Mark G. Papich

Antimicrobial Use Guidelines for Treatment of Urinary Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases

Urinary tract disease is a common reason for use (and likely misuse, improper use, and overuse) of antimicrobials in dogs and cats. There is a lack of comprehensive treatment guidelines such as those that are available for human medicine. Accordingly, guidelines for diagnosis and management of urinary tract infections were created by a Working Group of the International Society for Companion Animal Infectious Diseases. While objective data are currently limited, these guidelines provide information to assist in the diagnosis and management of upper and lower urinary tract infections in dogs and cats.

Dosing Regimen Matters: the Importance of Early Intervention and Rapid Attainment of the Pharmacokinetic/Pharmacodynamic Target

ABSTRACT To date, the majority of pharmacokinetic/pharmacodynamic (PK/PD) discussions have focused on PK/PD relationships evaluated at steady-state drug concentrations. However, a concern with reliance upon steady-state drug concentrations is that it ignores events occurring while the pathogen is exposed to intermittent suboptimal systemic drug concentrations prior to the attainment of a steady state. Suboptimal (inadequate) exposure can produce amplification of resistant bacteria. This minireview provides an overview of published evidence supporting the positions that, in most situations, it is the exposure achieved during the first dose that is relevant for determining the therapeutic outcome of an infection, therapeutic intervention should be initiated as soon as possible to minimize the size of the bacterial burden at the infection site, and the duration of drug administration should be kept as brief as clinically appropriate to reduce the risk of selecting for resistant (or phenotypically nonresponsive) microbial strains. To support these recommendations, we briefly discuss data on inoculum effects, persister cells, and the concept of time within some defined mutation selection window.

An Update on Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Small Animals

There are several choices of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating dogs that have osteoarthritis. However, fewer drugs are available for cats. Like people, there may be greater differences among individuals in their response than there are differences among the drugs. In past practice, veterinarians often selected aspirin or phenylbutazone as an initial drug, and then progressed to off-label human drugs or other agents as an alternative. Now we have the advantage of several approved NSAIDs for which there are excellent published studies and US Food and Drug Administration or foreign approval to guide clinical use and safe dosages.

Efficacy of Ronidazole for Treatment of Feline Tritrichomonas foetus Infection

OBJECTIVES To determine the efficacy of ronidazole (RDZ), tinidazole (TDZ), and metronidazole (MDZ) against Tritrichomonas foetus in vitro and of RDZ for treatment of feline naturally occurring or experimentally induced T. foetus infection. ANIMALS A cat naturally infected with T. foetus infection and diarrhea. Ten specific-pathogen-free (SPF) kittens. PROCEDURE RDZ, TDZ, and MDZ were tested for activity against 3 different feline isolates of T. foetus in vitro. RDZ then was administered to a naturally infected cat at 10 mg/kg PO q24h for 10 days. SPF kittens were infected orogastrically with feline T. foetus and treated with either placebo or RDZ (10 mg/kg PO q12h for 14 days). Cats with relapsing infection or those receiving placebo were treated subsequently with RDZ (either 30 or 50 mg/kg PO q12h for 14 days). Feces were examined for T. foetus by direct microscopy, culture, and polymerase chain reaction (PCR) testing weekly. RESULTS Both RDZ and TDZ killed T. foetus at concentrations >0.1 microg/mL in vitro. In the naturally infected cat, RDZ abolished diarrhea and T. foetus infection for 85 days after treatment, at which time infection and diarrhea relapsed. Retreatment with RDZ eradicated diarrhea and T. foetus infection for over 407 days. In experimentally induced infection, RDZ at 10 mg/kg caused initial improvement, but infection relapsed in all 5 cats 2 to 20 weeks after treatment. At 30 or 50 mg/kg, 10/10 cats were negative for T. foetus infection for follow-up durations of 21 to 30 weeks after treatment. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of RDZ at 30 to 50 mg/kg q12h for 14 days resolved diarrhea and eradicated infection (on the basis of polymerase chain reaction [PCR] testing) in 1 naturally infected cat and 10 experimentally inoculated cats receiving a different isolate of T. foetus.

Comparison of transdermal fentanyl and intramuscular oxymorphone on post-operative behaviour after ovariohysterectomy in dogs

The effects of transdermal fentanyl and i.m. oxymorphone on behavioural and physiological responses, after ovariohysterectomy in dogs, were investigated. The study involved three groups of 10 dogs: fentanyl/surgery (FS), oxymorphone/surgery (OS), fentanyl/control (FC). A transdermal fentanyl delivery system (50 microg hour(-1)) (FS and FC) was applied 20 hours before surgery, or i.m. oxymorphone (OS) was administered. After ovariohysterectomy (FS and OS) or anaesthesia alone (FC), dogs were continuously videotaped for 24 hours and a standardised hourly interaction with a handler performed. The videotapes were analysed, and interactive and non-interactive behaviours evaluated. In addition, pain and sedation scores, pulse and respiratory rates, rectal temperature, arterial blood pressure, plasma cortisol and plasma fentanyl concentrations were measured. This study showed that transdermal fentanyl and i.m. oxymorphone (0.05 mg kg(-1)) produced comparable analgesic effects over a 24 hour recording period. I.m. oxymorphone produced significantly more sedation and lower rectal temperatures than transdermal fentanyl. There were no significant differences between groups in respiratory and heart rates, and arterial blood pressures.

Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds.

OBJECTIVE To determine the pharmacokinetics of tramadol, the active metabolite O-desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O-didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds. ANIMALS 6 healthy 2- to 3-year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg. PROCEDURES A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device. RESULTS Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h·ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration. CONCLUSIONS AND CLINICAL RELEVANCE Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds.

Pharmacokinetic-pharmacodynamic (PK-PD) modeling and the rational selection of dosage regimes for the prudent use of antimicrobial drugs.

One of the strategies to decrease inappropriate antimicrobial use in veterinary medicine is to apply pharmacokinetic-pharmacodynamic (PK-PD) principles to dosing regimens. If antimicrobials are used appropriately by applying these principles to attain targets for area-under-the-curve to MIC ratio (AUC/MIC), peak concentration to MIC ratio (CMAX/MIC), and time above MIC (T>MIC), more effective antibiotic therapy is possible, thus avoiding ineffective administration. Another mechanism whereby inappropriate antibiotic administration can be avoided is to use accurate Interpretive Criteria established by the Clinical Laboratory Standards Institute (CLSI) for breakpoint selection. Inaccurate breakpoints will encourage antibiotic administration that is likely to be ineffective. For newly approved antimicrobials, three criteria are used for determining breakpoints: PK-PD criteria, MIC distributions, and clinical response. For older (often generic drugs) evaluated by the CLSI, recent clinical data may not be available and breakpoints are derived from PK-PD principles, wild-type distributions, and Monte Carlo simulations. It is the goal of the CLSI subcommittee that these revised breakpoints will encourage more effective antimicrobial use and avoid unnecessary antimicrobial administration.

Efficacy of Doxycycline, Azithromycin, or Trovafloxacin for Treatment of Experimental Rocky Mountain Spotted Fever in Dogs

ABSTRACT Dogs were experimentally inoculated with Rickettsia rickettsii (canine origin) in order to compare the efficacies of azithromycin and trovafloxacin to that of the current antibiotic standard, doxycycline, for the treatment of Rocky Mountain spotted fever. Clinicopathologic parameters, isolation of rickettsiae in tissue culture, and PCR amplification of rickettsial DNA were used to evaluate the response to therapy or duration of illness (untreated infection control group) in the four groups. Concentrations of the three antibiotics in plasma and blood cells were measured by high-performance liquid chromatography. Doxycycline and trovafloxacin treatments resulted in more-rapid defervescence, whereas all three antibiotics caused rapid improvement in attitudinal scores, blood platelet numbers, and the albumin/total-protein ratio. Based upon detection of retinal vascular lesions by fluorescein angiography, trovafloxacin and doxycycline substantially decreased rickettsia-induced vascular injury to the eye, whereas the number of ocular lesions in the azithromycin group did not differ from that in the infection control group. As assessed by tissue culture isolation, doxycycline resulted in the earliest apparent clearance of viable circulating rickettsiae; however, rickettsial DNA could still be detected in the blood of some dogs from all four groups on day 21 postinfection, despite our inability to isolate viable rickettsiae at that point. As administered in this study, trovafloxacin was as efficacious as doxycycline but azithromycin proved less efficacious, possibly due to the short duration of administration.

Disposition and Analgesic Effects of Fentanyl in White Cockatoos (Cacatua alba)

Abstract Fentanyl is a mu opioid agonist with 80–100 times the analgesic potency of morphine. Fentanyl is used in several mammalian species for relief of severe pain, but its use has not been investigated in psittacine birds. To determine the pharmacologic disposition of fentanyl in healthy white cockatoos (Cacatua alba), we measured fentanyl plasma concentrations in sequentially collected samples after administration of fentanyl at 0.01 or 0.02 mg/kg IM. To investigate the analgesic effects of fentanyl in conscious cockatoos, we compared the change in pre- and posttreatment levels of electrical and thermal noxious stimuli necessary to elicit a withdrawal response in birds administered fentanyl at 2 different doses (0.02 mg/kg IM or 0.2 mg/kg SC) and those given saline. Fentanyl was rapidly absorbed and plasma concentrations declined with an elimination half-life of 1.2–1.4 hours. Plasma concentrations considered to be analgesic in humans were maintained for at least 2 hours with the 0.02 mg/kg dose. However, no significant difference was found in analgesic response between birds given saline and those given fentanyl at 0.02 mg/kg IM. Although the 0.2 mg/kg SC dose provided significant analgesia in some birds, fentanyl at this dose is not recommended as a routine analgesic agent because a large volume of drug must be injected and this dose causes hyperactivity in some birds.

Efficacy of Oral Famotidine and 2 Omeprazole Formulations for the Control of Intragastric pH in Dogs

BACKGROUND Little is known about the efficacy of commonly used acid suppressants on intragastric pH in dogs. OBJECTIVE To compare the effect of oral famotidine, 2 formulations of omeprazole, and placebo on intragastric pH in dogs with a catheter-free, continuous pH monitoring system. ANIMALS Six healthy adult mixed-breed colony dogs. METHODS Utilizing a randomized, 4-way cross over, open-label study, dogs were administered famotidine PO (1.0-1.3 mg/kg q12h), omeprazole tablet (1.5-2.6 mg/kg q24h), omeprazole reformulated paste (RP) (Gastrogard, 1.5-2.6 mg/kg q24h), and placebo for 7 days followed by a 10-day washout period. Radiotelemetric pH capsules were placed with gastroscopy assistance to continuously record intragastric pH for 4 days (days 4-7 of dosing). The percentage of time that intragastric pH was ≥3 and ≥4 was compared among treatment groups using repeated measures of analysis of variance. Tukeys Studentized range test was used to determine which groups were different with α= 0.05. RESULTS Mean ± SD percent time intragastric pH was ≥3 and ≥4 was 22 ± 8% and 14 ± 6% for famotidine, 63 ± 14% and 52 ± 17% for omeprazole tablet, 54 ± 17% and 44 ± 18% for omeprazole RP, and 6 ± 6% and 5 ± 5% for placebo. Both omeprazole formulations significantly increased intragastric pH compared with famotidine and placebo, but omeprazole tablet and RP was not significantly different from each other. CONCLUSION Oral omeprazole tablet and RP provide superior gastric acid suppression to famotidine, and should therefore be considered more effective for the treatment of acid related disorders in dogs.