BACKGROUND: Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan.
RESULTS: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for ≥ 6 months) or grade 3 PKDL, aged 6 to ≤ 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 87% of patients were ≤12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-LAmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in PM/MF arm and 28/55 (50.9%) in LAmB/MF arm, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported.
CONCLUSIONS: The PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL.
BACKGROUND: ClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955 ClinicalTrials.gov ClinicalTrials.gov.

High-resolution mass spectrometry was used for the label-free, direct localization and relative quantification of CMC+ -modifications of a neomycin-sensing riboswitch aptamer domain in the absence and presence of the aminoglycoside ligands neomycin B, ribostamycin, and paromomycin. The chemical probing and MS data for the free riboswitch show high exposure to solvent of the uridine nucleobases U7, U8, U13, U14, U18 as part of the proposed internal and apical loops, but those of U10 and U21 as part of the proposed internal loop were found to be far less exposed than expected. Thus, our data are in better agreement with the proposed secondary structure of the riboswitch in complexes with aminoglycosides than with that of free RNA. For the riboswitch in complexes with neomycin B, ribostamycin, and paromomycin, we found highly similar CMC+ -modification patterns and excellent agreement with previous NMR studies. Differences between the chemical probing and MS data in the absence and presence of the aminoglycoside ligands were quantitative rather than qualitative (i. e., the same nucleobases were labeled, but to different extents) and can be rationalized by stabilization of both the proposed bulge and the apical loop by aminoglycoside binding. Our study shows that chemical probing and mass spectrometry can provide important structural information and complement other techniques such as NMR spectroscopy.

This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.
An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.
Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults.
PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa.
NCT03129646.

Present study aims to investigate how is soil affected following irrigation with treated effluents of different origins by analysing the bacterial diversity, metabolic diversity and antibiotic resistance genes (ARGs). Comparative analysis with previously reported ARGs in effluents was performed to understand the mobility of ARGs from treated wastewater to the irrigated soil with respect to the control soil regimen. Acinetobacter, Burkholderia and Pseudomonas were observed as the most abundant genera in all the samples. The metabolic gene abundance of all the samples suggests a prominent contribution to natural mineral recycling. Most abundant ARGs observed encode resistance for clindamycin, kanamycin A, macrolides, paromomycin, spectinomycin and tetracycline. Treated effluent reuse did not appear to enhance the ARG levels in soils in most cases except for institutional treatment site (M), where the ARGs for aminoglycosides, β-lactams and sulfonamides were found to be abundantly present in both treated effluent and the irrigated soil. This study finds the importance of wastewater treatment from different origins and the impact of treated wastewater reuse in irrigation. This study also emphasises on the better understanding of ARGs mobility from water to soil.

Visceral leishmaniasis (VL) is one of the most neglected tropical infectious diseases. It is fatal if left untreated. The objective of this study was to assess the efficacy and safety of 17-day injections of combined regimen of sodium stibogluconate and paromomycin (SSG/PM) in HIV-negative VL patients.
A retrospective analysis of medical records of VL patients treated in the University of Gondar Hospital during period 2012-2019 was carried out.
A total of 2836 patients were treated for VL from 2012 to 2019. Of these 1233 were treated with SSG-PM, and 1000 of them were included in the study. Initial cure was achieved in 922 (92.2%) patients. The frequency of treatment failure, treatment interruptions, default and deaths respectively were 30 (3%), 20 (2%), 13 (1.3%) and 15 (1.5%). Among 280 patients who completed 6-month follow up, the final cure was 93.9% (263/280), 4 (1.4%) relapsed and 13 (4.6%) developed post-kala-azar dermal leishmaniasis (PKDL). The most common adverse events (AEs) were raised liver transaminases (35.1%; 351 patients), injection site pain (29.1%, 291 patients) and raised serum alpha-amylase (29.1%, 291 patients). Factors associated with poor treatment outcomes were sepsis, pneumonia, and adverse events.
A combination of SSG at 20mg/kg with upper daily maximum dose of 850mg and PM was effective for achieving initial cure at end of treatment and safe for treatment of HIV negative VL patients in northwestern Ethiopia. Our data are consistent with previous reports and confirms effectiveness of SSG/PM treatment regimen in the Eastern African countries. Efficacy at 6-months (93.9%) was estimated on data derived from patients who completed follow up and needs to be interrogated by future studies.

OBJECTIVE: Infectious complications are as high as 30% in elective colorectal surgery. In recent years, several studies have discussed the topic of preoperative bowel decontamination prior to colorectal surgery in order to reduce postoperative infectious complications and have found significant effects of oral antibiotic administration with a large variety of drugs used. No study has evaluated the combination of oral paromomycin and metronidazole in this context.
METHODS: We performed a prospective single-center study with a matched-pair retrospective cohort to evaluate postoperative infectious complications (superficial site infections, organ space abscess, anastomotic leakage) in elective colorectal surgery.
METHODS: A total of 120 patients were available for study inclusion; 101 gave informed consent and were included. A total of 92 patients were matched and subsequently analyzed. We could show a reduction in overall infectious complications in the intervention group (15.2% vs 30.8%, p = 0.018; odds ratio 0.333, 95% CI 0.142-0.784) as well as a reduction in superficial surgical site infections (8.7 vs 19.6%, p = 0.041, OR 0.333, 95% CI 0.121-0.917). The frequency of the other infectious complications such as intraabdominal abscesses and anastomotic leakage showed a tendency towards decreased frequencies in the intervention group (OR 0.714, 95% CI 0.235-2.169 and OR 0.571; 95% CI 0.167-1.952, respectively). Finally, the oral antibiotic administration led to an almost significantly reduced length of stay (12.24 days vs 15.25 days; p = 0.057).
CONCLUSIONS: Oral paromomycin and metronidazole with intravenous ertapenem effectively reduce infectious complications in elective colorectal surgery.
BACKGROUND: The study was registered at Clinicaltrials.gov (NCT03759886) December 17, 2018.

Dientamoeba fragilis is an intestinal protozoan, an inhabitant of the human gastrointestinal tract, with a worldwide distribution. The reported prevalence of D. fragilis varies worldwide in different populations between 0.3% and 82.9%, and its role as a pathogen is still unclear. The parasite has been identified in the faeces of asymptomatic patients and with different acute and chronic symptoms, like abdominal pain, diarrhoea, flatulence, nausea and vomiting. The aims of this study were to evaluate the prevalence of D. fragilis in the North-East of Italy, and the clinical improvement of symptoms after recommended treatment with paromomycin or metronidazole. Furthermore, a literature review of D. fragilis prevalence studies in Italy was carried out to show the Italian situation. Of 575 enrolled people, 85 (14.8%) were positive for D. fragilis. The most prevalent symptoms were abdominal pain 28.2%, anal itching 27.1%, watery diarrhoea 18.8%, meteorism 16.5% and nausea/lack of appetite 14.1%. The high rate of anal itching was unexpected, because it wasn\'t a common symptom. 32 patients were co-infected with B. hominis (37.7%) and three with G. lamblia (3.5%). Our study showed paromomycin had a high efficacy for treatment of D. fragilis infections 100.0% (45/45), while caution must be used when using metronidazole 53.3% (24/40). We recommend paromomycin for empirical treatment, given its great effectiveness in our population.

The aim of this 6-month, randomized, blinded, controlled clinical trial was to compare the efficacy and safety of aminosidine-allopurinol combination with that of meglumine antimoniate-allopurinol combination for the treatment of leishmaniosis in dogs without stage III or IV chronic kidney disease. Forty client-owned dogs were randomly assigned to group A [n = 20; aminosidine (15 mg/kg, subcutaneously, once daily, for 28 days) and allopurinol (10 mg/kg, per os, twice daily, for 6 months)] or group B [(n = 20; meglumine antimoniate (100 mg/kg SC, once daily, for 28 days) and allopurinol (10 mg/kg, per os, twice daily, for 6 months)]. Clinical and clinicopathological evaluations, parasitic load measurement (lymph node and bone marrow microscopy, bone marrow real-time PCR), specific serology and leishmanin skin test (LST) were performed at baseline (time 1) and after 14 (time 2), 28 (time 3), 60 (time 4) and 180 (time 5) days. Both treatments were safe and resulted in significant clinical and clinicopathological improvement, reduction of parasitic load and of indirect immunofluorescence antibody test (IFAT) titer and induction of positive LST. There was no significant difference between groups with regards to the primary outcome measures of the trial that included the proportion of dogs that presented severe treatment-related side effects, were cured and were parasitologically negative at time 5. However, some (proportion of dogs that presented no clinical signs, no hyperglobulinemia and negative serology at time 5) secondary outcome measures showed significant differences in favor of the meglumine antimoniate-allopurinol treatment arm. Treatment-related death occurred in one dog in each group, while injection site reactions appeared at a similar frequency in both groups. Due to the differences in some secondary outcome measures in association with the low power of this trial, it cannot be definitively concluded that the two treatments are equally effective. Therefore, the aminisodine-allopurinol combination cannot be proposed as a first-line treatment of CanL but rather as a second-line treatment that may be particularly useful to avoid repeated administration of meglumine antimoniate and in countries where the latter is not available or registered.

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.

Local therapies have been proposed as safe and effective alternatives to systemic drugs in cutaneous leishmaniasis (CL), especially among less severe cases. However, they are not widely available and used in endemic places, including Colombia, which has a high burden of disease. Further complicating the uptake of local therapies is that different treatment guidelines have been established by the World Health Organization (WHO) and Pan American Health Organization (PAHO). Using data from a large referral center in Colombia, we determined the proportion of patients who would be eligible for and potentially benefit from local therapies according to both international guidelines. The sample included 1,891 confirmed cases of CL aged ≥ 12 years, mostly infected with Leishmania Viannia panamensis (91%, n = 601/660), between 2004 and 2014. Overall, 57% of the sample had one lesion, whereas another 31% had two to three lesions. For 74% of patients, all lesions were in an area other than head or neck. The maximum lesion size was ≤ 3 cm for 58% and < 5 cm for 88% of the sample. Based on our data, up to 56% of patients could have been eligible for local therapies according to the WHO criteria. By contrast, only 23% were eligible according to the more restrictive PAHO criteria. Regardless, these data suggest that a substantial proportion of CL patients in Colombia may benefit from local therapies given their relatively mild presentation of disease and low risk of complications. Individualized risk-benefit assessment and guideline adjustments may increase local therapy eligibility and benefit a large number of patients.