Pharmacokinetics and Absorption of Paromomycin and Gentamicin from Topical Creams Used To Treat Cutaneous Leishmaniasis

This study evaluated the pharmacokinetics of topical creams containing 15% paromomycin (“paromomycin alone”) and 15% paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the paromomycin area under the concentration-time curve from 0 to 24 h (AUC0–24) was 2,180 +/- 2,621 ng · h/ml (mean +/- standard deviation [SD]) for the paromomycin-alone group and 975.6 +/- 1,078 ng · h/ml for the WR 279,396 group. After 20 days of application, the paromomycin AUC0–24 and maximum concentration of drug (Cmax) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC0–24 was 8,575 +/- 7,268 ng · h/ml and the Cmax was 1,000 +/- 750 ng/ml, compared with 6,037 +/- 3,956 ng · h/ml and 660 +/- 486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences (P\u3e0.05) in the AUC0–24 or Cmax were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0% +/- 6.26% and 9.68% +/- 6.05% for paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.

Evaluation of a diagnostic device, CL Detect rapid test for the diagnosis of new world cutaneous leishmaniasis in Peru.

BackgroundCutaneous leishmaniasis (CL) is a neglected disease and a public health problem in Latin America. The diagnosis of CL in poor hyperendemic regions relies to large extent on the identification of amastigotes in Giemsa-stained smears. There is an urgent need for a rapid, sensitive and low cost diagnostic method for use in field conditions for CL as current modalities are not readily available. The primary objective of this study was to determine the sensitivity and specificity of the FDA-cleared CL Detect Rapid Test in Peru, using modified test procedures rather than the instructions-for-use, by 1) increasing the extraction time and 2) increasing the volume of the sample added to the test strip. CL Detect Rapid Test results were compared against microscopy and kDNA-PCR, for the diagnosis of CL in ulcerated lesions. In addition, we compared two collection methods the dental broach used and mentioned in the CL Detect insert and the standard less invasive and easier to conduct scrapping method.MethodologyParticipants were patients who presented for medical consultation due to a suspected CL lesion. Four samples from the index lesion were collected using a dental broach, per package insert, and lancet scraping and tested by the modified CL Detect Rapid Test, microscopy, and PCR.Principal findingsA total of 156 subjects were eligible and evaluated. The modified CL Detect sensitivity was higher in specimens obtained by scraping (83.3%) than those from dental broach (64.2%). The specificity was lower in scrapings (77.8%) with a false positive rate of 22.2% compared with dental broach samples (91.7%) with a false positive rate of 8.3%. However, molecular analysis showed that all 8 false negative microscopy scrapings (those positive by modified CL Detect and negative by microscopy) were positive by kDNA-PCR, meaning that the modified CL Detect was more sensitive than microscopy.ConclusionsThese modifications to the package insert that resulted in a diagnostic sensitivity (83.3%) comparable to microscopy for species found in Peru may enable earlier anti-leishmanial drug treatment decisions based on a positive result from the CL Detect Rapid Test alone until further diagnostic tests like microscopy and PCR can be performed.Trial registrationNCT03762070; Clinicaltrials.gov

Parasite Load Decrease during Application of a Safe and Easily Applied Antileishmanial Aminoglycoside Cream

<p>Parasite Load Decrease during Application of a Safe and Easily Applied Antileishmanial Aminoglycoside Cream</p

Summary of subject enrollment, treatment, and follow-up.

<p>Values are numbers of study subjects. Of the 74 subjects screened, 26 failed screening, most commonly due to having only one lesion that was already substantially healed (17 subjects). Forty-eight subjects were randomized, 24 in each study group. In the polyurethane group, one subject was discontinued due to an unsatisfactory result (enlargement of the index lesion at day 20). In the gauze-and-tape group, two subjects failed to return to the study site and were lost to follow-up. Forty-seven of 48 randomized subjects received a full 20-day course of WR 279,396 as planned in the protocol; one subject in the polyurethane group failed to return for further treatment after day 6.</p

Geometric mean aminoglycoside concentrations in superficial and deep dermis.

†<p>Number of samples tested.</p><p>*Wilcoxon Rank Sum Test two-sided p-value for superficial versus deep dermis.</p>‡<p>Number of samples with detectable levels.</p><p>[Note: The lower limit of quantitation (LLOQ) was 20.0 ng/mL for paromomycin, 2.64 ng/mL for gentamicin C1, 2.45 ng/mL for gentamicin C1a, 4.25 ng/mL for gentamicin C2, and 50 ng/mL for total gentamicin.]</p

Baseline characteristics of study patients.

<p>Baseline characteristics of study patients.</p