Early treatment response to piperacillin/tazobactam in patients with bloodstream infections caused by non-ESBL ampicillin/sulbactam-resistant Escherichia coli: a binational cohort study.

PURPOSE: This study aimed to compare treatment outcomes for bloodstream infections (BSI) caused by a piperacillin/tazobactam (PIP/TAZ)-susceptible E. coli among three patient groups: BSI caused by ampicillin/sulbactam (AMP/SLB)-resistant isolates treated with PIP/TAZ, BSI caused by AMP/SLB-sensitive isolates treated with PIP/TAZ, and BSI caused by AMP/SLB-resistant isolates treated with another monotherapy. METHODS: This retrospective study was conducted in two academic centres in Europe. Adult patients with E. coli BSI were screened from 2014 to 2020. Inclusion criteria were non-ESBL BSI and initial monotherapy for ≥ 72 h. To reduce the expected bias between the patient groups, propensity score matching was performed. The primary outcome was early treatment response after 72 h and required absence of SOFA score increase in ICU/IMC patients, as well as resolution of fever, leukocytosis, and bacteraemia. RESULTS: Of the 1707 patients screened, 315 (18.5%) were included in the final analysis. Urinary tract infection was the most common source of BSI (54.9%). Monotherapies other than PIP/TAZ were cephalosporins (48.6%), carbapenems (34.3%), and quinolones (17.1%). Enhanced early treatment response rate was detected (p = 0.04) in patients with BSI caused by AMP/SLB-resistant isolates treated with another monotherapy (74.3%) compared to those treated with PIP/TAZ (57.1%), and was mainly driven by the use of cephalosporins and quinolones (p ≤ 0.03). Clinical success, 28-day mortality, and rate of relapsing BSI did not significantly differ between the groups. CONCLUSIONS: Our study suggests that initial use of PIP/TAZ may be associated with reduced early treatment response in E. coli BSI caused by AMP/SLB-resistant isolates compared to alternative monotherapies.

Antibiotic resistance of the bacterial spectrum of deep space head and neck infections in oral and maxillofacial surgery - a retrospective study.

OBJECTIVES: The aim of this study was to evaluate the current resistance situation concerning routinely used antibiotics for treatment in odontogenic abscesses. MATERIALS AND METHODS: This retrospective study assessed patients with deep space head and neck infections who were treated by surgical intervention under general anesthesia at our department. The target parameter was the ascertainment of the resistance rates in order to identify the bacterial spectrum, sites in the body, length of inpatient stay, and the age and sex of the patients. RESULTS: A total of 539 patients, 268 (49.7%) males and 271 (50.3%) females were included in the study. The mean age was 36.5 ± 22.1 years. There was no significant difference between the two sexes with regard to the mean duration of hospitalization (p = 0.574). The predominant bacteria in the aerobic spectrum were streptococci of the viridans group and staphylococci, in the anaerobic spectrum Prevotella and Propionibacteria spp. Rates of resistance to clindamycin were between 34 and 47% in both the facultative and obligate anaerobic spectrum. Increased resistance was likewise found in the facultative anaerobic spectrum, with 94% resistance to ampicillin and 45% to erythromycin. CONCLUSION: Due to the increasing levels of resistance to clindamycin, their use in empiric antibiotic treatment for deep space head and neck infections should be viewed critically. CLINICAL RELEVANCE: Resistance rates continue to increase compared to previous studies. The use of these antibiotic groups in patients with a penicillin allergy needs to be called into question and alternative medications sought.

Streptococcus pneumoniae colonization in health care professionals at a tertiary university pediatric hospital.

Streptococcus pneumoniae is a commensal of the human upper respiratory tract. In certain cases, it can lead to serious invasive infections peaking in very young children and the elderly. Especially young children are frequent carriers and are thus regarded as the reservoir for horizontal transmission of pneumococci. This is the first study evaluating pneumococcal colonization patterns in healthcare professionals working in a tertiary care pediatric hospital, including carriage prevalence, serotype distribution, and risk factors for carriage. One oropharyngeal and one nasal swab per individual were directly plated onto appropriate agar plates and conventional culture was used for bacterial identification. Pneumococcal isolates underwent serotyping using Neufeld's Quellung reaction with type-specific antisera. Additional nasal and oropharyngeal swabs were taken for qPCR analysis targeting lytA. In total, 437 individuals were enrolled. S. pneumoniae was isolated in 4.8% (21/437) of the study cohort using conventional culture and in 20.1% (88/437) of subjects using qPCR. Independent risk factors for pneumococcal carriage were living in the same household with children under 8 years of age and being aged 36-45 years with a carriage prevalence reaching 11.6% (vs. 2.9%, p = 0.002) and 6.7% (vs. 4.3%, p = 0.029), respectively. The most common serotypes were 6C and 3. A total of 71.4% (15/21) of the detected serotypes are not included in any currently available pneumococcal vaccine; 28.6% (6/21) of the carried serotypes are included in the PCV13 vaccine. We found a relevant amount of pneumococcal carriage bearing the potential risk of horizontal in-hospital transmission.

Pharyngeal carriage rates of Neisseria meningitidis in health care professionals at a tertiary university pediatric hospital.

Pharyngeal carriage is the reservoir for Neisseria meningitidis in the population and the first step in disease transmission. Especially in young infants and adolescents, N. meningitidis can cause serious invasive infection with high fatality rates and high rates of long-term sequelae among survivors. The aim of this study was to determine N. meningitidis colonization rates in asymptomatic health care professionals at a tertiary university pediatric hospital and to identify risk factors for carriage. This cross-sectional meningococcal carriage survey was conducted between April and October 2018 at the Medical University of Vienna. Individuals working as nurses, pediatricians, or medical students were enrolled. Oropharyngeal swabs were directly plated onto selective agar plates and conventional culture was used for bacterial identification. Meningococcal isolates were further characterized using whole-genome sequencing. A total of 437 oropharyngeal specimens were collected. Overall, meningococcal carriage prevalence was 1.14% (5/437), with 0.7% (3/437) for capsular genotype B, and 0.5% (2/437) for capsular genotype W. Mean age of carriers was significantly lower than of non-carriers (24.2 vs. 35.8; p = 0.004). The highest carriage rate of 4.4% (4/91) was found in the age group 18-25. Carriage was negatively associated with age and timespan working in pediatrics. This is the first study evaluating the prevalence of Neisseria meningitidis carriage in health care professionals working in Pediatrics and Adolescent Medicine. Carriage was in general lower than expected for all age groups, implicating a low risk of meningococcal transmission via this population.

A Phase 3, Double-Blind, Randomized Study of Arterolane Maleate-Piperaquine Phosphate vs Artemether-Lumefantrine for Falciparum Malaria in Adolescent and Adult Patients in Asia and Africa.

BACKGROUND: Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicatedPlasmodium falciparummalaria. METHODS: In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12-65 years withP. falciparummonoinfection received either AM-PQP (714 patients) once daily or artemether-lumefantrine (A-L; 358 patients) twice daily for 3 days. All patients were followed up until day 42. RESULTS: Of the 714 patients in the AM-PQP group, 638 (89.4%) completed the study; of the 358 patients in the A-L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR-corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable. CONCLUSIONS: AM-PQP showed comparable efficacy and safety to A-L in the treatment of uncomplicatedP. falciparummalaria in adolescent and adult patients. AM-PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance. CLINICAL TRIALS REGISTRATION: India. CTRI/2009/091/000101.

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia.

The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.

Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.

BACKGROUND: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. METHODS: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. RESULTS: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. CONCLUSIONS: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

Antibacterial activity of a sterile antimicrobial polyisoprene surgical glove against transient flora following a 2-hours simulated use.

BACKGROUND: A surgical glove will protect surgeons and patients only if the glove's integrity remains intact. However, several studies have demonstrated that undetected micro-perforations of surgical gloves are common. Because of the possibility of surgical glove puncture, an antimicrobial surgical glove was developed. The aim of this laboratory based experimental study was to assess the antibacterial efficacy of the interior chlorhexidine-gluconate (CHG)-coat of an antimicrobial synthetic polyisoprene surgical glove by using a standardized microbiological challenge. METHODS: Sixteen healthy adult participants donned one antimicrobial surgical glove and one non-antimicrobial surgical glove randomly allocated to their dominant and non-dominant hand following a crossover design. During a 2-h wear time, participants performed standardized finger and hand movements. Thereafter, the interior surface of excised fingers of the removed gloves was challenged with 8.00 log10 cfu/mL S. aureus (ATCC 6538) or K. pneumoniae (ATCC 4352), respectively. The main outcome measure was the viable mean log10 cfu counts of the two glove groups after 5 min contact with the interior glove's surface. RESULTS: When comparing an antimicrobial glove against an untreated reference glove after 2-h simulated use wear-time, a mean reduction factor of 6.24 log10 (S. aureus) and 6.22 log10 (K. pneumoniae) was achieved after 5 min contact. CONCLUSION: These results demonstrate that wearing antibacterial gloves on hands does not negatively impact their antibacterial activity after 2-h of wear. This may have a potential benefit for patient safety in case of glove puncture during surgical procedures.

Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates.

BACKGROUND: Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. METHODS: In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. RESULTS: Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC50) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. CONCLUSIONS: Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria.

High prevalence of asymptomatic malaria in south-eastern Bangladesh.

BACKGROUND: The WHO has reported that RDT and microscopy-confirmed malaria cases have declined in recent years. However, it is still unclear if this reflects a real decrease in incidence in Bangladesh, as particularly the hilly and forested areas of the Chittagong Hill Tract (CHT) Districts report more than 80% of all cases and deaths. surveillance and epidemiological data on malaria from the CHT are limited; existing data report Plasmodium falciparum and Plasmodium vivax as the dominant species. METHODS: A cross-sectional survey was conducted in the District of Bandarban, the southernmost of the three Hill Tracts Districts, to collect district-wide malaria prevalence data from one of the regions with the highest malaria endemicity in Bangladesh. A multistage cluster sampling technique was used to collect blood samples from febrile and afebrile participants and malaria microscopy and standardized nested PCR for diagnosis were performed. Demographic data, vital signs and splenomegaly were recorded. RESULTS: Malaria prevalence across all subdistricts in the monsoon season was 30.7% (95% CI: 28.3-33.2) and 14.2% (95% CI: 12.5-16.2) by PCR and microscopy, respectively. Plasmodium falciparum mono-infections accounted for 58.9%, P. vivax mono-infections for 13.6%, Plasmodium malariae for 1.8%, and Plasmodium ovale for 1.4% of all positive cases. In 24.4% of all cases mixed infections were identified by PCR. The proportion of asymptomatic infections among PCR-confirmed cases was 77.0%, oligosymptomatic and symptomatic cases accounted for only 19.8 and 3.2%, respectively. Significantly (p < 0.01) more asymptomatic cases were recorded among participants older than 15 years as compared to younger participants, whereas prevalence and parasite density were significantly (p < 0.01) higher in patients younger than 15 years. Spleen rate and malaria prevalence in two to nine year olds were 18.6 and 34.6%, respectively. No significant difference in malaria prevalence and parasite density was observed between dry and rainy season. CONCLUSIONS: A large proportion of asymptomatic plasmodial infections was found which likely act as a reservoir of transmission. This has major implications for ongoing malaria control programmes that are based on the treatment of symptomatic patients. These findings highlight the need for new intervention strategies targeting asymptomatic carriers.

High prevalence and genetic diversity of Plasmodium malariae and no evidence of Plasmodium knowlesi in Bangladesh.

Although the prevalence of malaria remains high in parts of Bangladesh, there continues to be a substantial shortage of information regarding the less common malaria parasites such as Plasmodium malariae or Plasmodium knowlesi. Recent studies indicate that P. malariae may be extremely rare, and so far, there are no data on the presence (or absence) of P. knowlesi in southeastern Bangladesh. Genus- and species-specific nested polymerase chain reaction (PCR) analysis of the small subunit ribosomal RNA gene was performed to assess the presence and prevalence of P. malariae and P. knowlesi in 2,246 samples originating from asymptomatic and febrile participants of a cross-sectional and a febrile illnesses study in the Chittagong Hill Tracts in southeastern Bangladesh. P. malariae was detected in 60 samples (2.7%) corresponding to 8% of the 746 samples giving positive PCR results for Plasmodium sp., mainly because of the high prevalence (9.5%) among asymptomatic study participants testing positive for malaria. Symptomatic cases were more common (4.3% of all symptomatic malaria cases) during the dry season. Parasitemias were low (1,120-2,560/µl in symptomatic and 120-520/µl in asymptomatic carriers). Symptomatic patients presented mild to moderate symptoms like fever, chills, headache, dizziness, fatigue and myalgia.Although both the intermediate as well as the definite host are known to be endemic in southeastern Bangladesh, no evidence for the presence of P. knowlesi was found. We conclude that the role of P. malariae is highly underestimated in rural Bangladesh with major implications for malaria control and elimination strategies.

Differences in oxazolidinone resistance mechanisms and small colony variants emergence of Staphylococcus aureus induced in an in vitro resistance development model.

Invasive Staphylococcus aureus infections are associated with a high burden of disease, case fatality rate and healthcare costs. Oxazolidinones such as linezolid and tedizolid are considered potential treatment choices for conditions involving methicillin resistance or penicillin allergies. Additionally, they are being investigated as potential inhibitors of toxins in toxin-mediated diseases. In this study, linezolid and tedizolid were evaluated in an in vitro resistance development model for induction of resistance in S. aureus. Whole genome sequencing was conducted to elucidate resistance mechanisms through the identification of causal mutations. After inducing resistance to both linezolid and tedizolid, several partially novel single nucleotide variants (SNVs) were detected in the rplC gene, which encodes the 50S ribosome protein L3 in S. aureus. These SNVs were found to decrease the binding affinity, potentially serving as the underlying cause for oxazolidinone resistance. Furthermore, in opposite to linezolid we were able to induce phenotypically small colony variants of S. aureus after induction of resistance with tedizolid for the first time in literature. In summary, even if different antibiotic concentrations were required and SNVs were detected, the principal capacity of S. aureus to develop resistance to oxazolidinones seems to differ between linezolid and tedizolid in-vivo but not in vitro. Stepwise induction of resistance seems to be a time and cost-effective tool for assessing resistance evolution. Inducted-resistant strains should be examined and documented for epidemiological reasons, if MICs start to rise or oxazolidinone-resistant S. aureus outbreaks become more frequent.

Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones.

Malaria is still a major threat in many parts of the world with resistance spreading to almost all classes of antimalarials. The limited arsenal of available antimalarial drugs emphasizes the urgent need for novel antimalarial compounds. Owing to the fact that novel leads from nature have traditionally played a pivotal role in the development of various classes of antimalarials, we investigated a set of eight naturally occurring dietary flavonoids and their analogues for their antiplasmodial activity on clinical field isolates in southeastern Bangladesh and culture-adapted chloroquine-sensitive and chloroquine-resistant parasite clones. Except for taxifolin, all the other flavonoids had 50% inhibitory concentrations below 14 µM, both in the field and laboratory-adapted parasites. Neither of the flavonoids showed any activity correlation with chloroquine. The quercetin analogue rutin (7.10 ± 10.32 µM) was the most active substance in field isolates as well as laboratory-adapted cultures (3.53 ± 13.34 µM in 3D7 and 10.38 ± 15.08 µM in K1), providing the first evidence of its activity against Plasmodium falciparum parasites. Thus, our results provide important evidence of the antimalarial activity of flavonoids in traditional use and thus warrant further investigation of these compounds as potential antiplasmodial agents.

Novel nested direct PCR technique for malaria diagnosis using filter paper samples.

The use of direct nested PCR enables the detection of Plasmodium spp. from blood samples collected on filter papers without requiring the time-consuming procedures associated with DNA extraction. Direct PCR provides a rapid, highly sensitive, and cost-effective alternative to diagnosing malaria using filter paper samples and standard nested PCR.

Azithromycin combination therapy for the treatment of uncomplicated falciparum malaria in Bangladesh: an open-label randomized, controlled clinical trial.

BACKGROUND: In recent studies, the combination of azithromycin and artesunate has proven to be a promising alternative for the treatment of uncomplicated falciparum malaria. METHODS: We conducted a randomized, controlled clinical trial assessing the efficacy of azithromycin-artesunate combination therapy. The study was conducted involving 228 patients aged 8-65 years. Patients were randomized to 1 of 2 cohorts at a ratio of 2:1, receiving either azithromycin-artesunate once daily for 3 days (30 mg/kg per day of azithromycin plus 4 mg/kg per day of artesunate) or an adult dose of 80 mg of artemether plus 960 mg of lumefantrine (4 tablets Coartem or the equivalent for children weighing <35 kg) twice daily for 3 days. RESULTS: The 42-day cure rate by Kaplan-Meier analysis was 94.6% (95% confidence interval [CI], 89.38%-97.44%) in the azithromycin-artesunate arm and 97.0% (95% CI, 89.45%-99.40%) in the control arm. Fever clearance times and parasite clearance times did not show any differences between the 2 arms (P=.59 and .95, respectively). No serious adverse events were seen, but the percentage of patients who developed any adverse event was higher in the control group (P=.03). CONCLUSIONS: Our data suggest that azithromycin-artesunate is an efficacious and well-tolerated treatment for patients with uncomplicated falciparum malaria in Bangladesh.

Clinical Usefulness of Susceptibility Breakpoints for Yeasts in the Treatment of Candidemia: A Noninterventional Study.

This prospective noninterventional study evaluated whether antifungal susceptibility data (MIC) provided for Candida clinical isolates on the basis of recently established breakpoints are taken into account by clinicians to guide their treatment decision making process, and assessed the response in MIC- and non-MIC-based treatment groups. During a six month period, the usage of systemic antifungals was recorded in detail and compared with mycological data (Candida species and MICs) in candidemia patients. Patients were assigned to a susceptible or resistant infection group based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints; treatment decisions were under the professional discretion of the treating physicians. 123 patients were evaluated with Candida albicans accounting for 59%, Candida glabrata for 19%, Candida parapsilosis for 15%, Candida tropicalis for 4% and Candida krusei for 3%. Antifungal treatment correlated with species and MICs in 80% (n = 99 patients), high MICs and species-dependent guideline recommendations were ignored in 20% (n = 24 patients); the overall outcome of candidemia cases in our study population was excellent, as by day 14, all patients were cleared from fungal blood stream infection (mean 5.6 days, range 2-12). The current variability in antifungal usage and the delay in initiating appropriate therapy indicate a need for antifungal stewardship to improve the management of invasive fungal infections.

Synergism between monodesbutyl-benflumetol and artemisinin in Plasmodium falciparum in vitro.

The sensitivity to artemisinin, monodesbutyl-benflumetol (DBB) and a 1:1 m/m combination of the two compounds was successfully investigated on 34 fresh isolates of Plasmodium falciparum. On a molar basis the combination was most active, followed by DBB and artemisinin. The geometric mean concentrations effecting full inhibition (GMCOC) were 49.25 nM for the combination, 279.12 nM for DBB, and 494.05 for artemisinin. The difference between the efficacy of the combination and that of its components was highly significant. Interaction between artemisinin and DBB showed moderate synergism at the EC(50) and strong synergism at EC(90) and EC(99). The individual parasite isolates showed a significant inverse correlation between the ECs and the degree of synergism. Positive specific pharmacodynamic interaction was therefore most marked in isolates with reduced sensitivity against artemisinin and DBB.

Interaction between lumefantrine and monodesbutyl-benflumetol in Plasmodium falciparum in vitro.

The pharmacodynamic interaction between lumefantrine and its monodesbutyl analogue (DBB) has been investigated in 35 fresh isolates of Plasmodium falciparum. Both compounds showed highly significant activity correlation. The geometric mean values for complete inhibition of schizont maturation (GMCOC) were 536,8 nM for lumefantrine, 246.0 nM for DBB, 235,5 nM for LUM-DBB 999:1, and 155,2 nM for LUM-DBB 995:5, with significant activity differences between lumefantrine and DBB as well as the LUM-DBB combinations. For the combination of lumefantrine and DBB 995:5 the sums of the fractional inhibitory concentrations according to Berenbaum (SFIC) indicated marked synergism, the intensity of interaction rising with the effective inhibitory concentrations.

Specific pharmacokinetic interaction between lumefantrine and monodesbutyl-benflumetol in Plasmodium falciparum.

The blood schizontocidal activity of lumefantrine, monodesbutyl-benflumetol (DBB) and a 999:1 combination of both compounds has been investigated in 26 fresh isolates of Plasmodium falciparum from northwestern Thailand, using the WHO standard protocol Mark II for determining the inhibition of schizont maturation. The geometric mean cut-off concentrations of schizont maturation (GMCOC) were 943.2 nM for lumefantrine, 146.3 nM for DBB and 182.2 nM for the 999:1 combination of lumefantrine and DBB. The EC(50) values were 27.3 nM for lumefantrine, 5.7 nM for DBB, and 16.5 nM for the combination, and the EC(90) values 163.1 nM for lumefantrine, 44.1 nM for DBB, and 78.3 nM for the combination. Despite the very low concentration in the combination, DBB exerted significant synergistic activity with lumefantrine that was strongest at the EC(90) and EC(99) levels. Correlation analysis indicates that DBB is the leading determinant for the activity of the combination.

In vitro interaction of dihydroartemisin and lumefantrine in clinical field isolates from Bangladesh.

The combination of artemether and lumefantrine was introduced in 2005 as the official first line therapy for uncomplicated falciparum malaria in Bangladesh. Fresh P. falciparum samples from patients with acute uncomplicated falciparum malaria who presented to the field site at the Bandarban Sadar Hospital in Bangladesh were tested in checkerboard in vitro drug sensitivity assays to assess the interaction between dihydroartemisinin (DHA) and lumefantrine (LUM). Clearly synergistic interactions with an overall mean FIC(50) of 0.52 and individual mean FICs between 0.26 and 0.85 were found. Lowest FICs were 0.41, 0.18, 0.22, 0.15 and 0.11 at different combination ratios. The optimal combination ratio of the drug combination indicated by the lowest mean FIC average was found to be 1:150 DHA:LUM. Although activity correlations between DHA and lumefantrine were significant, indicating possible cross sensitivity patterns, our data confirm that artemether-lumefantrine is a highly synergistic drug combination.