Increased Treatment Failure Research Articles

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Antimicrobial resistance: A significant public health issue of both human and veterinary concern

Abstract Introduction The discovery of antibiotics and the subsequent realization that these medications are the most effective treatments for a wide range of illnesses affecting the health of humans and animals constituted a revolution in medical history. Methods A review of the literature was done, looking for pertinent studies, using an explorative review method to discuss how the widespread use of antibiotics often led to bacterial resistance and antibiotic residue in food animals, which negatively impacted humans and animals. Results The study showed that treating bacterial resistance is a therapeutic challenge for physicians and veterinary professionals. Increased treatment failure rates, the severity of disease-causing infections, the frequency of blood infections, the length of time patients were sick, and the death rate in both humans and animals are all signs that the overuse of antibiotics is becoming a catastrophe. Discussion To prevent the negative effects of antibiotics in people, animals, and the environment, especially in developing nations, this article ends by recommending that strict guidelines, laws, and regulations regarding the use of antibiotics in clinical human and veterinary medicine be implemented. Concern must be expressed about the effects of inactivity on public health, both now and in the future. We may attempt to reverse the global resistance issue by increasing the use of antibiotics and reducing the frequency of resistance genes at all levels. Ultimately, the safety of animal products depends on the proper use of antibiotics in animal husbandry under the supervision of a veterinarian.

Low HIV drug resistance prevalence among recently diagnosed HIV-positive men who have sex with men in a setting of high PrEP use.

New South Wales (NSW) has one of the world's highest uptake rates of HIV pre-exposure prophylaxis (PrEP). This uptake has been credited with sharp declines in HIV transmission, particularly among Australian-born gay and bisexual men. Concerns have been raised around the potential for the emergence of tenofovir (TFV) and XTC (lamivudine/emtricitabine) resistance in settings of high PrEP use. Such an emergence could also increase treatment failure and associated clinical outcomes among people living with HIV (PLHIV). Despite low levels of nucleoside reverse-transcriptase inhibitor (NRTI) resistance relating to PrEP use in clinical settings, there are few published studies describing the prevalence of NRTI resistance among people newly diagnosed with HIV in a setting of high PrEP use. Using HIV antiretroviral drug resistance data linked to NSW HIV notifications records of people diagnosed from 1 January 2015 to 31 December 2021 and with HIV attributed to male-to-male sex, we described trends in TFV and XTC resistance. Resistance was identified using the Stanford HIV Drug Resistance genotypic resistance interpretation system. To focus on transmitted drug resistance, resistance prevalence estimates were generated using sequences taken less than 3 months post-HIV diagnosis. These estimates were stratified by timing of sequencing relative to the date of diagnosis, year of sequencing, birthplace, likely place of HIV acquisition, and stage of HIV at diagnosis. Among 1119 diagnoses linked to HIV genomes sequenced less than 3 months following diagnosis, overall XTC resistance prevalence was 1.3%. Between 2015 and 2021, XTC resistance fluctuated between 0.5% to 2.9% and was 1.0% in 2021. No TFV resistance was found over the study period in any of the sequences analysed. Higher XTC resistance prevalence was observed among people with newly acquired HIV (evidence of HIV acquisition in the 12 months prior to diagnosis; 2.9%, p = 0.008). In this Australian setting, TFV and XTC resistance prevalence in new HIV diagnoses remained low. Our findings offer further evidence for the safe scale-up of PrEP in high-income settings, without jeopardizing the treatment of those living with HIV.

Azole resistance in Aspergillus fumigatus- comprehensive review.

Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of respiratory infections, such as invasive aspergillosis, particularly in immunocompromised individuals. Azole antifungal agents are widely used for the treatment and prophylaxis of Aspergillus infections due to their efficacy and tolerability. However, the emergence of azole resistance in A. fumigatus has become a major concern in recent years due to their association with increased treatment failures and mortality rates. The development of azole resistance in A. fumigatus can occur through both acquired and intrinsic mechanisms. Acquired resistance typically arises from mutations in the target enzyme, lanosterol 14-α-demethylase (Cyp51A), reduces the affinity of azole antifungal agents for the enzyme, rendering them less effective, while intrinsic resistance refers to a natural resistance of certain A. fumigatus isolates to azole antifungals due to inherent genetic characteristics. The current review aims to provide a comprehensive overview of azole antifungal resistance in A. fumigatus, discusses underlying resistance mechanisms, including alterations in the target enzyme, Cyp51A, and the involvement of efflux pumps in drug efflux. Impact of azole fungicide uses in the environment and the spread of resistant strains is also explored.

Alexithymia and depression may predict treatment failure in patients undergoing Gamma Knife radiosurgery for trigeminal neuralgia: the potential contribution of colored pain drawings.

Gamma Knife radiosurgery (GKRS) effectively achieves high rates of pain control in trigeminal neuralgia (TN); however, psychological factors can also impact how individuals perceive pain and respond to treatment. The authors aimed to measure the effects of alexithymia and depression on GKRS outcomes, as well as the potential role of colored pain drawings (CPDs) in identifying patients who require additional psychological support. Seventy-three medically intractable, typical patients with TN were included. Participants completed a visual analog scale (VAS), the Toronto Alexithymia Scale (TAS-20), and the Turkish version of the Beck Depression Inventory-II (BDI-II). Participants used colored pens to draw their pain patterns on standardized face charts and CPDs were categorized as expected or unexpected. Based on the Barrow Neurological Institute pain scale, patients were categorized as responders or nonresponders. Most patients (63%) were female, and the median age was 60 (range 27-88) years. Of 73 patients, 56 (76.7%) were responders and 17 (23.3%) were nonresponders. Forty-nine patients (67.1%) had expected CPDs, whereas 24 (32.9%) had unexpected CPDs. Responder and nonresponder groups had similar ages, genders, education, comorbidities, and initial VAS scores. Both groups preferred the colors red and black to describe intense pain (79.2% vs 67.3%, p = 0.411). Significantly better pain relief was observed in patients with expected CPDs than in those with unexpected CPDs (87.8% vs 54.2%, p = 0.003). The unexpected CPD group had significantly more alexithymia (58.3% vs 32.7%, p = 0.045). The mean BDI-II score of the cohort was 26 (range 15-37) and was significantly higher in the unexpected group (28.3 vs 24.8, p = 0.028). Unexpected CPD (OR 12.540) and higher TAS-20 score (OR 3.22) increased treatment failure risk. The outcomes of TN treatment can be influenced by psychological factors, and patients with TN with higher total TAS-20 and BDI-II scores, along with unexpected CPDs, had an increased likelihood of treatment failure. CPDs can be accessed quickly and may allow the physician to screen out most patients with unfavorable psychometrics and proceed with the necessary treatment with appropriate psychological support.

What Is the Most Effective Treatment for Periprosthetic Joint Infection After Total Joint Arthroplasty in Patients with Rheumatoid Arthritis?: A Systematic Review.

Rheumatoid arthritis (RA) is a risk factor for periprosthetic joint infection (PJI) after total joint arthroplasty (TJA). The purpose of this study was to perform a systematic review comparing the failure rates of debridement, antibiotics, and implant retention (DAIR), one-stage exchange arthroplasty/revision (OSR), and 2-stage exchange arthroplasty/revision (TSR) for RA patients with PJI and identify risk factors in the RA population associated with increased treatment failure rate. PubMed, Ovid MEDLINE, and Ovid Embase databases were screened with the terms "rheumatoid arthritis," "total joint arthroplasty," "prosthetic joint infection," and "treatment for PJI" on August 29, 2021. Four hundred ninety-one studies were screened, of which 86 were evaluated. The primary outcome evaluated was failure of surgical treatment for PJI. Ten retrospective cohort studies were included after full-text screening, yielding 401 patients with RA. Additional demographic and PJI management data were obtained for 149 patients. Patients with RA who underwent TSR demonstrated a lower failure rate (26.8%) than both DAIR (60.1%) and OSR (39.2%) (χ2 = 37.463, p < 0.00001). Patients with RA who underwent DAIR had a 2.27 (95% CI, 1.66-3.10) times higher risk of experiencing treatment failure than those who underwent TSR. Among risk factors, there was a significant difference in the C-reactive protein of patients who did vs. did not experience treatment failure (p = 0.02). TSR has a higher rate of success in the management of PJI patients with RA compared with DAIR and OSR. The complete removal of the infected prosthesis and delayed reimplantation may lower the treatment failure rate. Level III. See Instructions for Authors for a complete description of levels of evidence.

Alcohol increases treatment failure for Helicobacter pylori eradication in Asian populations

Background and AimWhether alcohol intake is associated with Helicobacter pylori (H. pylori) eradication failure remains controversial, and this meta-analysis was aimed at investigating the effect of alcohol on the risk of H. pylori eradication failure.MethodsRelevant studies were systematically screened for and retrieved from PubMed and Web of Science (updated to January 2022), and relevant references were manually reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup, publication bias, and sensitivity analyses were also conducted.ResultsA total of 40 studies were included in the meta-analysis. No significant association was found between alcohol consumption and the risk of H. pylori eradication failure (OR = 1.09, 95% CI, 0.94–1.26). However, in subgroup analyses stratified by region, a positive association was found in Asian patients (OR = 1.23, 95% CI, 1.03–1.47). In Asian patients, alcohol consumption was associated with the risk of H. pylori eradication failure when the duration of therapy was > 7 days (OR = 1.17, 95% CI, 1.10–1.25), when the treatment regimen included nitroimidazoles (OR = 1.16, 95% CI, 1.09–1.24), and when patients were treated with bismuth-containing quadruple therapy (OR = 1.17, 95% CI, 1.10–1.25). Alcohol intake > 40 g/day was associated with H. pylori eradication failure (OR = 3.17, 95% CI, 1.56–6.41). Moreover, in Asian patients who were administered a vonoprazan (VPZ)-based therapy regimen, alcohol consumption had no effect on H. pylori eradication rates (OR = 1.73, 95% CI, 0.98–3.05).ConclusionOur meta-analysis clearly showed that a higher daily alcohol intake was associated with a higher risk of H. pylori eradication failure in Asian populations. Moreover, a VPZ-based treatment regimen can prevent this effect.

Effects of Interfraction Dose Variations of Target and Organs at Risk on Clinical Outcomes in High Dose Rate Brachytherapy for Cervical Cancer.

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose and probability of risk-free local control (RFLC) were calculated using the utility model. The IDVs were well-fitted by the left-skewed Beta distribution, which caused a 3.99% decrease in local control probability and a 1.80% increase in treatment failure. Utility with respect to IDV uncertainty increased the RFLC probability by 6.70% and predicted an optimal dose range of 83 Gy-91 Gy EQD2. It was also found that a 10 Gy dose escalation would not affect toxicity. In conclusion, HRCTV IDV uncertainty reduced LC probabilities and increased treatment failure rates. A dose escalation may help mitigate such effects.

Reporting the impact of artemisinin resistance: Molecular surveillance of pfK13 and pfEXO mutations in Plasmodium falciparum in Southern provinces of Vietnam

Background: Malaria, mainly caused by Plasmodium falciparum, is a major global health concern. In Vietnam, resistance to artemisinin-based combination therapies (ACTs) is rising, jeopardizing malaria control efforts. This study focuses on mutations in the pfK13 and pfEXO genes, particularly the E415G mutation, in Southern Vietnam.&#x0D; Methods: The study involved 421 patients across two cohorts. The first, with 63 patients from Binh Phuoc and Dak Nong, had uncomplicated P. falciparum malaria and were part of the Therapeutic Efficacy Studies (TES), treated according to WHO guidelines (2009). The second cohort, comprising 358 patients from the Central Highlands, aimed to assess mutation frequency in genes linked to artemisinin resistance. Molecular marker analysis, including Sanger sequencing for pfK13 and ARMS-PCR for E415G in pfEXO, was conducted. The study also examined the association of these mutations with Day 3 parasitemia and treatment outcomes using Dihydroartemisinin-Piperaquine (DHA-PPQ).&#x0D; Results: Most cases showed mutations in pfK13, linked to delayed parasite clearance and higher treatment failure, indicating pfK13 as a key marker for artemisinin resistance. The E415G mutation in pfEXO was common but not significantly associated with resistance or treatment outcomes, though there was a tendency towards increased treatment failure among these patients. Conclusion: Our study implies the critical role of the C580Y mutation in the pfK13 gene in artemisinin resistance and its impact on the efficacy of ACTs in Vietnam. The findings highlight the necessity for monitoring these mutations as molecular markers for drug resistance and call for the exploration of alternative treatment strategies in the face of evolving antimalarial drug resistance. This study contributes valuable insights to the molecular epidemiology of malaria in Southern provinces in Vietnam and emphasizes the urgency of addressing artemisinin resistance in the global fight against malaria.&#x0D; Key words: pfK13, E415G , artemisinin resistance, P. falciparum, malaria.

Reducing Ophthalmic Antibiotic Use for Non-severe Conjunctivitis in Children.

Antibiotics are often overprescribed for pediatric conjunctivitis. We implemented a system-level quality improvement (QI) intervention to reduce unnecessary ophthalmic antibiotic use. The multi-faceted intervention in Denver, CO comprised a clinical care pathway, nurse protocol modifications, electronic health record (EHR) changes, parent education materials, and clinician education. We evaluated children aged 6 months-17 years with conjunctivitis seen between November 2018 and December 2022. A multi-interrupted time series model evaluated the effectiveness of the intervention over three time periods: Pre-COVID, Pre-Intervention (November 2018-February 2020), COVID, Pre-Intervention (March 2020-March 2021), and Post-Intervention (April 2021-December 2022). Fisher's exact tests compared treatment failure and healthcare utilization rates between time periods and among children receiving or not receiving ophthalmic antibiotics. Among 6960 eligible encounters, ophthalmic antibiotic use was reduced by 18.8% (95% CI: 16.3, 21.3) from Pre-COVID, Pre-Intervention to Post-Intervention. During the Pre-Intervention period following the onset of COVID, a reduction of 16.1% (95% CI: 12.9, 19.3) was observed. Implementation of the intervention resulted in an additional 2.7% (95% CI: -0.4, 5.7) reduction in antibiotic prescribing, primarily in younger children (ages 6 months-5 years). The greatest reduction in prescribing occurred for nurse triage encounters with an 82.1% (95% CI: 76.8, 87.5) reduction in prescribing rates (92.6%-10.5%). Treatment failure occurred in 1301 (18.7%) children and was more common among children that received an ophthalmic antibiotic than those that did not (20.0 vs 17.9%; P = .03). The QI intervention significantly reduced ophthalmic antibiotic prescribing for pediatric conjunctivitis without increasing treatment failure rates or health care utilization.

Antimicrobial Resistance Molecular Mechanisms of Helicobacter pylori in Jordanian Children: A Cross-Sectional Observational Study

H. pylori antimicrobial resistance causes increasing treatment failure rates among H. pylori gastritis in children. This study investigates the molecular mechanisms of H. pylori antimicrobial resistance among Jordanian children. Demographic, clinical, and laboratory data were recorded for children referred to Prince Hamzah Hospital. Clarithromycin, Metronidazole, and Levofloxacin susceptibility were tested via E-test. Clarithromycin-related mutations were investigated using Real-Time (RT)-PCR and Levofloxacin resistance was analyzed with DNA sequencing of the gyrA gene. 116 children were recruited, including 55.2% females and 55.2% in the age range of 10.1 to 14 years. A total of 82.7% were naïve to eradication therapy. H. pylori positivity was 93.9%, 89.6%, 61.7%, and 84.3% according to Rapid Urease Test, histology, culture, and RT-PCR, respectively. Resistance rates were 25.9% for Clarithromycin, 50% for Metronidazole, and 6.9% for Levofloxacin via E-test. A2142G or A2143G or a combination of both mutations concerning Clarithromycin resistance were documented in 26.1% of samples, while mutations in gyrA gen-related to Levofloxacin resistance were reported in 5.3% of samples. Antibiotic resistance was significantly affected by abdominal pain, anemia, hematemesis, and histological findings (p < 0.05). H. pylori resistance was documented for Metronidazole and Clarithromycin. RT-PCR for H. pylori identification and microbial resistance determination are valuable alternatives for cultures in determining antimicrobial susceptibility.

Management of Older Patients with Head and Neck Cancer: A Comprehensive Review.

The projected increase in life expectancy over the next few decades is expected to result in a rise in age-related diseases, including cancer. Head and neck cancer (HNC) is a worldwide health problem with high rates of morbidity and mortality. In this report, we have critically reviewed the literature reporting the management of older patients with HNC. Older adults are more prone to complications and toxicities secondary to HNC treatment, especially those patients who are frail or have comorbidities. Thus, this population should be screened prior to treatment for such predispositions to maximize medical management of comorbidities. Chronologic age itself is not a reason for choosing less intensive treatment for older HNC patients. Whenever possible, also older patients should be treated according to the best standard of care, as nonstandard approaches may result in increased treatment failure rates and mortality. The treatment plan is best established by a multidisciplinary tumor board with shared decision-making with patients and family. Treatment modifications should be considered for those patients who have severe comorbidities, evidence of frailty (low performance status), or low performance status or those who refuse the recommendations of the tumor board.

O04 A novel, fast, accurate, cost-effective antimicrobial susceptibility test for urine samples

Abstract Objectives To show that iFAST (impedance-based fast antimicrobial susceptibility test) can give accurate susceptibility results for urinary tract infection (UTI) samples in less than 5 h. Background UTIs are one of the most common forms of infection and reasons for antibiotic prescribing. Empirical prescribing without reference to antimicrobial susceptibility tests (ASTs) is common due to the high incidence, burden of symptoms and the length of time needed for an AST (24–48 h). However, untreated UTIs can lead to complications and in severe cases to bacteraemia and death. In addition, resistance to frontline antibiotics is increasing, leading to increased treatment failure. There is, therefore, a need for a fast, accurate and cost-effective AST for urine samples. Bacterial impedance cytometry can measure the opacity and electrical size of individual cells by measuring the change in the electrical current as single cells flow between micro-electrodes. Bacteria treated with antibiotics change their electrical size and opacity compared with untreated cells. This change is visible on the iFAST within 2 h of exposure to above MIC of antibiotics, thereby enabling detection of cells susceptible to breakpoint concentrations of antibiotics. The iFAST technology and workflow can fit into current diagnostic laboratory practice. Methods Fifty-eight Escherichia coli and Klebsiella pneumoniae strains were streaked onto standard agar plates and incubated at 37°C. After 2 h a streak of cells was inoculated into 0.9% saline. Cell count was measured using the iFAST and adjusted to 5 × 105 cfu/mL. 100 μL samples were exposed to EUCAST susceptibility breakpoint concentrations of frontline UTI antibiotics in MH2: co-amoxiclav (2/8 mg/L), amoxicillin (8 mg/L), ceftazidime (1mg/L), cefalexin (16mg/L), ciprofloxacin (0.25mg/L), gentamicin (2 mg/L), nitrofurantoin (64mg/L), trimethoprim (4mg/L) or a no antibiotic control and incubated at 37°C. After 2 h, 60 μL of each culture were measured in the iFAST for 2 min and compared with the no antibiotic control, using percentage cell count and a 50% population contour. In parallel, a gold standard microbroth dilution MIC was carried out, according to EUCAST guidelines, on the cultures. Results For the 441 tests conducted (58 strains in 8 antibiotics, nitrofurantoin is only recommended for E. coli treatment and was therefore disregarded for K. pneumoniae), overall concordance with the gold standard microbroth dilution MIC method was 95.2% for total cell count metric and 94.9% for cells in the population contour. The highest concordance was seen for ceftazidime (100% for both metrics) and amoxicillin (100 and 99% respectively), the lowest for trimethoprim (92% and 89% respectively). All non-concordances, except one strain with trimethoprim, showed an MIC of ±1 log2 (doubling dilution) different to the breakpoint concentration, which was used for iFAST. This is the normal technical variability of the gold standard method. Conclusions iFAST has up to 100% concordance with current gold standard MIC methods and delivers the results in less than 5 h compared with 24–48 h for current ASTs. This novel, fast, accurate and cost-effective AST could increase evidence-based antibiotic prescribing, thereby improving patient treatment, decreasing risk of UTI complications and overall decreasing antimicrobial resistance development.

Incidence and treatment outcomes of Graves’ disease in Thailand: a single-center retrospective observational study

BackgroundTreatment patterns and outcomes of Graves’ disease (GD) are variable around the world. However, studies on treatment outcomes of GD from the Asian populations are limited. We aimed to evaluate treatment outcomes of GD in Thailand.MethodsPatients with new diagnoses of GD in a single center between 2014–2018 were retrospectively reviewed. The diagnosis of GD was based on clinical features, which included diffuse goiter, Graves’ orbitopathy (GO), pretibial myxedema and acropachy.ResultsThe age-adjusted incidence of GD was 26.57 per 100,000 per year. The study included 355 patients aged 15 years or above with a follow-up period of at least 24 months. Antithyroid drug (ATD) was the most popular first-line treatment modality with 98.7% patients receiving the treatment, followed by radioactive iodine (RAI) treatment in 1.3% patients. The most effective treatment modality was surgery with a remission rate of 100%. ATD had a lowest remission rate of 23.8%. Multivariable Cox regression analysis showed GO (HR 1.76, 95% CI 1.08–2.88) and initial TSH < 0.01 uIU/ml (HR 1.61, 95% CI 1.14–2.28) were significant factors associated with an increased treatment failure rate.ConclusionTreatment failure with ATD in patients with GD was frequent in this population. The diagnosis of GD based solely on clinical features may explain the high treatment failure rate in this study. More definitive treatment could be used to prevent relapse and complications of the disease.

A Subset Screen of the Compounds Australia Scaffold Library Identifies 7-Acylaminodibenzoxazepinones as Potent and Selective Hits for Anti-Giardia Drug Discovery.

On an annual basis the flagellate protozoan, Giardia duodenalis, is responsible for an estimated one billion human infections of which approximately two hundred million cause disease. However, the treatment of Giardia infections is reliant on a small group of chemotherapeutic classes that have a broad spectrum of antimicrobial activity and increasing treatment failure rates. To improve this situation, we need new drugs. In this study we screened the Compounds Australia Scaffolds Library for compounds with potent and selective activity against these parasites. Unlike previous drug discovery efforts that have focused on drug repurposing, this library is comprised of commercially available synthetic compounds arranged into lead-like scaffolds to facilitate structure activity relationship assessments and de novo drug discovery. A screen of 2451 compounds in this library identified 40 hits (&gt;50% inhibitory activity at 10 µM, over 48 h). Secondary testing identified three compounds with IC50 values &lt;1 μM and &gt;50-fold selectivity for parasites over mammalian cells and a hit series, CL9406, comprising compounds with potent (lowest IC50 180 nM) and selective activity for Giardia parasites. The most promising compound in this series, SN00797640, displayed selective activity against assemblage A, B, and metronidazole resistant parasites which was parasiticidal (minimum lethal concentration 625 nM) and synergistic with albendazole. SN00797640 was well-tolerated when administered to mice at doses of 50 mg/kg daily for three days paving the way for pre-clinical in vivo activity assessment.

High Frequency of CYP2A6*4, CYP2A6*7, and CYP2A6*9 Alleles Detected Among Patients with Type 2 Diabetic: Genetic Study in The Private Hospital in Yogyakarta

Smoking is a risk factor for type 2 diabetic (T2DM), since the nicotine in cigarettes can cause insulin resistance and increase lipolysis. Both of these can worsen the condition of patients with T2DM and increase treatment failure. Nicotine is metabolized to cotinine by the CYP2A6 enzyme encoded by the CYP2A6 gene. This gene is highly polymorphic, with several inactive alleles, which are CYP2A6 *4, CYP2A6 *7, and CYP2A6 *9. Someone who has an inactive gene will experience being a slow or poor metabolizer. Therefore, the nicotine metabolism will decrease, nicotine blood levels will increase, causing therapy failure among patients with T2DM. This study aims to determine the distribution of CYP2A6*4, CYP2A6*7, and CYP2A6*9 among patients with T2DM who have been routinely treated using oral antidiabetics. We also investigated whether HbA1c levels is a predictor for the success of the treatment. This observational study was conducted with a cross-sectional design. Polymerase chain reaction was used to analyze the three inactive alleles with specific primers. Based on our study, there is a high frequency of the inactive alleles, i.e., CYP2A6*4, CYP2A6*7, and CYP2A6*9, among the patients with T2DM. The presence of these inactive alleles will worsen and reduce the effectiveness of the therapy. Smoking cessation programs are needed to increase the effectiveness of the anti-diabetic therapy.

Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: The "RAMP” Multicenter Prospective Study

Ruxolitinib (RUX) is beneficial in myelofibrosis (MF) and polycythemia vera (PV) patients (pts). However, little is known about patient adherence (ADH) to this chronic therapy. Poor ADH may increase treatment failure, with serious welfare and economic consequences (Osterberg L, N Engl J Med 2005). The Adherence to Refills and Medications Scale (ARMS) (Kripalani S, Value Health 2009) and the Distress Thermometer and Problem List (DTPL) (Donovan KA, Psycho-oncology 2014) measure drug ADH and psychological distress, respectively. After IRB approval, the RAMP (Rux Adherence in MF and PV) multicenter prospective observational study included 189 consecutive pts with MF (n. 141, 75%) or PV (n.48, 25%), that received RUX according to routine practice in 9 Hematology Centers. The ARMS included 12 questions, 6 evaluating intentional and 6 unintentional ADH. The DT describes pts’ level of distress using a scale of 0 (no distress) to 10 (extreme distress). Also, pts can select problems from a list (39 areas divided in 5 subgroups). First tests administration occurred at the earliest convenient time (week, wk0), irrespective of the time of RUX start, and again after 4 (wk4), 8 (wk8), 12 (wk12), 24 (wk24) and 48 weeks (wk48). The aims of the RAMP study are to evaluate: 1) baseline level of RUX ADH and distress, and characteristics associated to low ADH; 2) modifications of ARMS/DTPL scores over time; 3) impact of ARMS/DTPL scores on IWG-MRT defined spleen response in MF. Between June 2020 and March 2022, 189 pts completed ≥1 ARMS and DTPL test; median age, 70 yrs (33-89); 59.2% males. The first questionnaire was completed within 1 yr from RUX start in 127 pts (67.2%) (EARLY-ADH), and after >1 yr of RUX therapy in 62 pts (32.8%). At wk0, the mean ARMS and DT scores were 13.2 (SD, 1.95) and 2.9 (SD, 2.79), respectively. Based on the DT ≥4 cutoff, 76 pts (38.1%) had high distress (Table 1). Overall, 11.1%, 4.5%, 28.5% and 55.9% of pts had no emotional/physical problems, only emotional, only physical and both problems, respectively. 77.8% of pts with both emotional/physical problems also had high distress (compared to 41.5% in pts with low distress, p=0.002). Overall, 95 pts (50.3%) had HIGH-ADH (ARMS score of ≥14) and 94 (49.7%) had LOW-ADH (score <14). LOW-ADH was intentional in 49 (52.1%), unintentional in 20 (21.3%) and both in 25 pts (26.6%). LOW-ADH was comparable in PV (45.8%) and MF (51.8%) pts (p=0.48); however, unintentional LOW-ADH was more frequent in PV than in MF pts (43.8% vs 25.5%, p=0.02). In multivariate regression analysis, LOW-ADH was associated to male sex (odd ratio, OR: 3.2, p=0.007), high distress (OR: 3.7, p=0.003), and RUX duration >1yr (OR: 2.23, p=0.003). Male sex and high distress remained associated with LOW-ADH in MF pts (OR:3.7p=0.002; OR: 3.6, p=0.002 respectively) and only in those who completed the ARMS/DTPL > 1 yr after RUX start (OR: 3.7, p=0.002; OR: 3.7, p=0.003, respectively). Overall, 146 (77.2%) pts completed both tests at w24. Full completers with HIGH-ADH tended to increase over time (from 47.3% at wk0 to 52.4% at wk24), while pts with high distress decreased (from 44.3% to 36.2%). Pts with high distress more frequently also showed LOW-ADH (p=0.05). Over time, 25% of pts with baseline LOW-ADH acquired a HIGH-ADH, while distress improved in 27% of pts. MF pts who maintained high ADH and low distress over time were more likely to obtain or maintain spleen response at 24 weeks (Mc Nemar test, p=0.02 and p=0.04) (Table 2). At wk24, pts reporting sexual dysfunctions (13.7% vs 7.5%, p=0.04) and insomnia (24.6% vs 15.1%, p=0.01) significantly decreased compared to wk0, along with emotional distress (60.9% vs 29.5%, p<0.001). ARMS/DTPL results at wk48 will also be provided to explore long-term ADH/distress. The RAMP study highlights that LOW-ADH to RUX remains an unmet clinical need in MF and PV. The association between LOW-ADH and spleen response supports that ADH evaluation in real-life practice may improve MF therapy and prognosis. LOW-ADH is more frequently intentional in MF, and unintentional in PV; thus, differentiated corrective interventions are needed in the two diseases. Male pts and those on RUX for >1 yr are at higher risk for LOW-ADH and should be monitored more closely. As ADH increased over time, it is possible that periodic ARMS administration may be beneficial in itself. Since high distress correlates with LOW-ADH, DTPL evaluation and targeted support may also improve treatment success. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Emerging multidrug resistance contributes to treatment failure in Mycoplasma genitalium infected patients in China

The increased treatment failure in patients with sexually transmitted Mycoplasma genitalium infection is associated with antimicrobial resistance. We performed a retrospective survey of antimicrobial clinical outcomes in M. genitalium-infected patients. In addition, we detected macrolide, fluoroquinolone and tetracycline resistance-associated markers to determine their role in treatment failure. The overall incidence of treatment failure was 28.29%, regardless of the drug used. In the present study, the prevalence of macrolide resistance-associated mutations in the 23S rRNA gene was 64%; that of fluroquinolone resistance-associated S83/D87 substitutions in the parC gene was 67.5%; and that of the tetracycline resistance-associated C1192T mutation in the 16S rRNA gene was 22.5%. Furthermore, evidence of dual antimicrobial resistance was found in 46.4% of pretreatment samples, and triple antimicrobial resistance was identified in 9.9%. These findings regarding the emergence of multidrug-resistant strains of M. genitalium in China are concerning and emphasize the importance of guiding M. genitalium treatment with antimicrobial resistance assays.

Sclerotherapy Improves Symptoms in Patients with Small and Moderate Diameter Low-Flow Vascular Malformations: A Prospective Cohort Study

Vascular malformations are rare diseases and treatment remains controversial. Sclerotherapy is accepted as a minimally invasive treatment with good results; however, some patients do not report good response to sclerotherapy, and it is not clear which variables influence treatment outcome, preventing optimal patient selection. We hypothesized that large diameter lesions have reduced efficacy and satisfaction with sclerotherapy. Therefore, we prospectively evaluated the clinical response of low-flow vascular malformations treated with 1% polidocanol foam sclerotherapy and determined the correlation of symptom improvement with clinical variables. Prospective cohort study of patients with symptomatic low flow vascular malformations treated at the Hospital das Clínicas between December 2016 and November 2018. Lesions were classified according to location, extension, diameter, type of vessels, margins, and symptoms. Sclerotherapy was performed by direct injection of 1% polidocanol foam, with a maximum volume of 10ml per session. Symptom improvement was evaluated using the visual analog scale and patient-reported quality of life was assessed by the Short-form 6 dimensions (SF-6D) questionnaire. Follow-up was performed every 3months after treatment. Forty lesions were treated in 38 patients, with 19 women and 19 men; median age was 20.5years (range 4months to 63years). Most lesions (80%) were venous, and most commonly in the lower limbs (47.5%); 27.5% were superficial, 35% were deep, and 37.5% affected both compartments. The most common clinical presentations were deformity (95%), pain (78%), and functional limitation (58%); deep compartment lesions were more associated with functional limitation (69% vs. 27%; P=0.030). Fifty-three per cent of lesions were >10cm and were associated with increased numbers of psychosocial symptoms (P=0.038). Two-hundred and forty-two sessions of sclerotherapy were performed, with 6 mean treatments per lesion (range 1-15). The mean follow-up time was 23months (range 2-23months). The most common complications were pain and local edema, without any major complications; some patients reported symptom recurrence (15% pain, 10% deformity, and 12% functional limitation). Sclerotherapy was associated with significant improvement of all symptoms (P<0.001). However, lesions >10cm were associated with poor improvement in deformity (P=0.003). Quality of life improved for most patients (60%) and treatment satisfaction was high (82%). Treatment of low-flow vascular malformations with 1% polidocanol foam is safe and effective; sclerotherapy improves symptoms and quality of life. Large diameter lesions (>10cm) are associated with increased treatment failure. A small percentage of patients reported recurrent symptoms and require other modalities for successful treatment.

P377 Study of the prevalence of candidemia and its antifungal susceptibility pattern in a tertiary care hospital

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PMObjectivesStudy of the prevalence of candidemia and its resistance pattern in a tertiary care hospital.MethodsRetrospective observational studyStudy period—January 1, 2020-December 31, 2021Blood culture bottles (aerobic and anaerobic) were received in the laboratoryIncubated in BacT Alert 3D (Biomerieux) for 5 daysAfter flagging positive, a direct gram stain was prepared from the culture bottle and informed to the clinician. Culture plating was done on Blood agar and Mac Conkey Agar which were incubated for 18-24 h at 37°C.After 24 h, growth was obtained on the culture plate and identification was done by using MALDI-TOF MS (Biomerieux) and Susceptibility Testing was done using VITEK 2 Compact (Biomerieux).Antifungal sensitivity testing was done using VITEK 2 Compact for fluconazole, voriconazole, caspofungin, micafungin, amphotericin B, and flucytosine.ResultsDuring the study period, 18 235 blood culture bottles were received, and 1652 blood culture bottles were flagged positive. The most common organism causing bloodstream infection belonged to Burkholderia spp. Candida sp (4%) was found to be the sixth most common organism causing bloodstream infection.Among Candida spp most common isolate was C. tropicalis 42% followed by C. parapsilopsis 21%, C. albicans 21%, and C. auris 12%, and the least isolated species was C. glabrata 4%.Maximum number of Candida spp were isolated from intensive care units.Susceptibility testing was given by VITEK 2 compact for all Candida spp except for Candida auris.The isolated Candida spp showed the least susceptibility to fluconazole (resistant rate R 30.6%) as compared to micafungin, caspofungin, flucytosine, and amphotericin B (R 13.9%, 13.9%, 22.2%, and 5.6%,) respectively. Candida glabrata showed less sensitivity toward caspofungin as compared to other antifungals.Conclusion Candida spp. are a part of the normal flora of healthy hosts but are also found to be a major cause of invasive fungal infections which is now found to be one of the leading causes of mortality in hospitalized patients. The emergence of unusual and relatively unknown Candida species as nosocomial pathogens with increasing treatment failure, emphasizes the need to isolate and identify all species and to start early definitive treatment according to the susceptibility pattern reported to decrease mortality and morbidity rates.