Abstract
Simple SummaryDoxycycline is an antimicrobial used for treating chlamydial infections in various species, including the koala. The dose and route of administration used initially are based on first principles. Therefore, this study investigates the absorption, distribution, metabolism, and excretion of subcutaneous doxycycline injections, and evaluates the suitability of the current dosage regimen for inhibiting chlamydial pathogens. The results suggest that the current doxycycline dosage remained therapeutically effective for up to six days after each dose, with some accumulation over successive doses. All koalas in the study improved clinically and tested negative for chlamydial pathogens post-treatment before being released. This study contributes to determining the optimal dosage of doxycycline to treat chlamydiosis safely and effectively in infected koalas.Six mature, male koalas (Phascolarctos cinereus), with clinical signs of chlamydiosis, were administered doxycycline as a 5 mg/kg subcutaneous injection, once a week for four weeks. Blood was collected at standardised time points (T = 0 to 672 h) to quantify the plasma doxycycline concentrations through high-pressure liquid chromatography (HPLC). In five koalas, the doxycycline plasma concentration over the first 48 h appeared to have two distinct elimination gradients; therefore, a two-compartmental analysis was undertaken to describe the pharmacokinetic (PK) profile. The average ± SD maximum plasma concentration (Cmax) was 312.30 ± 107.74 ng/mL, while the average time ± SD taken to reach the maximum plasma concentration (Tmax) was 1.68 ± 1.49 h. The mean ± SD half-life of the distribution phase (T1/2 α) and the elimination phase (T1/2 β) were 10.51 ± 7.15 h and 82.93 ± 37.76 h, respectively. The average ± SD percentage of doxycycline binding to koala plasma protein was 83.65 ± 4.03% at three different concentrations, with a mean unbound fraction (fu) of 0.16. Using probability of target attainment modelling, doxycycline plasma concentrations were likely to inhibit 90% of pathogens with the doxycycline minimum inhibitory concentration (MIC) of 8.0–31.0 ng/mL, and the reported doxycycline MIC to inhibit Chlamydia pecorum isolates at the area under the curve/minimum inhibitory concentration (AUC/MIC) target of ≥24. All koalas were confirmed to be negative for Chlamydia pecorum using loop-mediated isothermal amplification (LAMP), from ocular and penile urethra swabs, three weeks after the last doxycycline injection.
Highlights
Chlamydiosis, predominantly caused by Chlamydia pecorum, is the most significant infectious disease affecting wild koalas, with 52% of koalas in South-East Queensland (SEQ) displaying clinical signs suggestive of chlamydiosis, and an infectious prevalence of up to 100% in some populations [1,2]
The administration of once-weekly subcutaneous (s.c.) doxycycline injections at 5 mg/kg has been recently recommended as a treatment option for chlamydiosis in koalas [6,7], but the pharmacokinetic (PK) profile of doxycycline in the koala has not been reported for this route of administration
The stability of doxycycline in koala plasma was evaluated over three months, where doxycycline was stable until the third month (22.56% degraded from the previous month) when the sample was stored at −20 ◦ C away from light
Summary
Chlamydiosis, predominantly caused by Chlamydia pecorum, is the most significant infectious disease affecting wild koalas, with 52% of koalas in South-East Queensland (SEQ) displaying clinical signs suggestive of chlamydiosis, and an infectious prevalence of up to 100% in some populations [1,2]. Common clinical signs in koalas associated with chlamydial infection include conjunctivitis leading to blindness [2], and/or inflammation of the urogenital tract causing cystitis, both of which are painful and can result in significant morbidity and mortality [1]. The investigation of an alternative systemic administration route is warranted, as increased risk has been associated with doxycycline treatments administered orally to the koala, resulting in the disruption of gut microbiome and consequent dysbiosis [5]. The administration of once-weekly subcutaneous (s.c.) doxycycline injections at 5 mg/kg has been recently recommended as a treatment option for chlamydiosis in koalas [6,7], but the pharmacokinetic (PK) profile of doxycycline in the koala has not been reported for this route of administration. The aim of this study was to describe the PK profile of doxycycline when administered subcutaneously to koalas at this dosage regimen, and to evaluate the suitability of this dosage regimen to inhibit chlamydial pathogens
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