Treatment Failure in a UK Malaria Patient Harboring Genetically Variant Plasmodium falciparum From Uganda With Reduced In Vitro Susceptibility to Artemisinin and Lumefantrine.

BACKGROUND: Recent cases of clinical failure in malaria patients in the United Kingdom (UK) treated with artemether-lumefantrine have implications for malaria chemotherapy worldwide. METHODS: Parasites were isolated from an index case of confirmed Plasmodium falciparum treatment failure after standard treatment, and from comparable travel-acquired UK malaria cases. Drug susceptibility in vitro and genotypes at 6 resistance-associated loci were determined for all parasite isolates and compared with clinical outcomes for each parasite donor. RESULTS: A traveler, who returned to the UK from Uganda in 2022 with Plasmodium falciparum malaria, twice failed treatment with full courses of artemether-lumefantrine. Parasites from the patient exhibited significantly reduced susceptibility to artemisinin (ring-stage survival, 17.3% [95% confidence interval {CI}, 13.6%-21.1%]; P < .0001) and lumefantrine (effective concentration preventing 50% of growth = 259.4 nM [95% CI, 130.6-388.2 nM]; P = .001). Parasite genotyping identified an allele of pfk13 encoding both the A675V variant in the Pfk13 propeller domain and a novel L145V nonpropeller variant. In vitro susceptibility testing of 6 other P. falciparum lines of Ugandan origin identified reduced susceptibility to artemisinin and lumefantrine in 1 additional line, also from a 2022 treatment failure case. These parasites did not harbor a pfk13 propeller domain variant but rather the novel nonpropeller variant T349I. Variant alleles of pfubp1, pfap2mu, and pfcoronin were also identified among the 7 parasite lines. CONCLUSIONS: We confirm, in a documented case of artemether-lumefantrine treatment failure imported from Uganda, the presence of pfk13 mutations encoding L145V and A675V. Parasites with reduced susceptibility to both artemisinin and lumefantrine may be emerging in Uganda.

Novel external quality assurance scheme for drug susceptibility testing of non-tuberculous mycobacteria: a multicentre pilot study.

OBJECTIVES: Our aim was to conduct a multicentre study involving laboratories participating in the European TB Reference Laboratory Network aiming to develop a pilot external quality assessment (EQA) scheme for drug susceptibility testing (DST) of non-tuberculous mycobacteria (NTM). METHODS: The study comprised a survey using a structured questionnaire followed by a pilot EQA round using identical panels of 10 Mycobacterium avium (MAV) and Mycobacterium abscessus (MAB) isolates. EQA results were received from 16 laboratories utilizing the broth microdilution method. Consensus modal MIC values were determined, and essential and categorical agreement rates were calculated. RESULTS: Twenty-four out of 31 laboratories (77.4%) reported DST for NTM routinely. Essential agreement ranged from 78.8% (amikacin) to 96.2% (linezolid) for MAV and from 76.0% (amikacin) to 100% (doxycycline) for MAB. Categorical agreement ranged from 56.8% (moxifloxacin) to 100% (clarithromycin) for MAV and from 53.6% (linezolid) to 100% (doxycycline) for MAB. CONCLUSIONS: Our results show that interlaboratory reproducibility of DST for NTM is insufficient, highlighting the need for expanding EQA schemes. As EQAs for Mycobacterium tuberculosis complex have led to more reliable and reproducible DST, we propose to follow a similar approach for clinically relevant NTM.

Phase 1 clinical trial of live attenuated Shigella dysenteriae type-1 DeltaicsA Deltaent Deltafep DeltastxA:HgR oral vaccine SC599 in healthy human adult volunteers.

Twenty-eight adults received between 10(2) and 10(8)colony forming units of live Shigella dysenteriae type-1 vaccine SC599, attenuated by deletion of invasion (icsA), iron chelation (ent, fep) and shiga toxin A-subunit (stxA) genes, followed by ciprofloxacin on day 4. Dose-independent diarrhea or change in bowel habit was seen in 3 subjects, without dysentery, vaccinaemia or serious adverse events. Hematology and biochemical parameters were unchanged. Doses of 10(5) or greater induced dose-independent SD1 lipopolysaccharide-specific antibody secreting cell (ASC) responses. Geometric mean number of IgA ASCs per 10(6) PBMCs for 10(5), 10(6), 10(7) and 10(8) groups were respectively 41, 8.8, 26 and 8.5. Serum antibody responses were seen in three subjects. SC599 appears immunogenic with maximum tolerated dose greater than 10(8)CFU.

Epidemiology of invasive pneumococcal disease in Kumasi, Ghana.

There are few data on the epidemiology of invasive pneumococcal disease in Africa. We undertook a prospective study of these infections in Kumasi, Ghana, collecting clinical data on all patients with laboratory-confirmed pneumococcal meningitis, pneumonia or systemic sepsis associated with bacteraemia. A total of 140 cases were identified in the period from January 2002 to April 2005. The disease was most prevalent among patients <5 years of age and immediately following the peak of the harmattan wind. The majority of patients were treated with a combination of antibiotics, in part reflecting concerns regarding antibiotic resistance. Mortality was high (47%), with no evidence of an improved prognosis compared with earlier studies in the region. Although most isolates of pneumococci were resistant to tetracyclines and co-trimoxazole, there was no high-level resistance to penicillin and only 12% of isolates showed intermediate level resistance. Serotype 1 was the most common serotype (36%), whilst intermediate-level penicillin resistance was associated with serotype 14. Theoretical coverage by existing 7-, 9-, 11- and 23-valent vaccines was 26%, 63%, 64% and 76%, respectively. Vaccination may improve control of pneumococcal disease in Ghana, although modified vaccine formulations are required for local use.

Haemophilus influenzae type b reemergence after combination immunization.

An increase in Haemophilus influenzae type b (Hib) in British children has been linked to the widespread use of a diphtheria/tetanus/acellular pertussis combination vaccine (DTaP-Hib). We measured anti-polyribosyl-ribitol phosphate antibody concentration and avidity before and after a Hib booster in 176 children 2-4 years of age who had received 3 doses of DTP-Hib (either DT whole cell pertussis-Hib or DTaP-Hib) combination vaccine in infancy. We also measured pharyngeal carriage of Hib. Antibody concentrations before and avidity indices after vaccination were low (geometric mean concentration 0.46 mug/mL, 95% confidence interval [CI] 0.36-0.58; geometric mean avidity index 0.16, 95% CI 0.14-0.18) and inversely related to the number of previous doses of DTaP-Hib (p = 0.02 and p<0.001, respectively). Hib was found in 2.1% (95% CI 0.7%-6.0%) of study participants. Our data support an association between DTaP-Hib vaccine combinations and clinical Hib disease through an effect on antibody concentration and avidity.