Joe S. Smith Since the 1980s, the numbers of the two domestic species of New World camelids (NWCs), llamas and alpacas, have increased rapidly in North America, Australia, and most recently Europe. The combined populations of these animals have been previously estimated at 7 million in South America (Peru, Chile, Bolivia, and Argentina), 300,000 in North America, 80,000 in Australia, and 30,000 in Europe. Population growth outside South America has slowed considerably in the past 10 years, but in many countries llamas and alpacas are cherished pets whose owners expect quality healthcare. Clinicians working with NWCs have historically found them to be challenging, because camelids possess a stoic nature which hides disease signs; physical examination and laboratory evaluation often yield no immediate answers; disease pathogenesis and progression are often unique; and reference material lags behind medical advances. There is rising recognition of a number of specific infectious conditions affecting camelids. One distinct feature of the sick camelid is that it often has impressive leukogram changes, particularly neutrophilia with or without a left shift. These changes may or may not reflect infectious disease – stress neutrophilia is common and can lead to nucleated cell counts as high as 50,000 cells/μl, as well as moderate increases in band cell counts. Unfortunately, in the absence of other definitive diagnostic information, neutrophilia is often used to justify empirical use of antimicrobials. The choice of antimicrobial therapy is usually empirical, with broad‐spectrum coverage desired. This leads to the next frustration: there is a persistent lack of disease prevalence data as well as pharmacokinetic and pharmacodynamic data from NWCs. Camelids are anatomically and physiologically unique, making any sort of extrapolation of drug information from another species dangerous. Only a few medications in a few countries are approved for NWCs, and dosages found in clinical reports can differ from each other as much as 25‐fold. Although camelids are generally considered as pets in North America, and are considered companion or production animals in the EU, their rising population coupled with economic issues has led to reversion to one of their traditional South American roles as an animal protein source (Zarrin et al., 2020). Veterinarians need to be aware of individual circumstances, consider residues and the legality of using certain medications, and discuss these issues with owners. One topic that has received attention in recent years is the dosing difference between llamas and alpacas. Pharmacokinetic studies have approximately followed species popularity, with the earlier studies done in llamas and more recent studies done in alpacas, though the greater availability of llamas as research animals means that they are still studied. Few studies have compared the two species, which recently have been declared members of separate genera. Data from studies involving glucose indicate that adult alpacas have an extracellular (interstitial) fluid compartment that is approximately 37% larger than adult llamas (Cebra et al., 2006a). This is similar to the difference in volume of distribution for oxytetracycline found in one study (Christensen et al., 2001), whereas the volume of distribution for ceftiofur is reported to be 2.5–3 times larger in alpacas than llamas (Drew et al., 2004; Christensen et al., 1996). A physical basis for the difference in volumes of distribution is found in the contributions of various organs to whole body weight. The full gastric viscera of llamas make up approximately 4% more of whole body weight in llamas than alpacas, meaning alpacas generally have proportionally more soft tissue and interstitial fluid (Cebra et al., 2006b). Very lipophilic compounds such as florfenicol distribute into the gastric compartments and hence have similar volumes of distribution between llamas and alpacas, whereas hydrophilic compounds do not, and distribute over a proportionally larger volume in alpacas than in llamas. Dosage adjustment may be necessary, and has been demonstrated with oxytetracycline. Aminoglycosides are hydrophilic, appear to diffuse more slowly out of the vascular compartment, and would be less affected by this. Therefore, they should not be dosed higher in alpacas. The same argument can be used to adjust dosages for younger camelids. Glucose studies suggest that unweaned llama crias between two and four weeks of age have an extracellular fluid compartment that is approximately 30% larger than adult llamas (Cebra et al., 2005). Unfortunately, the importance of this difference in antimicrobial dosages has not been investigated. Compared with many other common domestic species, much less information is available concerning the frequency and importance of bacterial isolates. A table of what has been seen at Oregon State University has been included in the previous version of this chapter. Others have compiled similar findings from other institutions in unpublished formats (Dechant et al., 2012; Anderson, 2009). Sufficient data were not available to derive meaningful in vitro susceptibility conclusions. Since many of these bacteria are opportunists, they would likely have similar susceptibility profiles to isolates from other species. Of particular note are the alpha‐hemolytic streptococci, which often are resistant to penicillin and may be the cause of some treatment failures. Also of note are the increasing published and anecdotal reports of Salmonella and Streptococcus equi subsp. zooepidemicus infection (Tillotson et al., 1997; Saulez et al., 2004; Middleton et al., 2006; Hewson et al., 2001; Jones et al., 2009). These last microorganisms are primary pathogens in camelids and may affect multiple, otherwise healthy camelids on one property. With Salmonella, camelids may also be involved in multispecies outbreaks. Corynebacterium pseudotuberculosis is another primary pathogen involved in multispecies outbreaks that is being increasingly recognized as a cause of peripheral or internal lymph node abscessation in camelids. As the popularity of camelids increases, the danger of transmissible diseases and cross‐species transmission also increases. This includes increasing risk of transmission to people, particularly with microorganisms such as Salmonella, Listeria, and E. coli O157 (Featherstone et al., 2011). One emerging organism may be Rhodococcus equi, which has been reported as the cause of a fatal infection in an alpaca (Sting et al., 2022). While treatment was not successful, susceptibility testing of the isolate suggested low MIC values for doxycycline, erythromycin, gentamicin, neomycin, tetracycline, rifampicin, trimethoprim/sulfamethoxazole, and vancomycin. As stated above, specific localized syndromes (such as bacterial pneumonia or enteritis) are rare, so aside from chronic, focal infections, most bacterial diseases have been grouped together as septic conditions. These animals usually present with general systemic signs including fever, inappetence, obtundation, and weakness, but may also have specific signs referable to the affected organs. As a general conclusion, the relative equality between Gram‐negative and Gram‐positive isolates from wounds and camelids with sepsis supports the initial use of broad‐spectrum antimicrobials. Combinations of an aminoglycoside with a beta‐lactam antimicrobial, or of ceftiofur alone or in combination are most common. Other single medications, such as oxytetracycline, enrofloxacin, or florfenicol, may be useful in some situations. Collection and culture of pertinent body fluids (blood, peritoneal fluid, pleural fluid, cerebrospinal fluid, urine, feces, aspirates, etc.) may yield information about specific pathogens and allow refinement of antimicrobial selection. Female reproductive tract infections frequently involve Gram‐negative enteric bacteria and have been historically mentioned as treated with gentamicin infusions or systematic ceftiofur, whereas tooth root abscesses and other tissue abscesses more frequently involve Gram‐positive or anaerobic bacteria and are most commonly treated with long courses (20–60 days) of penicillin, ceftiofur, or florfenicol. The camelid blood parasite Mycoplasma haemolamae is most commonly treated with long‐acting oxytetracycline preparations. Practitioners should be aware that chemosterilization of M. haemolamae is considered not possible, so even with treatment, relapses can occur. Chapters on the individual antimicrobials should be consulted for additional information concerning use and specific contraindications. Currently, no Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) validated breakpoints exist for bacterial isolates from llamas or alpacas. With this in mind, clinicians should be aware that interpretation of data from submitted culture and susceptibility testing are likely based on breakpoints from other species. Similar to sheep and goats, clinicians in regions where NWCs are considered food animals should be aware that diagnostic labs may report results for antimicrobials that may be prohibited from use in food animals in certain countries. Due to their nature and challenges with vascular access, SC administration is a common route for NWCs. Route of administration can affect the parameters of different drugs in NWCs. For example, ceftiofur sodium and gentamicin appear to have similar pharmacokinetic properties whether given IV or IM, so that the same dosage and dosing frequency may be used for either route. Additionally, evidence from other species suggests that many antimicrobials have comparable absorption from the SC route. The SC route has become very popular in camelids for all antimicrobials formerly administered IM due to lack of large muscle masses and ease of administration. Unless a very rapid effect is desired or the particular antimicrobial is known to cause adverse reactions when given SC, this route is considered acceptable. Oral antimicrobials have been studied less extensively than injectable preparations. Adult camelids should be expected to have similar problems with absorption as adult ruminants, and several studies demonstrate the flip‐flop phenomenon, where apparent prolonged elimination actually reflects prolonged absorption overlapping with elimination. Trimethoprim, sulfamethoxazole, and sulfadiamethoxine antimicrobials appear to have poor absorption at ruminant dosages and cannot be recommended for systemic disorders (Chakwenya et al., 2002; Junkins et al., 2003; Snook et al., 2002). Trimethoprim is virtually undetectable in the blood after oral dosing, and ion trapping of sulfas, which is a relatively greater problem in a forage‐fed camelid versus a steer on an acidifying feedlot ration, and likely to be worse in any ruminant or camelid with inappetence and relative forestomach alkalinization, may contribute to their poor absorption. Oral antimicrobials might be more useful in preruminant camelids, but this usage has not been investigated. A variety of antimicrobials have been administered to camelids. However, most dosage regimens are anecdotal, and the attending veterinarian must assume the responsibility for extra‐label drug use and potential adverse effects. As a general rule, antimicrobials have longer plasma elimination half‐lives in camelids than in domestic ruminants, potentially prolonging their therapeutic effect but also increasing risk of toxicity. This may be due to a lower rate of urine production in camelids (Lackey et al., 1995), which may increase the half‐life of antimicrobials excreted primarily through the kidneys (e.g., penicillins, aminoglycosides). This slower renal elimination may be affected by concurrent fluid treatments in hospital settings (such as IV fluid therapy), and may allow for NWCs in these environments to be treated similarly to domestic ruminants. Camelids treated in the field must be dosed more conservatively. As another general rule, volume of distribution varies tremendously among individual camelids. Higher dosages are generally recommended to avoid subtherapeutic drug concentrations. Thus, the most useful antimicrobials are those with a high margin of safety. Pharmacokinetic data for selected antimicrobials in llamas and alpacas are presented in Table 32.1. Ceftiofur sodium has been studied in both llamas and alpacas, and also has the broadest range of dosages in clinical reports (Christensen et al., 1996; Drew et al., 2004). The two main studies provide conflicting information concerning the volume of distribution at steady state and plasma elimination half‐lives, but similar information for clearance and area under the curve. Additionally, individual camelids in the larger study had volumes of distribution at steady state that varied by up to 100%. Thus, while the larger study reports pharmacokinetic parameters similar to those seen in small ruminants, twice‐daily dosing to adults at 2.2 mg/kg IV or IM is recommended to avoid subtherapeutic concentrations in the camelids with greater volumes of distribution. Subcutaneous administration at the same dose and interval has become popular, and is empirically successful, but has not been studied scientifically. Higher doses (4–8 mg/kg, IV, IM, or SC q 12 h) have been used in crias up to 12 weeks of age and in adults for which more aggressive antimicrobial protocols were deemed necessary (Buchheit et al., 2010; Simpson et al., 2011); no complications have been reported with these higher doses but they also have not been studied scientifically. Ceftiofur hydrochloride is used somewhat interchangeably with ceftiofur sodium by the IM and SC routes without reported problems (Lewis et al., 2009). Ceftiofur crystalline free acid is used where long‐acting coverage is desired (Jones et al., 2009). One study demonstrated that a single 6.6 mg/kg SC injection in the axillary region resulted in plasma concentrations of ceftiofur and active metabolites that remained above 0.25 μg/ml for six days in adult alpacas, but also suggested that higher concentrations were necessary to be effective against the majority of bacterial isolates (Dechant et al., 2012). Fifty‐four percent of Gram‐positive and 27% of Gram‐negative isolates from camelids were susceptible to ceftiofur concentrations ≤0.25 μg/ml, 71% of Gram‐positive and 45% of Gram‐negative isolates were susceptible to concentrations ≤0.5 μg/ml, and 88% of Gram‐positive and 64% of Gram‐negative isolates were susceptible at ≤1.0 μg/ml. Thus, dosing every 2–5 days may be necessary to achieve true broad‐spectrum coverage. Single doses of ceftiofur crystalline free acid were well tolerated, but repeated dosing led to local, nonpainful reactions in half the test alpacas. Ceftiofur is highly protein bound, which affects its distribution. Table 32.1 Pharmacokinetic data for selected antimicrobials in llamas and alpacas.
32
Antimicrobial Therapy in New World Camelids
Introduction
Pharmacokinetics and Pharmacodynamics in NWCs
Culture and Susceptibility Interpretation
Route of Administration
Antimicrobials Used in New World Camelids
Beta‐lactams
Agent
Species
Dose (mg/kg)
Route
Volume of distribution (l/kg)
Clearance (ml/min/kg)
Elimination half‐life (hours)
AUC (μg h/ml)
Peak concentration (μg/ml)
Time to peak (hours)
Ampicillina
Llama
12
IV
0.28 ± 0.09
0.88 ± 0.28
3.33 ± 0.50
228 ± 73
Ceftiofura
Llama
2.2
IV
0.19 ± 0.02
0.98 ± 0.15
2.19 ± 0.14
38.4 ± 5.8
Ceftiofurb
Llama
2.2
IM
0.61 ± 0.19
1.03 ± 0.41
8.00 ± 1.85
40.1 ± 12.9
5.52 ± 1.11
0.77 ± 0.56
Ceftiofurb
Llama
2.62–2.99
IM
0.61 ± 0.20
0.97 ± 0.36
8.81 ± 3.04
54.8 ± 20.8
6.33 ± 2.20
0.91 ± 0.55
Ceftiofurb
Alpaca
1
IV
0.54 ± 0.15
1.36 ± 0.39
5.60 ± 1.57
13.4 ± 4.4
Ceftiofurb
Alpaca
1.27–1.44
IV
0.55 ± 0.18
1.44 ± 0.37
4.62 ± 1.18
14.6 ± 3.1
Ceftiofurb
Alpaca
1
IM
0.57 ± 0.12
1.12 ± 0.36
4.31 ± 1.35
15.4 ± 5.1
2.09 ± 0.42
0.49 ± 0.16
Ceftiofurb
Alpaca
1.30–1.51
IM
0.64 ± 0.14
1.15 ± 0.27
7.42 ± 1.41
20.9 ± 3.9
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