Duration Of Combination Therapy Research Articles

Risk of acute kidney injury in patients receiving vancomycin and concomitant piperacillin-tazobactam or carbapenem: a multicenter, retrospective cohort study

ABSTRACT Background Vancomycin (VAN) is empirically used with other broad-spectrum antibiotics, such as piperacillin-tazobactam (PTZ) or carbapenem (CBP). However, conflicting literature on the rates of acute kidney injury (AKI) of VAN with PTZ has been reported. Research design and methods A multicenter, retrospective cohort study of the risk of AKI was conducted in patients receiving VAN and concomitant PTZ or CBP from January 2019 and June 2023. Results In total, 514 eligible patients were included. AKI occurred in a total of 91 patients (17.70%). The prevalence of AKI was significantly higher in the VAN+PTZ group than in the VAN+CBP group (23.37% vs 15.27%, p = 0.028). The survival curves depicting the time to AKI showed the increased incidence and more rapid onset of AKI among patients in the VAN+PTZ group compared to those of the VAN+CBP group (HR 2.186, 95%CI 1.351-3.538, p = 0.0015). VAN+PTZ was associated with a consistently higher AKI rate over VAN+CBP (HR 1.762, 95%CI 1.111-2.795, p = 0.0161) throughout the 14-day combination therapy. VAN with concomitant PTZ, duration of combination therapy ≤4 days and VAN trough concentration >20 mg/L were independent risk factors associated with AKI. Conclusion The prevalence of AKI was found to be higher in patients receiving VAN+PTZ therapy compared to those receiving VAN+CBP therapy based on creatinine-defined AKI.

Development and validation of a prognostic nomogram to predict 30-day all-cause mortality in patients with CRO infection treated with colistin sulfate.

Carbapenem-resistant Gram-negative organism (CRO) infection is a critical clinical disease with high mortality rates. The 30-day mortality rate following antibiotic treatment serves as a benchmark for assessing the quality of care. Colistin sulfate is currently considered the last resort therapy against infections caused by CRO. Nevertheless, there is a scarcity of reliable tools for personalized prognosis of CRO infections. This study aimed to develop and validate a nomogram to predict the 30-day all-cause mortality in patients with CRO infection who underwent colistin sulfate treatment. A prediction model was developed and preliminarily validated using CRO-infected patients treated with colistin sulfate at Tongji Hospital in Wuhan, China, who were hospitalized between May 2018 and May 2023, forming the study cohort. Patients admitted to Xianning Central Hospital in Xianning, China, between May 2018 and May 2023 were considered for external validation. Multivariate logistic regression was performed to identify independent predictors and establish a nomogram to predict the occurrence of 30-day all-cause mortality. The receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), and the calibration curve were used to evaluate model performance. The decision curve analysis (DCA) was used to assess the model clinical utility. A total of 170 patients in the study cohort and 65 patients in the external validation cohort were included. Factors such as age, duration of combination therapy, nasogastric tube placement, history of previous surgery, presence of polymicrobial infections, and occurrence of septic shock were independently associated with 30-day all-cause mortality and were used to construct the nomogram. The AUC of the nomogram constructed from the above six factors was 0.888 in the training set. The Hosmer-Lemeshow test showed that the model was a good fit (p = 0.944). The calibration curve of the nomogram was close to the ideal diagonal line. Furthermore, the decision curve analysis demonstrated significantly better net benefit in the model. The external validation proved the reliability of the prediction nomogram. A nomogram was developed and validated to predict the occurrence of 30-day all-cause mortality in patients with CRO infection treated with colistin sulfate. This nomogram offers healthcare providers a precise and efficient means for early prediction, treatment management, and patient notification in cases of CRO infection treated with colistin sulfate.

Combination therapy of gabapentin and pregabalin for postherpetic neuralgia in 15 Patients

Abstract Background Postherpetic neuralgia (PHN), a common sequela of herpes zoster, is a significant health concern, especially among the elderly. It is estimated that approximately 65% of patients above 60 years old develop PHN, and up to 75% of individuals with herpes zoster over 70 years old may develop PHN. While several drugs have been found effective, the numbers needed to treat these drugs is over six. Many patients still experience inadequate pain relief. Combination therapy is often considered when adequate pain relief is not achieved. Gabapentin is sometimes combined with pregabalin for PHN treatment and this therapy is not recommended by relevant treatment guidelines. Methods We conducted a retrospective analysis of medical records of PHN patients who received combination therapy with gabapentin and pregabalin at our hospital. Data collected included numeric rating scale (NRS) pain scores before and after combination therapy, as well as the duration of each therapy. Statistical analysis was performed using SPSS software. Results A total of 15 patients were included in this study. The mean NRS score before combination therapy was 4.40 ± 1.35, which decreased significantly to 2.20 ± 1.30 post-treatment (P = 0.001). The duration of combination therapy was comparable to that of monotherapy. One patient reported adverse reactions following the switch to combination therapy. Conclusion For PHN patients who do not respond adequately to monotherapy, combining gabapentin and pregabalin is a viable option. However, larger studies with randomized controlled trials are needed to further validate the findings.

Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study

Key messagesIn this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy.BackgroundThe benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria.MethodsWe included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock.ResultsAmong the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73–1.77; P = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53–1.20; P = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71–1.63; P = 0.73). Multivariable regression models and subgroup analyses provided similar results.ConclusionsInitial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

Profil Terapi Penggunaan Obat BPH (Benign Prostatic Hyperplasia) Tamsulosin dengan Dutasteride pada Pasien Pembesaran Prostat Jinak

Background: Benign Prostatic Hyperplasia (BPH) is a term for hyperplasia and hyperplasia. stromal cells prostate gland epithelium. Basically, BPH grows in men who are old and have testes that still produce testosterone. Previous studies suggest that the combination of tamsulosin and dutasteride provides a better therapeutic effect for BPH, significantly reducing the risk of developing BPH-related symptoms. Objectives: The purpose of this study was to identify the socio demographics of BPH patients including age and occupation, identify the type of BPH drug therapy and the effectiveness of Tamsulosin therapy and the combination of tamsulosin with dutasteride based on the duration of drug therapy in Outpatient BPH patients Method: the research was descriptive design with a cross-sectional by looking at the description of the type of BPH drug therapy. Results: From the results of the study, it was found that a sample of 136 BPH patients, BPH patients were more common in the age group 60-74 (75%), the most occupational status worked as independent workers (53.7%), the most type of therapy was combination therapy with tamsulosin and dutasteride (62.5%), and duration of combination therapy (tamsulosin with dutasteride) &gt;1 year (39%). Conclusion: The period of combination therapy is per the effectiveness of the duration of BPH drug therapy.

Radiotherapy combined with immune checkpoint inhibitors in locally advanced/metastatic esophageal squamous cell carcinoma: clinical trials, efficacy and future directions.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide and often diagnosed at advanced stages with poor prognosis. Combination of radiotherapy and immunotherapy seems to be a promising approach for treating ESCC. This comprehensive review article summarizes the current state of combination of radiotherapy and immunotherapy in locally advanced/metastatic ESCC, delineates the clinical trials that merit attention, and outlines unresolved issues and future research directions in this field. The clinical trial findings suggest that radio-immunotherapy combination may improve tumor response and overall survival with manageable side effects, highlighting the importance of patient selection and the necessity for further research to optimize treatment strategies. Issues such as irradiation dosage, fractionation regimen, irradiation site and technique of radiotherapy, as well as the timing, sequence and duration of combination therapy will all affect treatment outcomes, justifying further in-depth investigation.

Correlation of Brain-Derived Neurotrophin Factor Levels in Epilepsy Patients Treated with Valproic Acid and Phenytoin with Cognitive Function

BACKGROUND: Epilepsy cases requiring OAE multitherapy are found in 40% of total epilepsy cases. Many epilepsy patients are referred to Dr. Kariadi Hospital Semarang because of the occurrence of intractable epilepsy. Valproic acid is one of the OAEs that are widely used in the BPJS era in Indonesia as a combination of phenytoin. Seizures increase the expression of BDNF mRNA and protein. METHODS: This study is a cross-sectional study that took place from January to May 2022. The subjects of this study were epilepsy patients who used a combination of phenytoin-valproic acid who met the inclusion criteria. Patient data were obtained from medical records and filling out questionnaires. Patients were asked to fast for ± 8−10 h. Furthermore, blood sampling (±5 ml) of BDNF was carried out at 08.00−10.00 WIB. Cognitive function assessments were performed using MoCA-Ina and the Hamilton depression rating scale at the same time. Data were analyzed by Spearman correlation test and partial correlation test. The results are said to be meaningful if p &lt; 0.05. RESULTS: Thirty-two study subjects used a combination of phenytoin-valproic acid. The Spearman correlation test between the relationship between BDNF levels and cognitive function in epilepsy patients treated with valproic acid and phenytoin showed a significant relationship with the direction and strength of which was strongly positive (r = 0.676 and p ≤ 0.001). The partial correlation test between the relationship between BDNF levels and cognitive function after controlling for age (r = 0.692), seizure frequency (r = 0.641), duration of combination therapy (r = 0.700), and age of seizure onset (r = 0.693) remained the same, while after controlling for the level of education (r = 0.812) and the type of seizure (r = 0.747) increased. CONCLUSION: There is a strong correlation between BDNF levels and cognitive function in epilepsy patients treated with valproic acid and phenytoin. The relationship between BDNF levels and cognitive function remained the same after controlling for age, frequency of seizures, duration of combination therapy, and age of onset of epilepsy.

DOP75 Loss-of-response and immunogenicity following immunomodulator withdrawal from anti-tumour necrosis factor alpha combination therapy: Results from a large retrospective cohort study

Abstract Background Combination therapy with anti-TNF compounds and immunomodulators (IMM; thiopurine or methotrexate) is superior to IMM or anti-TNF monotherapy in patients with inflammatory bowel disease (IBD). IMMs are frequently discontinued during the maintenance phase to mitigate the risk of adverse events, but long-term consequences of this practice are not well studied. We explored the real-world outcomes after IMM discontinuation, including loss-of-response (LOR), dose escalations, immunogenicity and trough levels. Methods This was a multicenter, retrospective cohort study in a general hospital and a tertiary referral center. We included adult patients with IBD, treated &amp;gt;4 months with infliximab (IFX) or adalimumab (ADA) and an IMM at baseline between 2011–2019. The IMM had to be started within 30 days of anti-TNF initiation, or continued for &amp;gt;30 days in case of prior IMM monotherapy. LOR was defined as anti-TNF discontinuation due to disease activity. Adjusted hazards rates (aHR) were calculated using mixed-effects Cox regression analysis with time-varying covariates, accounting for follow-up prior to and after IMM cessation. We adjusted for sex, age, BMI, smoking, Crohn’s disease (CD) vs ulcerative colitis (UC), disease duration, primary sclerosing cholangitis, rheumatological comorbidity, ADA vs IFX, and prior anti-TNF exposure. Results We included 615 episodes of combination therapy (543 individual patients; CD, n=382, 70%). The IMM was discontinued in 296 (48%) episodes after a median of 0.9 (IQR: 0.6 – 2.1) years, at which point 252 (85%) patients were in clinical remission. IMM withdrawal was performed as part of a de-escalation strategy (n=158, 53%), for intolerance (n=86, 29%) or for miscellaneous reasons (n=52, 18%). During a median follow-up of 1.7 (IQR 0.8 – 3.5) years after IMM withdrawal, 46 (16%) patients experienced LOR, 79 (32%) required dose-escalation and 31 (10.3%) developed anti-drug antibodies. Compared to IMM continuation, withdrawal did not significantly increase the risk of LOR (aHR 1.10, 95%CI: 0.74 – 1.64), but more patients required dose escalations (aHR 1.42, 95%CI 1.02 – 1.97) or developed anti-drug antibodies (aHR 2.22, 95%CI 1.21 – 4.08). Among patients who stopped the IMM, clinical remission at IMM withdrawal was the only predictor of LOR (aHR 0.48, 95%CI 0.23 – 0.99), while higher BMI (aHR 1.09, 95%CI 1.01 – 1.17) and shorter duration of combination therapy (Figure 1, aHR 0.57 per year, 95%CI 0.33 – 0.96) increased the risk of immunogenicity. IFX, but not ADA, trough levels decreased significantly after IMM withdrawal. Conclusion Withdrawal of immunomodulators is not associated with higher risk of LOR, but does increase the risk of dose-escalation and unfavorable pharmacokinetics.

Acute kidney injury risk with piperacillin‐tazobactam and vancomycin combination therapy: single centre retrospective study

AbstractAimTo evaluate the risk of acute kidney injury (AKI) in patients who receive vancomycin (VNC) and piperacillin‐tazobactam (PTZ) combination therapy.MethodA single centre, retrospective audit of adult patients treated with VNC alone and in combination with PTZ between 2014–2015. Data was extracted from digital medical records and therapeutic drug monitoring sheets completed by clinical pharmacists. Rates of AKI and duration of combination therapy were analysed by chi‐square, with logistic regression analysis completed to control for nephrotoxins, intensive care unit admission, use of inotropes and pre‐existing chronic kidney disease.ResultsOut of 525 vancomycin courses, that met the inclusion criteria, 211 had PTZ co‐prescribed during the study period. Combination therapy was significantly both associated with an increased rate of AKI compared to VNC use alone (17.5% vs 10.5%, P = 0.02). The mean duration of combination therapy was 4 days (1–17 days). Increased duration of exposure to combination therapy was also associated with a higher incidence of AKI (3.8 days vs. 5.2 days, P = 0.014). VNC‐TPZ combination was identified to be an independent risk factor for AKI (OR 1.73, 95% CI 1.01–2.96, P = 0.046) after adjusting for other known risk factors for AKI, including vasopressor use and intensive care unit admission.ConclusionCombined use of VNC‐PTZ, as well as the duration of combination therapy are both associated with an increased risk of AKI compared with VNC alone. The results are similar to previous literature reports of AKI from the combination of antibiotics. Healthcare providers need to be vigilant and limit the exposure to this combination as clinically appropriate.

Duration of combination therapy and risk of treatment failure in patients with inflammatory bowel disease

Patients who receive infliximab (IFX) combined with a thiopurine, for inflammatory bowel disease, have a better clinical response and less frequent immunization towards IFX than those treated with IFX alone. The benefits of combination therapy must be weighed against the risks of infection and cancer. We studied the association between the duration of combination therapy and the risk of treatment failure by two year from initiation. Participants had Crohn's disease or ulcerative colitis and were in clinical and biological remission, 6 months after initiation of combination therapy. The risk of subsequent treatment failure (i.e., undetectable trough IFX levels and/or clinical relapse followed by surgical treatment or switch of maintenance treatment) was estimated using Kaplan-Meier method and adjusted Hazard Ratios (aHRs), in patients whohadreceived 6 to 11 months vs. 12 months or more of combination therapy. We performed a similar analysis in which the follow-up was started at discontinuation of the immunosuppressant. Among 139 patients (48% women; median age 31.1), with a median follow-up of 18.9 months, we observed 26 treatment failures (including 15 patients with undetectable trough IFX levels). After adjustment for gender and type of immunomodulator, a shorter duration of combination therapy was not associated with a higher risk of treatment failure (aHR=0.42; 95% confidence interval (95%CI): 0.13-1.40; p=0.16). When the follow-up was started at discontinuation of the immunosuppressant, a combination therapy of 6-11 months was associated with a numerically lower risk of treatment failure as compared with a longer combination therapy (HR=0.12; 95%CI: 0.01-1.05; p=0.055). Our results do not show any benefit for continuation of combination therapy for more than 12 months after achieving clinical remission in IBD patients.

The Clinical Course of α1 Blocker Discontinuation in Patients with LUTS/BPH Receiving Combination Therapy of Dutasteride and α1 Blocker

We retrospectively investigated the clinical course of α1 blocker discontinuation in patients who had lower urinary tract symptoms with benign prostate hypertrophy (LUTS/BPH) and received combination therapy ofdutasteride and α1 blocker. Among the patients with LUTS/BPH who had been receiving combination therapy, those who wished to reduce the number ofprescribed drugs and discontinue the use of α1 blocker because ofsymptom improvement were recruited in this study. Symptom scores including International Prostate Symptom Score (IPSS) and overactive bladder symptom score (OABSS), parameters ofuroflowmetry and prostate volume (PV) were evaluated at the time of α 1 blocker discontinuation. Twenty-two patients discontinued the use of α 1 blocker. The mean PV at the time of α 1 blocker discontinuation was 43.2 ml, and the mean duration ofcombination therapy was 39.4 months. In 11 (50%) patients, dutasteride monotherapy without α1 blocker was maintained for a mean follow-up of 10.5 months (9-12 months) after α1 blocker discontinuation (Non-resumption group). In the other 11 patients (50%), α1 blocker was resumed because ofthe patient's request to resume the use of α1 blocker (Resumption group). The mean length ofdutasteride monotherapy was 4. 5 months (1-8 months) in the resumption group. Compared with the non-resumption group, IPSS total score and storage sub-score ofIPSS at the time of α1 blocker discontinuation were significantly higher in the resumption group. Based on the ROC curve, IPSS total score <16, IPSS voiding/storage symptom score <7, OABSS <7 and PV 54 ml or more at the time of α1 blocker discontinuation were predictors ofnon-resumption of α1 blocker. These results suggest that if LUTS is controlled by a long-term combination therapy ofdutasteride and α1 blocker and still PV is large enough, α1 blocker can be discontinued.

Association between Nephrotoxic Drug Combinations and Acute Kidney Injury in the Neonatal Intensive Care Unit

To determine the incidence of acute kidney injury (AKI) in infants exposed to nephrotoxic drug combinations admitted to 268 neonatal intensive care units managed by the Pediatrix Medical Group. We included infants born at 22-36weeks gestational age, ≤120days postnatal age, exposed to nephrotoxic drug combinations, with serum creatinine measurements available, and discharged between 2007 and 2016. To identify risk factors associated with a serum creatinine definition of AKI based on the Kidney Disease: Improving Global Outcomes criteria, we performed multivariable logistic and Cox regression adjusting for gestational age, sex, birth weight, postnatal age, race/ethnicity, sepsis, respiratory distress syndrome, baseline serum creatinine, and duration of combination drug exposure. The adjusted odds of AKI were determined relative to gentamicin+indomethacin for the following nephrotoxic drug combinations: chlorothiazide+ibuprofen; chlorothiazide+indomethacin; furosemide+gentamicin; furosemide+ibuprofen; furosemide+tobramycin; ibuprofen+spironolactone; and vancomycin+piperacillin-tazobactam. Among 8286 included infants, 1384 (17%) experienced AKI. On multivariable analysis, sepsis, lower baseline creatinine, and duration of combination therapy were associated with increased odds of AKI. Furosemide+tobramycin and vancomycin+piperacillin-tazobactam were associated with a decreased risk of AKI relative to gentamicin+indomethacin in both the multivariable and Cox regression models. In this cohort, infants receiving longer durations of nephrotoxic combination therapy had an increased odds of developing AKI.

Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome.

Acute coronary syndrome and atrial fibrillation are both common and can occur in the same patient. Combination therapy with dual antiplatelet therapy and oral anticoagulation increases risk of bleeding. Where the two conditions coexist, careful consideration is needed to determine the optimal antithrombotic treatment to reduce the risks of future ischaemic events associated with both conditions. Choices can be made in intraprocedural anticoagulation, type and dosing of oral anticoagulant, duration of combination therapy, and selection of P2Y12 inhibitor including genetic testing. This review article provides an overview of the available evidence to support clinicians in finding the delicate balance between antithrombotic efficacy and bleeding risk in patients with acute coronary syndrome and atrial fibrillation.

Veliparib (V) monotherapy (monoTx) following combination therapy with V + carboplatin/paclitaxel (CP) in patients with gBRCA-associated advanced breast cancer: Exploratory results from BROCADE3.

1091 Background: In BROCADE3 (NCT02163694), addition of PARP inhibitor V to CP resulted in improved progression-free survival (PFS) (HR 0.71 [95% CI 0.57−0.88], p=0.002) in patients (pts) with advanced HER2-negative breast cancer and g BRCA1/2 mutation. A subset of pts transitioned to V/placebo (PL) monoTx at an intensified dose/schedule after CP discontinuation prior to progression (investigator discretion). Here, we evaluate the impact of this transition on efficacy and safety. Methods: Pts were randomized 2:1 to CP with V (n=337) or PL (n=172). V (120 mg po BID) or PL was given on Days (D) −2 to 5, C (AUC 6) on D1, and P (80 mg/m2) on D1, 8, and 15 (21-day cycles). Pts who transitioned to monoTx received V/PL 300-400mg BID daily until progression. A Cox model with a time varying covariate indicating transition from V/PL with CP to V/PL monoTx was fit to estimate treatment effect during combination and monoTx phases. PFS by cycles of CP prior to monoTx and AEs during monoTx are summarized. Results: A subgroup of 136 (40%) and 58 (34%) pts on the V and PL arms, respectively, received monoTx. When a Cox model with a time-varying covariate was fit for PFS (per investigator), the nominal P-value for treatment by covariate interaction was 0.038. The HRs (95% CI) for V vs PL during combination therapy and monoTx were 0.81 (0.62–1.06) and 0.49 (0.33–0.73). The Table summarizes PFS by cycles of C and/or P prior to monoTx. Common AEs (&gt;20% of pts) during V or PL monoTx were nausea (52%/10%), fatigue (23%/12%), headache (21%/17%), and diarrhea (21%/9%). Seizures (2.2%/0%) were reported during monoTx. Rates of cytopenias for V or PL monoTx were: anemia 12%/14%; neutropenia 13%/12%; and thrombocytopenia 10%/5%. Conclusions: These analyses suggest that pts treated with V + CP derive benefit from both combination therapy as well as V monoTx after CP discontinuation. Pts receiving V monoTx after ≤ 6 cycles of VCP experienced a similar benefit to those who transitioned to monoTx after 7–12 cycles of VCP, suggesting that V maintenance therapy may be suitable following a limited duration of combination therapy. Clinical trial information: NCT02163694 . [Table: see text]

Outcomes of combination therapy with tyrosine kinase inhibitors and immune checkpoint inhibitors in metastatic renal cell carcinoma - A retrospective study.

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic tumor. At the time of this study, there was limited published data on the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors in patients who were heavily pretreated. At our institution, providers have used these combinations in heavily pretreated patients. We conducted a retrospective review of patients receiving this combination with the primary objectives of assessing duration of therapy and toxicities and a secondary objective of disease progression at six months. We included adult patients with confirmed mRCC receiving combination therapy (immune checkpoint inhibitors/tyrosine kinase inhibitors) any time after January 2015. Electronic medical records were reviewed for pertinent data and follow-up descriptive statistics were performed. Fifteen patients were on combination immune checkpoint inhibitors/tyrosine kinase inhibitors, with a median of three lines of previous therapy. The median duration of combination therapy was 7.2 months (range: 0.2 to 39.8) with 126 incidences of toxicities. The most frequent toxicity was fatigue (n = 15), followed by diarrhea (n = 8), anorexia (n = 7) and palmar-plantar erythrodysesthesia (n = 7). Overall, 9 (60%) patients experienced at least one grade 3 or 4 toxicity. Eight of 15 (53%) patients remained on therapy at the six-month mark and did not have progression confirmed by an oncologist. Of the 15 patients, 10 discontinued therapy due to progression, 2 due to intolerable side effects, 2 transitioned to end of life care, and 1 patient was still ongoing at the time of data collection. Based on this review, it appears that combination tyrosine kinase inhibitors/immune checkpoint inhibitors therapy in pre-treated patients with mRCC is tolerable and beneficial.

PS1162 COMBINATION THERAPY TO PREVENT IBRUTINIB WITHDRAWAL: CONTINUED IBRUTINIB WITH THE ADDITION OF VENETOCLAX AT TIME OF PROGRESSION IN IBRUTINIB‐TREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Background:We have previously reported that ∼50% of CLL patients (pts) experience rapid flare of disease when they discontinue ibrutinib therapy due to progression of disease (CLL or Richter's transformation [RT]) (Hampel et al, JCO suppl, 2018). This lead to the clinical practice of overlapping venetoclax with ibrutinib for combination therapy in this setting to prevent ibrutinib withdrawal.Aims:To evaluate the role of continuing ibrutinib beyond the start of salvage venetoclax in pts who have progression of disease on ibrutinib monotherapy, both in preventing ibrutinib withdrawal associated with ibrutinib discontinuation and in disease response.Methods:We identified all CLL pts at Mayo Clinic (3/2017–11/2018) who had disease progression on ibrutinib therapy, where venetoclax was added as subsequent treatment while ibrutinib was continued. CLL‐specific characteristics, treatment timeline and toxicities, and disease course following combination therapy were ascertained. All pts started venetoclax according to the weekly ramp‐up per the package instructions.Results:Eighteen pts treated with the addition of venetoclax to ibrutinib therapy were identified; indications were CLL progression (n = 13) and RT (n = 5). BTK or PLCG2 mutations were present in 8/13 pts. Median duration of follow‐up was 9.6 months after the start of combination therapy.The target venetoclax dose was reached by 5 weeks in 13 pts; reasons for delaying or stopping dose escalation included diarrhea (n = 2), sepsis (n = 2), and neutropenia (n = 1). No patient experienced a disease flare during venetoclax ramp‐up.The median duration of combination ibrutinib and venetoclax therapy was 3 months (range, 0–14 months). Of 18 pts who started combination therapy with ibrutinib and venetoclax, ibrutinib was discontinued in 10 pts. Reasons included hematopoietic stem cell transplant (n = 2), planned stop after adequate disease control (n = 4), financial reasons (n = 1), toxicity (neutropenia n = 1, immune thrombocytopenia/bleeding risk n = 1), and death (n = 1). Only 1 patient experienced ibrutinib withdrawal, which occurred following planned discontinuation after clinical complete response (CR) with a 41 day overlap and toleration of venetoclax 400 mg daily; management with re‐initiation of ibrutinib was effective in regaining disease control. Of 9 pts who stopped ibrutinib, 4 pts had a slow taper over 2–8 weeks, and 2 pts also received corticosteroids at the time of ibrutinib discontinuation.Among the other 8 pts who did not discontinue ibrutinib, 6 pts remain on the combination with venetoclax (median duration 6.5 months, range 3–14 months), and 2 pts continued on ibrutinib following venetoclax discontinuation due to disease progression (both pts received further combination of ibrutinib with multi‐agent chemotherapy).The overall response rate (ORR) to combination therapy with ibrutinib and venetoclax was 81% (CR/clinical CR n = 9, partial response n = 4, stable disease n = 1, and primary refractory disease n = 2). The duration of combination therapy was &lt;4 weeks in 2 pts, precluding response assessment. The estimated 12‐month event‐free survival was 54% (95% CI 33–87%), and the estimated 12‐month overall survival from start of combination therapy was 79% (95% CI 60–100%); see Figure 1.Summary/Conclusion:Among CLL pts who develop progression of disease on ibrutinib monotherapy, continued ibrutinib therapy with addition of venetoclax was feasible, ameliorated ibrutinib withdrawal, and was associated with high ORR.image

The Risk of Acute Kidney Injury in Critically Ill Patients Receiving Concomitant Vancomycin With Piperacillin-Tazobactam or Cefepime.

The objective of this study was to compare the incidence of acute kidney injury (AKI) among critically ill patients receiving combination therapy with vancomycin plus piperacillin-tazobactam (VPT) against patients receiving vancomycin plus cefepime (VC). A retrospective cohort study of adult patients admitted to an intensive care unit between September 2012 and December 2016 was conducted. Patients were included if they received combination therapy with VPT or VC for ≥48 hours. Patients were excluded if creatinine clearance was <60 mL/min or received renal replacement therapy prior to the initiation of therapy. The primary end point was AKI, as defined by the Acute Kidney Injury Network classification, during or within 48 hours of completion of therapy. The incidence of AKI was compared between groups and multivariate analysis was performed to control for relevant confounders. A total of 394 patients received either VPT (n = 258) or VC (n = 136). There were no differences in baseline serum creatinine (0.8 [0.3]mg/dL vs 0.7 [0.3] mg/dL, P = 0.207), use of vasopressors (44% vs 38%, P = 0.255), mechanical ventilation (45% vs 40%, P = 0.350), or initial vancomycin trough (11.2 [5] mg/L vs 11 [4.8] mg/L, P = 0.668) between VPT and VC groups, respectively. The incidence of AKI was 28.7% for VPT patients versus 21.3% for VC patients (P = 0.114). Multivariate analysis revealed vancomycin trough >20 mg/L (odds ratio, OR [95% confidence interval, CI] = 2.69 [1.62-4.47]), baseline SCr (OR [95% CI] = 3.34 [1.43-7.80]), vasopressors (OR [95% CI] = 1.77 [1.04-3.04]), and duration of combination therapy (OR [95% CI] = 1.009 [1.003-1.015]) as independent risk factors for AKI. The risk of AKI was similar between VPT and VC groups in critically ill patients. Risk factors for AKI were related to baseline renal function, duration of combination therapy, supratherapeutic vancomycin troughs, and severity of illness.

Is radiotherapy the missing link to enhancing the outcomes in non-small cell lung cancer patients treated with immunotherapy?

Significant improvements in outcomes for locally advanced and metastatic non-small cell lung cancer (NSCLC) have been seen with increased use of immune checkpoint inhibitors (ICIs), and their role in the treatment of early-stage NSCLC is a subject of active investigation. Mounting evidence from preclinical and clinical trials involving immunotherapy for NSCLC has demonstrated the importance of understanding the tumor microenvironment (TME) and the host anti-tumor response. Incorporation of radiation, specifically in hypofractionated regimens, may potentiate the anti-tumor response stimulated by ICIs and thereby improve the efficacy of immunotherapy for these patients. Additional studies are in progress to determine the optimal sequence, dose, fractionation, and duration of combination therapy.

Incidence of Nephrotoxicity Among Patients Initiated on Vancomycin and Β-lactam Combination Therapies

Abstract Background Vancomycin and β-lactam combinations are used to provide empiric coverage in hospitalized patients. Recent literature has illustrated an increased incidence of nephrotoxicity with such combinations, predominantly with piperacillin-tazobactam and vancomycin. The objective of this study is to evaluate the incidence of nephrotoxicity among patients receiving vancomycin and piperacillin-tazobactam vs., cefepime, or aztreonam. Methods A retrospective, observational, cohort study was conducted at Hahnemann University Hospital in adult patients who received vancomycin plus piperacillin-tazobactam, cefepime, or aztreonam for at least 48 hours between June 2013 and August 2016. Patients were excluded if they had chronic kidney disease Stage III or higher or on continuous renal replacement therapy. The following data were collected: demographics, renal function, number of concomitant nephrotoxic agents, total duration of combination therapy, and vancomycin levels. The primary outcome was the incidence of nephrotoxicity according to the Risk Injury Failure End Stage Renal Disease (RIFLE) criteria. Secondary outcomes were the total length of hospital (LOS) and intensive care unit (ICU) LOS. Statistical analyses were conducted using the Analysis of Variance and the Chi-square test. Results A total of 757 charts were reviewed of which 203 were included in the analysis; 69 in the piperacillin-tazobactam arm, 74 in the cefepime arm, and 60 in the aztreonam arm. The incidence of nephrotoxicity as assessed by the RIFLE criteria was higher in the piperacillin-tazobactam arm (41%) compared with cefepime (15%) and aztreonam arms (17%); P = 0.052. Majority of patients with nephrotoxicity experienced injury according to the RIFLE criteria. No differences were found in the total LOS, ICU LOS, or duration of nephrotoxicity. Patients who experienced nephrotoxicity in the piperacillin-tazobactam arm occurred earlier upon antibiotic initiation at 48 hours compared with the other arms extending past 72 hours; P = 0.004. Conclusion There was a trend towards more patients experiencing nephrotoxicity in the piperacillin-tazobactam arm compared with the other groups. Clinicians should remain vigilant when utilizing combination therapy. Disclosures T. Bias, Merck: Grant Investigator, Research grant. The Medicines Company: Speaker’s Bureau, Speaker honorarium.

P573 Impact of the duration of combination therapy on clinical and pharmacological efficacy of infliximab in inflammatory bowel diseases

P573 Impact of the duration of combination therapy on clinical and pharmacological efficacy of infliximab in inflammatory bowel diseases