Current status of the small molecule anti-HIV drugs in the pipeline or recently approved.

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.

Confronting the complexities of antimicrobial management for Staphyloccous aureus causing bovine mastitis: an innovative paradigm.

Globally, Mastitis is a disease commonly affecting dairy cattle which leads to the use of antimicrobials. The majority of mastitis etiological agents are bacterial pathogens and Staphylococcus aureus is the predominant causative agent. Antimicrobial treatment is administered mainly via intramammary and intramuscular routes. Due to increasing antimicrobial resistance (AMR) often associated with antimicrobial misuse, the treatment of mastitis is becoming challenging with less alternative treatment options. Besides, biofilms formation and ability of mastitis-causing bacteria to enter and adhere within the cells of the mammary epithelium complicate the treatment of bovine mastitis. In this review article, we address the challenges in treating mastitis through conventional antibiotic treatment because of the rising AMR, biofilms formation, and the intracellular survival of bacteria. This review article describes different alternative treatments including phytochemical compounds, antimicrobial peptides (AMPs), phage therapy, and Graphene Nanomaterial-Based Therapy that can potentially be further developed to complement existing antimicrobial therapy and overcome the growing threat of AMR in etiologies of mastitis.

Exploring Prescription Practices: Insights from an Antimicrobial Stewardship Program at a Tertiary Healthcare Facility, Rwanda.

Antimicrobial resistance (AMR) is a major public health threat linked to increased morbidity and mortality. It has the potential to return us to the pre-antibiotic era. Antimicrobial stewardship (AMS) programs are recognized as a key intervention to improve antimicrobial use and combat AMR. However, implementation of AMS remains limited in Africa, particularly in Rwanda. This study aimed to assess prescription practices, identify areas for improvement, and promote adherence to AMS principles. Conducted at King Faisal Hospital in Rwanda, this qualitative study used semi-structured interviews with eight participants until saturation was reached. The interviews were recorded, transcribed, and thematically analyzed, revealing four emerging themes. The first theme was on AMS activities that were working well based on availability of microbiology laboratory results and prescription guidelines as factors influencing antibiotic prescription adjustments. The second theme was related to challenges during the implementation of the AMS program, including the prescription of broad-spectrum antibiotics, limited local data on AMR patterns, and stock-outs of essential antibiotics. The third theme was on the importance of adhering to AMR management guidelines at KFH. The last emerged on recommendations from participants centered on regular training for healthcare workers, widespread dissemination of AMR findings across departments, and the enforcement of antibiotic restriction policies. These actions can improve prescription behaviors, upholding the highest standards of patient care, and strengthening the nascent AMS program.

Ethnobotany, Ethnopharmacology, and Phytochemistry of Medicinal Plants Used for Treating Human Diarrheal Cases in Rwanda: A Review.

Diarrhea, often caused by microorganisms, has been associated with high morbidity and mortality in Africa. Increased rates of antimicrobial-resistant pathogens have reignited the quest for alternative therapies. This review aimed at identifying medicinal plants used in the treatment of human diarrheal cases in Rwanda and analyzing their ethnobotany, ethnopharmacology, and phytochemistry. We searched PubMed/Medline, Google Scholar, ScienceDirect, and the Web of Science for published articles on medicinal plants used to treat diarrhea in Rwanda. Additionally, specialized herbarium documents of different institutes were reviewed. Articles were assessed for relevance, quality, and taxonomical accuracy before being included in this review. Overall, 63 species of medicinal plants belonging to 35 families were recorded. Asteraceae was the predominant family with six species, followed by Fabaceae and Lamiaceae, with five species each. The most reported species with anti-diarrheal properties were Vernonia amygdalina Delile, Tetradenia riparia (Hochst.) Codd, Clerodendrum myricoides R. Br. and Chenopodium ugandae (Aellen) Aellen. Leaves (66.7%) and roots (17.5%) were the commonly used plant parts in the preparation of medicine. Phytochemicals from medicinal plants with antidiarrheic activities were sesquiterpene lactones (V. amygdalina); terpene, sterols, saponosides, and flavonoids (C. ugandae); saponins and tannins (T. riparia); and tannins, flavonoids, and alkaloids (C. myricoides). Six studies tested the antimicrobial activities of the plants against bacteria and viruses known to cause diarrhea. Erythrina abyssinica, Euphorbia tirucalli, Dracaena afromontana, and Ficus thonningii are socio-culturally important. Further research on toxicity and posology is needed to ensure the safety of medicinal plants.

Antimicrobial Resistance Profiles, Virulence Genes, and Genetic Diversity of Thermophilic Campylobacter Species Isolated From a Layer Poultry Farm in Korea.

Thermophilic Campylobacter species are among the major etiologies of bacterial enteritis globally. This study aimed at assessing the antimicrobial resistance (AMR) profiles, virulence genes, and genetic diversity of thermophilic Campylobacter species isolated from a layer poultry farm in South Korea. One hundred fifty-three chicken feces were collected from two layer poultry farms in Gangneung, South Korea. The Campylobacter species were isolated by cultural techniques, while PCR and sequencing were used for species confirmation. Antimicrobial susceptibility testing for six antimicrobials [ciprofloxacin (CIP), nalidixic acid (NAL), sitafloxacin (SIT), erythromycin (ERY), tetracycline (TET), and gentamicin (GEN)] was carried out by broth microdilution. Three AMR and nine virulence genes were screened by PCR. Genotyping was performed by flaA-restriction fragment length polymorphism (RFLP) and multilocus sequence typing (MLST). Of the 153 samples, Campylobacter spp. were detected in 55 (35.9%), with Campylobacter jejuni and Campylobacter coli being 49 (89.1%) and six (10.9%), respectively. High-level resistance was observed for CIP (100%), NAL (100%), and TET (C. jejuni, 93.9%; C. coli: 83.3%). No resistance was observed for SIT. The missense mutation (C257T) in gyrA gene was confirmed by sequencing, while the tet(O) gene was similar to known sequences in GenBank. The rate of multidrug-resistant (MDR) strains was 8.2%, and they all belonged to C. jejuni. All Campylobacter isolates possessed five virulence genes (cdtB, cstII, flaA, cadF, and dnaJ), but none possessed ggt, while the rates for other genes (csrA, ciaB, and pldA) ranged between 33.3 and 95.9%. The flaA-RFLP yielded 26 flaA types (C. jejuni: 21 and C. coli: five), while the MLST showed 10 sequence types (STs) for C. jejuni and three STs for C. coli, with CC-607 (STs 3611) and CC-460 (ST-460) being predominant. Among the 10 STs of C. jejuni, three were newly assigned. The findings of this study highlight the increased resistance to quinolones and TET, the virulence potential, and the diverse genotypes among Campylobacter strains isolated from the layer poultry farm.

Genomic Characterization of Fluoroquinolone-Resistant Thermophilic Campylobacter Strains Isolated from Layer Chicken Feces in Gangneung, South Korea by Whole-Genome Sequencing.

Thermophilic Campylobacter species of poultry origin have been associated with up to 80% of human campylobacteriosis cases. Layer chickens have received less attention as possible reservoirs of Campylobacter species. Initially, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of two archived Campylobacter isolates (Campylobacter jejuni strain 200605 and Campylobacter coli strain 200606) from layer chickens to five antimicrobials (ciprofloxacin, nalidixic acid, erythromycin, tetracycline, and gentamicin) were determined using broth microdilution while the presence of selected antimicrobial resistance genes was performed by polymerase chain reaction (PCR) using specific primers. Whole-genome sequencing (WGS) was performed by the Illumina HiSeq X platform. The analysis involved antimicrobial resistance genes, virulome, multilocus sequence typing (MLST), and phylogeny. Both isolates were phenotypically resistant to ciprofloxacin (MIC: 32 vs. 32 µg/mL), nalidixic acid (MIC: 128 vs. 64 µg/mL), and tetracycline (MIC: 64 vs. 64 µg/mL), but sensitive to erythromycin (MIC: 1 vs. 2 µg/mL) and gentamicin (MIC: 0.25 vs. 1 µg/mL) for C. jejuni strain 200605 and C. coli strain 200606, respectively. WGS confirmed C257T mutation in the gyrA gene and the presence of cmeABC complex conferring resistance to FQs in both strains. Both strains also exhibited tet(O) genes associated with tetracycline resistance. Various virulence genes associated with motility, chemotaxis, and capsule formation were found in both isolates. However, the analysis of virulence genes showed that C. jejuni strain 200605 is more virulent than C. coli strain 200606. The MLST showed that C. jejuni strain 200605 belongs to sequence type ST-5229 while C. coli strain 200606 belongs to ST-5935, and both STs are less common. The phylogenetic analysis clustered C. jejuni strain 200605 along with other strains reported in Korea (CP028933 from chicken and CP014344 from human) while C. coli strain 200606 formed a separate cluster with C. coli (CP007181) from turkey. The WGS confirmed FQ-resistance in both strains and showed potential virulence of both strains. Further studies are recommended to understand the reasons behind the regional distribution (Korea, China, and Vietnam) of such rare STs.

Prevalence, Risk Factors, and Antimicrobial Resistance Profiles of Thermophilic Campylobacter Species in Humans and Animals in Sub-Saharan Africa: A Systematic Review.

Thermophilic Campylobacter species are clinically important aetiologies of gastroenteritis in humans throughout the world. The colonization of different animal reservoirs by Campylobacter poses an important risk for humans through shedding of the pathogen in livestock waste and contamination of water sources, environment, and food. A review of published articles was conducted to obtain information on the prevalence and antimicrobial resistance (AMR) profiles of thermophilic Campylobacter species in humans and animals in sub-Saharan Africa (SSA). Electronic databases, namely, PubMed, Google Scholar, Research4life-HINARI Health, and Researchgate.net, were searched using the following search terms "thermophilic Campylobacter," "Campylobacter jejuni," "Campylobacter coli," "diarrhea/diarrhoea," "antimicrobial resistance," "antibiotic resistance," "humans," "animals," "Sub-Saharan Africa," and "a specific country name." Initially, a total of 614 articles were identified, and the lists of references were screened in which 22 more articles were identified. After screening, 33 articles on humans and 34 on animals and animal products were included in this review. In humans, Nigeria reported the highest prevalence (62.7%), followed by Malawi (21%) and South Africa (20.3%). For Campylobacter infections in under-five children, Kenya reported 16.4%, followed by Rwanda (15.5%) and Ethiopia (14.5%). The country-level mean prevalence in all ages and under-five children was 18.6% and 9.4%, respectively. The prevalence ranged from 1.7%-62.7% in humans and 1.2%-80% in animals. The most reported species were C. jejuni and C. coli. The AMR to commonly used antimicrobials ranged from 0-100% in both humans and animals. Poultry consumption and drinking surface water were the main risk factors for campylobacteriosis. The present review provides evidence of thermophilic Campylobacter occurrence in humans and animals and high levels of AMR in SSA, emphasizing the need for strengthening both national and regional multisectoral antimicrobial resistance standard surveillance protocols to curb both the campylobacteriosis burden and increase of antimicrobial resistance in the region.

Susceptibility of Campylobacter Strains to Selected Natural Products and Frontline Antibiotics.

Campylobacter species have developed resistance to existing antibiotics. The development of alternative therapies is, therefore, a necessity. This study evaluates the susceptibility of Campylobacter strains to selected natural products (NPs) and frontline antibiotics. Two C. jejuni strains (ATCC® 33560TM and MT947450) and two C. coli strains (ATCC® 33559TM and MT947451) were used. The antimicrobial potential of the NPs, including plant extracts, essential oils, and pure phytochemicals, was evaluated by broth microdilution. The growth was measured by spectrophotometry and iodonitrotetrazolium chloride. Antibiotic resistance genes (tet(O) and gyrA) were characterized at the molecular level. The minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) ranged from 25 to 1600 µg/mL. Cinnamon oil, (E)-Cinnamaldehyde, clove oil, eugenol, and baicalein had the lowest MIC and MBC values (25-100 µg/mL). MT947450 and MT947451 were sensitive to erythromycin and gentamicin but resistant to quinolones and tetracycline. Mutations in gyrA and tet(O) genes from resistant strains were confirmed by sequencing. The findings show that NPs are effective against drug-sensitive and drug-resistant Campylobacter strains. The resistance to antibiotics was confirmed at phenotypic and genotypic levels. This merits further studies to decipher the action mechanisms and synergistic activities of NPs.