This study compared rates of empirical-therapy use and negative patient outcomes between complicated and recurrent urinary tract infection (r/cUTI) cases diagnosed with a multiplex polymerase chain ...reaction or pooled antibiotic susceptibility testing (M-PCR/P-AST) vs. standard urine culture (SUC). Subjects were 577 symptomatic adults (n = 207 males and n = 370 females) presenting to urology/urogynecology clinics between 03/30/2022 and 05/24/2023. Treatment and outcomes were recorded by the clinician and patient surveys. The M-PCR/P-AST (n = 252) and SUC (n = 146) arms were compared after patient matching for confounding factors. The chi-square and Fisher’s exact tests were used to analyze demographics and clinical outcomes between study arms. Reduced empirical-treatment use (28.7% vs. 66.7%), lower composite negative events (34.5% vs. 46.6%, p = 0.018), and fewer individual negative outcomes of UTI-related medical provider visits and UTI-related visits for hospitalization/an urgent care center/an emergency room (p < 0.05) were observed in the M-PCR/P-AST arm compared with the SUC arm. A reduction in UTI symptom recurrence in patients ≥ 60 years old was observed in the M-PCR/P-AST arm (p < 0.05). Study results indicate that use of the M-PCR/P-AST test reduces empirical antibiotic treatment and negative patient outcomes in r/cUTI cases.
Abstract
Background
For new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary ...tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed.
Methods
This selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included.
Results
Microbiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP.
Conclusions
A study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics.
In cUTI trial data from 6 new antibiotics targeting MDR Gram-negative infections, proportion of acute pyelonephritis (AP) varied; influencing population demographics and baseline microbiology. Smaller proportion of AP resulted in older patient population, fewer females, less E coli, and lower treatment success.
Miscellaneous Perianal Afflictions Hagerman, Gonzalo F.; Silva-Velazco, Jorge; Molina-Lopez, Juan Francisco
Clinics in colon and rectal surgery,
09/2019, Letnik:
32, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Abstract
This article provides an overview of hidradenitis suppurativa, lichen planus, lichen sclerosis, calcinosis cuti, pyogenic granuloma, intertrigo, and seborrheic keratosis. This article also ...focuses on recognition and management of these pleomorphic afflictions of the perianal region.
The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections ...(cUTI).
The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients.
Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment.
CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68).
Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI.
Pasal 70 ayat (3) UU Nomor 10/2016 tentang Pilkada mewajibkan kepala daerah incumbent untuk cuti jika yang bersangkutan akan mencalonkan kembali pada daerah yang sama. Terhadap aturan tersebut ...kemudian menimbulkan pro dan kontra, apakah aturan cuti kampanye bagi kepala daerah incumbent layak dipertahankan atau tidak. Setiap peraturan pasti memiliki kelebihan dan kelemahan termasuk peraturan tentang cuti ini terutama jika dikaitkan dengan tujuan dari pilkada itu sendiri. Rumusan masalahnya:, Pertama, Bagaimana pengaturan persyaratan cuti kampanye bagi kepala daerah incumbent dalam UU Nomor 10/2016 ? Kedua, Apa kelebihan dan kelemahan adanya pengaturan persyaratan cuti kampanye bagi kepala daerah incumbent dalam pilkada? Penelitian ini adalah penelitian yuridis-normatif dengan menggunakan dua pendekatan yaitu pendekatan kasus dan pendekatan perundang-undangan. Penelitian ini menyimpulkan, bahwa pertama pasal 70 ayat (3) UU 10/2016 telah menimbulkan problematika hukum. Kedua, terdapat kelebihan dan kelemahan terhadap aturan cuti kampanye. Salah satu kelebihannya ialah untuk membatasi kekuasaan kepala daerah agar tidak terjadi penyalahgunaan kekuasaan, sedangkan salah satu kelemahannya bahwa kewajiban untuk cuti dapat merugikan hak kepala daerah incumbent untuk bekerja menuntaskan amanah rakyat hasil pemilihan langsung serta merugikan rakyat pemilih.
: Increasing resistance of gram-negative bacteria poses a serious threat to global health. Thus, efficacious and safe antibiotics against resistant pathogens are urgently needed. Cefiderocol, a ...siderophore cephalosporin, addresses this unmet need.
: For this article, we screened all preclinical and clinical studies on cefiderocol published by January 2021 on PubMed. Also, regulatory documents, recent conference contributions, and selected data of antibiotic competitors are reviewed. We provide a comprehensive overview of the mode of action,
and
activity, pharmacokinetics/pharmacodynamics, and human pharmacokinetics. Last, we discuss the efficacy and safety data from the pivotal trials.
: Cefiderocol was
potent against virtually all gram-negative pathogens and resistance was rare. The target site pharmacokinetics (i.e. urinary and lung penetration) have been well described in humans and important PK/PD targets were reached. In the clinical trials, cefiderocol was non-inferior to carbapenems in the treatment of complicated urinary tract infections and nosocomial pneumonia. Against carbapenem-resistant gram-negative pathogens, cefiderocol was similar to the best available therapy, which was mainly based on the backbone agent colistin. Overall, a substantial body of evidence supports the clinical use of cefiderocol in patients with gram-negative infections and limited treatment options.
Tazobactam/ceftolozane is a combination of a β-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g ...administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage.
Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 μg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 μg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population.
The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients.
The Li(Ni
0.6
Co
0.15
Mn
0.25
)
1−
x
(CuTi)
x
O
2
(
x
= 0.00, 0.01, 0.02, 0.03) cathode materials were synthesized via a hydroxide co-precipitation method followed by a solid-state reaction. The ...elementary composition, crystal structure features, morphology, and electrochemical performances of the powders were investigated in detail by inductively coupled plasma-atomic emission spectrometry (ICP-AES), X-ray diffraction (XRD), Rietveld refinement, scanning electron microscopy (SEM), galvanostatic charge/discharge test, electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV), respectively. The results of XRD and Rietveld refinements demonstrate that Cu and Ti co-substitution does not destroy the crystal structure, but can decrease cation ordering level and improve structural integrity. Electrochemical results show that Cu and Ti addition also results in an improved rate and cycling performances compared to pristine LiNi
0.6
Co
0.15
Mn
0.25
O
2
. An increase in rate performance and cycle stability upon copper and titanium co-substitution is related to the better hexagonal structure and enhanced kinetics of the intercalation process. Especially, Li(Ni
0.6
Co
0.15
Mn
0.25
)
0.99
(CuTi)
0.01
O
2
exhibits the best rate performance and cycle stability among all samples with discharge specific capacity of 178.8 mAh/g and capacity retention of 90.6% after 30 cycles at 0.2C, which are higher than those of other materials.
Al
2O
3 to Al
2O
3 joints were produced using a one stage active brazing technique based on CuTi, CuZr and AgCuTi active brazing alloys. Single- and double-butt joints were used for microstructural ...(light and scanning electron microscopy and X-ray diffraction) and mechanical property (double shear test) studies, respectively. The joints produced with CuZr filler alloys (containing 2%, 4%, 6% and 8% Zr, wt%) showed low shear strengths (0.2–0.4
MPa) due to the presence of ZrO
2 at the braze–substrate interface and failed in mode I crack opening. Higher shear strengths of 15–24 and 42
MPa were obtained by using CuTi filler alloys (containing 2%, 4%, 6%, 8% and 10% Ti, wt%) (mode II/mode III dependent on the Ti content) and the eutectic (Ag–27
wt% Cu–5
wt% Ti) alloy, respectively. The high shear strengths were attributed to the small amount of Cu
2(AlTi)
4O at the braze–substrate interface and led, in the case of the ternary alloy, to the failure of the substrate rather than the braze (mode III axial splitting).
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