scholarly journals Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Tomefa E. Asempa ◽  
Joseph L. Kuti ◽  
Julie D. Seroogy ◽  
Allison S. Komirenko ◽  
David P. Nicolau
Keyword(s):  
Urinary Tract ◽  
Area Under The Curve ◽  
Complicated Urinary Tract Infection ◽  
Aminoglycoside Antibiotic ◽  
Similar Proportion ◽  
Therapeutic Drug ◽  
Dosing Interval ◽  
Number Of Patients ◽  
Trough Concentrations ◽  
Tract Infections

ABSTRACT Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 μg/ml.

scholarly journals Antibacterial data synthesis challenges: a systematic review of treatments for complicated gram-negative urinary tract infections

2021 ◽  
Author(s):  
Ryan Dillon ◽  
Jennifer Uyei ◽  
Rajpal Singh ◽  
Eilish McCann
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Meta Analysis ◽  
Complicated Urinary Tract Infection ◽  
Clinical Trial Data ◽  
Patient Characteristics ◽  
Heterogeneous Data ◽  
Eligibility Criteria ◽  
Tract Infections

Aim: To determine the suitability of network meta-analysis (NMA) using antibacterial treatment evidence in complicated urinary tract infection. Materials & methods: We conducted a systematic literature review to identify published clinical trial data for complicated urinary tract infection treatments. We performed a feasibility assessment to determine whether the available evidence would support the creation of a robust NMA, considering key assumptions of homogeneity, similarity and consistency. Results: Twenty-five trials met eligibility criteria. Risk of bias was low, and individual studies met their primary end point(s). Assumptions central to the conduct of a robust NMA were not met. Heterogeneity was ubiquitous, including baseline pathogen, treatment and patient characteristics. Conclusion: Limited and heterogeneous data identified make the use of NMA to compare novel antibacterial agents impractical and likely unreliable.

scholarly journals Escherichia coli Mutators Present an Enhanced Risk for Emergence of Antibiotic Resistance during Urinary Tract Infections

2004 ◽  
Vol 48 (1) ◽  
pp. 23-29 ◽  
Author(s):  
Keith Miller ◽  
Alexander John O'Neill ◽  
Ian Chopra
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Urinary Tract Infections ◽  
Therapeutic Drug ◽  
Single Point Mutation ◽  
Low Level ◽  
Drug Concentrations ◽  
Tract Infections ◽  
Level Resistance

ABSTRACT Mutators may present an enhanced risk for the emergence of antibiotic resistance in bacteria during chemotherapy. Using Escherichia coli mutators as a model, we evaluated their ability to develop resistance to antibiotics routinely used for the treatment of urinary tract infections (UTIs). Under conditions that simulate therapeutic drug concentrations in humans, low-level resistance to trimethoprim, gentamicin, and cefotaxime emerged more frequently in mutators than normal strains. Resistance to trimethoprim in both cell types arose from a single point mutation in folA (Ile94→Leu) and cefotaxime resistance resulted from loss of outer membrane porin OmpF. The mechanisms of gentamicin resistance could not be defined, but resistance did not result from mutations in ribosomal protein L6 (rplF). Although similar mechanisms of low-level antibiotic resistance probably arise in these strains, mutators are a risk factor because the increased generation of mutants with low-level resistance enhances the opportunity for subsequent emergence of high-level resistance.

scholarly journals The Cpx Stress Response System Potentiates the Fitness and Virulence of Uropathogenic Escherichia coli

2013 ◽  
Vol 81 (5) ◽  
pp. 1450-1459 ◽  
Author(s):  
Irina Debnath ◽  
J. Paul Norton ◽  
Amelia E. Barber ◽  
Elizabeth M. Ott ◽  
Bijaya K. Dhakal ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract ◽  
Stress Response ◽  
Aminoglycoside Antibiotic ◽  
Deletion Mutants ◽  
Content Type ◽  
Response System ◽  
Stress Response System ◽  
Tract Infections ◽  
Auxiliary Factor

ABSTRACTStrains of uropathogenicEscherichia coli(UPEC) are the primary cause of urinary tract infections, representing one of the most widespread and successful groups of pathogens on the planet. To colonize and persist within the urinary tract, UPEC must be able to sense and respond appropriately to environmental stresses, many of which can compromise the bacterial envelope. The Cpx two-component envelope stress response system is comprised of the inner membrane histidine kinase CpxA, the cytosolic response regulator CpxR, and the periplasmic auxiliary factor CpxP. Here, by using deletion mutants along with mouse and zebrafish infection models, we show that the Cpx system is critical to the fitness and virulence of two reference UPEC strains, the cystitis isolate UTI89 and the urosepsis isolate CFT073. Specifically, deletion of thecpxRAoperon impaired the ability of UTI89 to colonize the murine bladder and greatly reduced the virulence of CFT073 during both systemic and localized infections within zebrafish embryos. These defects coincided with diminished host cell invasion by UTI89 and increased sensitivity of both strains to complement-mediated killing and the aminoglycoside antibiotic amikacin. Results obtained with thecpxPdeletion mutants were more complicated, indicating variable strain-dependent and niche-specific requirements for this well-conserved auxiliary factor.

scholarly journals 2662. Methenamine Hippurate Decreases the Incidence of Urinary Tract Infections in Adult Renal Transplant Recipients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S931-S932
Author(s):  
Orlando Quintero ◽  
Yoram Puius ◽  
Vagish Hemmige
Keyword(s):  
Urinary Tract ◽  
Renal Transplant ◽  
Creatinine Clearance ◽  
Kidney Transplant ◽  
Urinary Tract Infections ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Transplant Patients ◽  
Number Of Patients ◽  
Tract Infections

Abstract Background Urinary tract infections (UTIs) are a common complication of renal transplantation. Methenamine hippurate is a non-antibiotic alternative that reduces the frequency of UTIs in selected non-transplant patients, but which is not recommended in renal insufficiency. We conducted a retrospective study to determine the efficacy of methenamine prophylaxis in our kidney transplant population, and identify subgroups for which efficacy is greatest. Methods Retrospective chart review of adult kidney transplant patients at Montefiore Medical Center who were prescribed methenamine during January 1, 2016–December 31, 2017, with extraction of clinical data in the year before and after prophylaxis. Variables included demographics, creatinine clearance and hemoglobin A1c levels at the time of prescription, incidence of UTIs as determined by standardized literature definitions, hospital admissions for infections, and antibiotic use. Results The incidence of UTIs per 1000 patient-days decreased significantly, from 9.66 (95% CI 7.53–12.40) the year before to 3.24 (95% CI 2.00–5.24) the year after (P < 0.001). The effect was significantly more pronounced in patients who were transplanted due to diabetic nephropathy, with a decreased incidence of 13.05 (95% Cl 10.00–17.02) UTIs/1000 patient-days to 2.90 (95% Cl 1.58–5.32) in diabetics (P < 0.001), vs. 5.50 (95% Cl 3.65–8.28) UTIs/1000 patient-days to 3.81 (95% Cl 1.70–8.55) in non-diabetics (P = 0.44). The number of days of antibiotics for UTIs per 1000 days also decreased significantly for all patients, from 128.58 (95% CI 94.87–174.28) the year before to 49.78 (95% CI 31.74–78.07) the year after (P = 0.001). No significant differences in efficacy were seen based on sex or renal function. Three patients with indwelling urinary catheters or who required intermittent catheterization did not appear to benefit Conclusion Methenamine prophylaxis decreases the incidence of UTIs and number of antibiotic days in adult renal transplant recipients. This effect was seen even in patients with reduced creatinine clearance. Patients with diabetes benefited the most. The small number of patients who required catheterization did not appear to benefit. Disclosures All authors: No reported disclosures.

scholarly journals Complicated Urinary Tract Tuberculosis in a 13-Year-Old Adolescent with Chronic Kidney Disease and Antituberculous Drug-Induced Hepatotoxicity

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
Heda Melinda Nataprawira ◽  
Adhitya Agung Pratama ◽  
Ahmedz Widiasta ◽  
Jupiter Sibarani ◽  
Dany Hilmanto ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Left Kidney ◽  
Complicated Urinary Tract Infection ◽  
Significant Loss ◽  
Mantoux Test ◽  
British Thoracic Society ◽  
Drug Induced ◽  
Diuretic Renogram ◽  
The Right ◽  
Tract Infections

Urinary tract tuberculosis (TB) is a rare extrapulmonary manifestation of TB in children. The disease is potentially underdiagnosed because it clinically resembles other urinary tract infections. A 13-year-old adolescent girl presented with pain, difficulty in micturition, and gross hematuria for almost two years before admission, and she had left flank pain since one year ago and significant loss of body weight during the illness. The close TB contact was her grandmother who was on TB treatment. Acid-fast bacilli yielded positive result, Mantoux test was positive (17 mm), urine GeneXpert MTB/Rif was positive; tuberculoma was identified on kidney histopathology, and a diuretic renogram revealed an uncorrected glomerular filtration rate (GFR) of the right and left kidney to be 32.5 mL/min/1.73 m2 and 5 mL/min/1.73 m2, respectively. During the treatment, oral anti-TB drug-induced hepatotoxicity (ADIH) occurred to the patient. This problem was solved with management according to the British Thoracic Society (BTS) guidelines. Screening TB in children is very important for a better outcome. If children complain of some complicated urinary tract infection, TB should be suspected. Optimaly treating children with urinary tract TB exagerrated with ADIH and CKD is very challenging.

scholarly journals Explorative Randomized Phase II Clinical Study of the Efficacy and Safety of Finafloxacin versus Ciprofloxacin for Treatment of Complicated Urinary Tract Infections

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
F. Wagenlehner ◽  
M. Nowicki ◽  
C. Bentley ◽  
M. Lückermann ◽  
S. Wohlert ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Clinical Study ◽  
Phase Ii ◽  
Complicated Urinary Tract Infection ◽  
Clinical Effects ◽  
Urine Ph ◽  
Phase Ii Clinical Study ◽  
Intent To Treat ◽  
Tract Infections ◽  
Acidic Urine

ABSTRACT The broad-spectrum C-8-cyano-fluoroquinolone finafloxacin displays enhanced activity under acidic conditions. This phase II clinical study compared the efficacies and safeties of finafloxacin and ciprofloxacin in patients with complicated urinary tract infection and/or pyelonephritis. A 5-day regimen with 800 mg finafloxacin once a day (q.d.) (FINA05) had results similar to those of a 10-day regimen with 800 mg finafloxacin q.d. (FINA10). Combined microbiological and clinical responses at the test-of-cure (TOC) visit were 70% for FINA05, 68% for FINA10, and 57% for a 10-day ciprofloxacin regimen (CIPRO10) in 193 patients (64 for FINA05, 68 for FINA10, and 61 for CIPRO10) of the microbiological intent-to-treat (mITT) population. Additionally, the clinical effects of ciprofloxacin on patients with an acidic urine pH (80% of patients) were reduced, whereas the effects of finafloxacin were unchanged. Finafloxacin was safe and well tolerated. Overall, 43.4% of the patients in the FINA05 group, 42.7% in the FINA10 group, and 54.2% in the CIPRO10 group experienced mostly mild and treatment-emergent but unrelated adverse events. A short-course regimen of 5 days of finafloxacin resulted in high eradication and improved clinical outcome rates compared to those for treatment with ciprofloxacin for 10 days. In contrast to those of ciprofloxacin, the clinical effects of finafloxacin were not reduced by acidic urine pH. Hospitalized adults were randomized 1:1:1 to finafloxacin treatment (800 mg q.d.) for either 5 or 10 days or to ciprofloxacin treatment (400 mg/500 mg b.i.d.) for 10 days with an optional switch from intravenous (i.v.) to oral administration at day 3. The primary endpoint was the combined microbiological and clinical response at the TOC visit in the microbiological intent-to-treat population. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.)

scholarly journals 1461. Antimicrobial Susceptibility Patterns of Common Complicated Urinary Tract Infection Pathogens in US Hospitals, 2013–2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S534-S534
Author(s):  
Marya Zilberberg ◽  
Brian Nathanson ◽  
Kate Sulham ◽  
Andrew F Shorr
Keyword(s):  
Urinary Tract ◽  
Treatment Strategies ◽  
Complicated Urinary Tract Infection ◽  
The United States ◽  
Generation Cephalosporin ◽  
Resistance Rate ◽  
Hospitalized Patients ◽  
Resistance Patterns ◽  
Tract Infections ◽  
Antibiotic Resistance Patterns

Abstract Background In response to increasing rates of antimicrobial resistance, carbapenems have become first-line treatments for many infections. This, in turn, fosters the potential for resistance (CR). Efforts to mitigate the emergence of CR through carbapenem-sparing strategies must rest on a fundamental understanding of antibiotic resistance patterns among commonly encountered pathogens. Therefore, we examined the microbiology of complicated urinary tract infections (cUTI) in hospitalized patients in the United States. Methods We performed a multicenter retrospective cohort study in the Premier database of approximately 180 hospitals, 2013–2018. Using an ICD-9/10-based algorithm we identified all adult patients hospitalized with cUTI and included those with a positive blood or urine culture. Patients with carbapenem-resistant organisms were excluded. We examined the microbiology and susceptibilities to common cUTI antimicrobials (third-generation cephalosporin [C3], fluoroquinolones [FQ], trimethoprim-sulfamethoxazole [TMP/SMZ], fosfomycin [FFM], nitrofurantoin [NFT], and triple-resistant [TR]) over time. Results Among 28,057 organisms from 23,331 patients, the 3 most common pathogens were E. coli (EC, 41.0%), K. pneumoniae (KP, 12.1%), and P. aeruginosa (PA, 11.0%). Among these organisms, resistance to C3 was 10.4% among PA, 12.6% KP and 48.9% EC. EC was most likely to exhibit resistance to all agents of interest, and demonstrated the highest resistance rate to TMP/SMZ (61.5%), and lowest to NFT (10.4%). In contrast, KP had the highest rate of resistance to NFT (27.9%) and lowest to FQ (4.9%). The lowest rate of resistance among PA was to TMP/SMZ (1.9%), and highest to C3 (10.4%). The prevalence of TR in 2013–2014 and 2017–2018, respectively, was 34.2% and 37.4% for EC, 11.8% and 14.2% for KP, and 7.0% and 4.6% for PA. Conclusion Among the most common pathogens isolated in hospitalized patients with cUTI, and particularly in EC, high and increasing single resistance and TR rates to common antimicrobials were evident, Current empiric treatment strategies may be insufficient against the growing threat of TR. Disclosures All authors: No reported disclosures.

Pivmecillinam plus Pivampicillin in Complicated Urinary Tract Infection. Double-Blind Comparison of the Combination Pivmecillinam/Pivampicillin and Pivmecillinam Alone in Patients with Urinary Tract Infection

1981 ◽  
Vol 9 (4) ◽  
pp. 283-287 ◽  
Author(s):  
C Frimodt-Møller ◽  
R Vejlsgaard
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Clinical Success ◽  
Combined Therapy ◽  
Complicated Urinary Tract Infection ◽  
Fixed Dose ◽  
Double Blind ◽  
Promising Alternative ◽  
Tract Infections

Twenty-six surgical-urological patients with severe underlying diseases of the urinary tract and an acute urinary tract infection received a 10-day treatment with either pivmecillinam, 400 mg three tmes daily (twelve patients), or the fixed dose combination of pivmecillinam/pivampicillin (pivmecillinam 200 mg plus pivampicillin 250 mg) three times daily (fourteen patients). Eleven of the fourteen patients given combined therapy were cured bacteriologically, compared to only four out of twelve patients taking pivmecillinam alone. Clinical success was achieved in eleven out of fourteen patients who received combination therapy and in seven out of twelve subjects given pivmecillinam. Mild gastro-intestinal discomfort was recorded in a few patients in both treatment groups. The results suggest that the combination of pivmecillinam and pivampicillin is a promising alternative in patients with complicated urinary tract infections.

scholarly journals Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib

2021 ◽  
Vol 14 (6) ◽  
pp. 494
Author(s):  
Florent Ferrer ◽  
Jonathan Chauvin ◽  
Bénédicte DeVictor ◽  
Bruno Lacarelle ◽  
Jean-Laurent Deville ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Dose Adjustment ◽  
Complete Response ◽  
Therapeutic Window ◽  
Therapeutic Drug ◽  
Model Based ◽  
Target Exposure ◽  
Number Of Patients ◽  
Trough Concentrations ◽  
Dosing Strategy

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50–100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200–2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71–91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months.

scholarly journals Evaluasi Penggunaan Antibiotik pada Pasien Infeksi Saluran Kemih di Instalasi Rawat Inap RSUP X di Klaten Tahun 2017

2019 ◽  
Vol 16 (1) ◽  
pp. 38-48
Author(s):  
Nawang Nawakasari ◽  
Ambar Yunita Nugraheni
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Infections ◽  
Data Retrieval ◽  
Antibiotic Use ◽  
Number Of Patients ◽  
Common Causes ◽  
Exact Evaluation ◽  
Improper Use ◽  
The Right ◽  
Tract Infections

Urinary tract infections are infections are characterized by the presence of bacteria that grow and multiply in the urinary tract in excess of the normal amount. Based on the Indonesian Health Profile, urinary tract infections (UTI) are the 10 most common causes of death. Improper use of antibiotics can cause no therapeutic effect and resistance. This study aims to evaluate the accuracy of antibiotic use in patients with urinary tract infections in central hospital Klaten in 2017 covers the right indication, right patient, right medication, and right dosage. Research with non-experimental methods of data retrieval retrospectively and analyzed descriptively. The inclusion criteria in this study were adult patients 18-64 years old, inpatients suffering from urinary tract infections including cystitis and pyelonephritis, receiving antibiotics and complete medical record data. The results showed that patients with urinary tract infections in RSUP in Klaten 2017 had 72 patients with 76 antibiotic prescriptions. Based on the number of patients, the evaluation results showed the right indication is 100% and the right patients is 100%, while the exact evaluation results of the right drug is 96.05% and the right doses is 27,63%.

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