microbiota from early antimicrobial use could similarly impact the risk of immunologically-mediated diseases such as atopy and food allergy. Antimicrobial use in the mother during pregnancy can also impact the microbiota in humans (and presumably other species), and prenatal antimicrobial exposure is associated with increased risk of allergic disease in humans 23. While antimicrobials are necessary for treatment of bacterial diseases, these concerns highlight the need for good antimicrobial stewardship. Measures to reduce the risk of disease (e.g., good management, proper post-natal care) with antimicrobial use limited to where it is clearly indicated, can presumably have long-lasting benefits on puppy and kitten health.

Examples of antimicrobial use in neonates

Respiratory tract disease

Infectious respiratory tract disease is common, especially in kennel and shelter settings that involve abundant animal movement and mixing. A range of pathogens can be involved, only a subset of which are bacterial. Even when bacterial pathogens are involved, antimicrobial treatment is not always required, with the decision being influenced by disease severity and chronicity, if there is lower respiratory tract involvement, and the animal’s age.

Doxycycline is a good option for upper respiratory tract infection where it appears to have a bacterial component, or if there is concern about progression to bacterial pneumonia. This drug is also indicated if Mycoplasma spp. is suspected to be involved, although determining the relevance of this organism can be challenging. Amoxicillin/clavulanic acid may be considered for mild to moderate disease, but is suboptimal compared to doxycycline because of resistance in some important pathogens (e.g., Bordetella spp.), no activity against Mycoplasma, relatively poor activity against beta-lactamase producing Gram negative bacteria, and relatively poor penetration of epithelial lining fluid.

With more severe or rapidly progressive disease, broad spectrum coverage is indicated. Parenteral treatment is usually indicated with this severity of disease (e.g., cefotaxime, ceftiofur, ampicillin + amikacin, clindamycin + amikacin); however, of those, only clindamycin has some activity against Mycoplasma, and that is only marginal. Since this organism probably plays, at best, a co-infection role in patients with serious disease, these drugs remain good options for individuals with evidence of severe bacterial pneumonia, with or without sepsis. Oral treatment can be used in patients that have good gastrointestinal motility; options include cefpodoxime, but this should be avoided in severely ill patients. When ocular involvement is the main clinical issue, topical antimicrobials may be all that are required.

Septicemia

Septicemia is an acutely life-threatening condition that requires prompt and effective antimicrobial therapy. While culture-directed treatment is ideal, based on blood samples or culture of specimens from other affected sites, results are not available until days into treatment. Prompt and effective empirical treatment is therefore required, and unless a cause is strongly suspected (e.g., development of sepsis from a known septic focus from which culture results have been obtained), empirical broad-spectrum coverage is needed, with particular efficacy against enterobacteriaceae, staphylococci and streptococci species. Parenteral administration is indicated because of the potential for poor oral absorption, with the IV route used whenever possible. Various options for broad spectrum coverage include a 3^rd generation cephalosporin (e.g., cefotaxime, ceftiofur), or combinations of clindamycin and amikacin or ampicillin and amikacin. Cefotaxime or ceftiofur are likely safer options initially in highly compromised patients, because of the increased risk of nephrotoxicity and ototoxicity in dehydrated or otherwise poorly perfused patients, and is a common recommendation for human neonatal sepsis, with or without ampicillin. Cefovecin is not indicated because of its inactivity against E. coli in tissue and unclear pharmacokinetics in neonates. If enterococcal involvement is suspected – most often a concern in hospital-associated infections – ampicillin should be part of the chosen regimen (e.g., ampicillin + cefotaxime, ampicillin + amikacin).

Neonatal diarrhea

Neonatal diarrhea is common in most species and can have myriad infectious and non-infectious (e.g., dietary) causes. Diarrhea itself is not an indication for antimicrobial treatment, and indeed might be contraindicated, as the impact on the microbiota could be detrimental. Antimicrobial therapy decisions should be based on the systemic status of the individual and whether there is reasonable concern that the patient is, or is at high risk of becoming, septic. Altered mental status, abnormal body temperature and bloody diarrhea would raise concerns about bacterial translocation and sepsis, and are all reasonable indicators for initiating antimicrobial therapy. Since antimicrobials are directed at treating or preventing sepsis, the approach is the same as for sepsis (e.g., cefotaxime, ceftiofur).

Conclusion

Antimicrobials are potentially life-saving drugs, but they can also be life-altering through adverse effects and long-term developmental impacts. Proper and effective use of antimicrobial drugs in neonatal puppies and kittens is complicated by a lack of data, so assumptions about dosing must be made. Differences between young animals and their adult counterparts must be considered when choosing drugs and dosing regimens, to maximize the likelihood of efficacy and minimize the risk of adverse effects. Above all, efforts should be taken to optimize maternal and newborn health in order to reduce the need for antimicrobials, removing issues about uncertain dosing and long-term effects.