A Real-world Multicenter Outpatient Experience of Ceftolozane/Tazobactam.

Background: Ceftolozane/tazobactam (C/T) is indicated for the treatment of complicated intra-abdominal infection (IAI), complicated urinary tract infection (UTI), and hospital-acquired/ventilator-associated bacterial pneumonia caused by susceptible bacteria. As real-world data are limited, we report utilization and associated outcomes of C/T use in the outpatient setting. Methods: This is a multicenter, retrospective study of patients who received C/T between May 2015 and December 2020. Demographics, infection types, C/T utilization characteristics, microbiology, and health care resource utilization were collected. Clinical success was defined as complete or partial symptom resolution at completion of C/T. Persistent infection and discontinuation of C/T were deemed nonsuccess. Logistic regression analysis was used to identify predictors associated with clinical outcomes. Results: A total of 126 patients (median age, 59 years; 59% male; median Charlson index, 5) from 33 office infusion centers were identified. Infection types included 27% bone and joint infection (BJI), 23% UTI, 18% respiratory tract infection (RTI), 16% IAI, 13% complicated skin and soft tissue infection (cSSTI), and 3% bacteremia. The median daily dose of C/T was 4.5 g, primarily administered via elastomeric pumps as intermittent infusion. The most common gram-negative pathogen was P. aeruginosa (63%), 66% of which was multidrug-resistant and 45% carbapenem-resistant. Enterobacterales was identified in 26% of isolates, of which 44% were extended-spectrum beta-lactamase producers. The overall clinical success rate of C/T was 84.7%. Nonsuccessful outcomes were due to persistent infections (9.7%) and drug discontinuations (5.6%). Conclusions: C/T was successfully used in the outpatient setting to treat a variety of serious infections with a high prevalence of resistant pathogens.

Appropriate cleaning reduces potential risk of spore transmission from patients with Clostridioides difficile infection treated in outpatient infusion centers.

OBJECTIVES: Patients with Clostridioides difficile infection (CDI) who receive treatment at outpatient infusion centers (OICs) pose a risk for spore transmission. We investigated C. difficile contamination in the environment of CDI and non-CDI patients and evaluated the effectiveness of standard cleaning. METHODS: This is a multicenter, non-conventional study including 8 OICs between October 2019 and December 2020. Samples were collected at baseline, after infusion, and after cleaning CDI and non-CDI areas. Cleaning was performed using hypochlorite and non-hypochlorite products for CDI and non-CDI, respectively. Samples were cultured for toxigenic C. difficile and strain-typed via fluorescent PCR ribotyping and whole-genome sequencing. RESULTS: The overall C. difficile contamination rate was 7.9% (156/1969) with 8.1% in patient and 5.6% in non-patient care areas, respectively. For CDI areas, contamination rates were 5.9% at baseline, 15.0% after infusion, and significantly reduced to 6.2% after cleaning (P = 0.004). For non-CDI areas, contamination was similar at baseline (9.5%), after infusion (7.6%), and after cleaning (4.3%). The difference in C. difficile-positive samples after infusion was significant for CDI vs. non-CDI (15.0% vs. 7.6%, P = 0.004). Overall contamination was 11.5% for floors, 7.9% for infusion chairs, and 3.8% for equipment (P = 0.001). The most frequent ribotypes were F014-020 (42.6%), F106 (15.6%), F255 (6.1%), F001 (5.2%) and F027 (3.5%). Cleaning resulted in elimination of F106, F255, F001, F027 and partial reduction of F014-020. CONCLUSIONS: Environmental C. difficile contamination was increased after CDI infusions and significantly reduced after cleaning with a hypochlorite solution, reducing the potential risk of spore transmission to others.

Recurrent Clostridioides difficile infection worsens anxiety-related patient-reported quality of life.

BACKGROUND: Clostridioides difficile infection (CDI) is associated with high recurrence rates impacting health-related quality of life (HrQOL). However, patient-reported data are lacking particularly in the outpatient setting. We assessed changes in HrQOL over time in patients treated with bezlotoxumab at US infusion centers and determined clinical factors associated with HrQOL changes. METHODS: The HrQOL survey was conducted in adult patients with CDI, who received bezlotoxumab in 25 US outpatient infusion centers. The survey was adapted from the Cdiff32 instrument to assess anxiety-related changes to HrQOL and completed on the day of infusion (baseline) and at 90 days post bezlotoxumab (follow-up). Demographics, disease history, CDI risk factors, and recurrence of CDI (rCDI) at 90-day follow-up were collected. Changes in HrQOL scores were calculated and outcomes assessed using a multivariable linear regression model with P < 0.05 defined as statistically significant. RESULTS: A total of 144 patients (mean age: 68 ± 15 years, 63% female, median Charlson index: 4, 15.9% rCDI) were included. The overall mean baseline and follow-up HrQOL scores were 26.4 ± 11.5 and 56.4 ± 25.0, respectively. At follow-up, this score was significantly higher for patients who had primary CDI (34.5 ± 21.7) compared to those with multiple rCDI (24.7 ± 21.0; P = 0.039). The mean HrQOL change at follow-up was significantly higher for patients without rCDI (34.1 ± 28.8 increase) compared to patients with rCDI (6.7 ± 19.5 increase; P < 0.001), indicating improvement in anxiety. CONCLUSIONS: Using the Cdiff32 instrument, we demonstrated that HrQOL worsened significantly in patients with further rCDI. These findings support the use of Cdiff32 in assessing CDI-related humanistic outcomes.

Real-world Experience of Bezlotoxumab for Prevention of Clostridioides difficile Infection: A Retrospective Multicenter Cohort Study.

BACKGROUND: Bezlotoxumab is approved for prevention of recurrence of Clostridioides difficile infection (CDI) in adults receiving standard of care (SoC) therapy based on findings from MODIFY clinical trials. However, utilization practices and validation of trial results in the real world are limited. METHODS: Records of patients receiving bezlotoxumab between April 2017 and December 2018 across 34 infusion centers in the United States were retrospectively reviewed. Recurrent CDI (rCDI), defined as diarrhea lasting ≥2 days resulting in treatment, was assessed 90 days postbezlotoxumab. RESULTS: The study cohort included 200 patients (median age, 70 years; 66% female; median Charlson comorbidity index, 5), of whom 86% (n = 173) had prior CDI episodes and 79% (n = 158) had ≥2 risk factors for rCDI. SoC antibiotics included vancomycin (n = 137, 68%), fidaxomicin (n = 60, 30%), and metronidazole (n = 3, 2%). Median time from C. difficile stool test to bezlotoxumab and initiation of SoC to bezlotoxumab were 15 days and 11 days, respectively. Within 90 days, 31 of 195 patients (15.9%) experienced rCDI, which corresponds to a success rate of 84.1%. Patients with ≥2 CDI recurrences prebezlotoxumab had a higher risk of subsequent rCDI compared with those with 1 recurrence or primary CDI (hazard ratio, 2.77; 95% confidence interval, 1.14-6.76; P = .025). CONCLUSIONS: This real-world multicenter study demonstrated successful prevention of rCDI with bezlotoxumab comparable to clinical trial results regardless of type of SoC and timing of infusion. Multiple prior CDI recurrences were associated with a higher risk of subsequent rCDI, supporting the use of bezlotoxumab earlier in the disease course.

Outpatient treatment of osteomyelitis with telavancin.

Telavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens including Staphylococcus aureus, the most frequent cause of osteomyelitis. Treatment is often challenging due to needs for surgical intervention along with prolonged administration of intravenous antimicrobials, frequently in an outpatient setting. This was a retrospective analysis of the efficacy and safety of telavancin for treatment of osteomyelitis provided as outpatient parenteral antimicrobial therapy (OPAT) in physician office infusion centres. Medical records of 60 patients receiving telavancin for osteomyelitis in 22 physician office infusion centres from 2010 to 2011 and 2013 to 2015 were reviewed. Of these, 60% were treated without hospitalisation, 37% had orthopaedic hardware and 56% had concurrent infections. Staphylococcus aureus was the most common pathogen (78%), primarily methicillin-resistant. The median duration of telavancin treatment in the outpatient setting was 21 days (range 3-105 days). Telavancin was used as first-line therapy in 32% of cases, following prior antibiotic failure in 47% and due to intolerance to previous agents in 22%, predominantly daptomycin or vancomycin. The telavancin dose was 10 mg/kg/day, adjusted for renal function in 25% of patients. The majority of patients self-administered telavancin at home via an elastomeric infusion pump. Overall clinical success was 73%. No significant differences in outcomes were observed with the presence of hardware, concurrent infection, concomitant therapies or type of osteomyelitis. Telavancin-associated adverse events occurred in 57%, with discontinuation in three patients (5%). These data demonstrate the effective and safe OPAT use of telavancin, providing an alternative for successful treatment of patients with osteomyelitis.

Simultaneous inhibition of COX-2 and 5-LOX activities augments growth arrest and death of premalignant and malignant human lung cell lines.

The arachidonic acid-metabolizing enzymes cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LOX) are overexpressed during lung carcinogenesis and their end products (e.g.; PGE2, 5-HETE, and LTB4) have been implicated in tumor development. Recently, COX-2 inhibitors (e.g.; celecoxib) and 5-LOX inhibitors (e.g.; MK886 and REV5901) used as single agents have shown promising activities in the treatment and chemoprevention of cancer. However, little is known about the effects of combinations of these inhibitors. We found that simultaneous treatment of premalignant and malignant human lung cell lines with celecoxib, MK886, and REV5901 is more potent in growth suppression and induction of cell death than single or dual combination of these agents. However, their sensitivity to the inhibitors was not directly associated with the expression of COX-2, 5-LOX, or 5-LOX-activating protein (FLAP), but correlated with the production of corresponding metabolites. Furthermore, partial protection of cell death was observed when PGE2 and/or 5-HETE was added to cell cultures treated with celecoxib, MK886, and REV5901 simultaneously. Our data indicate that a triple drug combination of distinct inhibitors of the eicosanoid metabolism at clinically feasible concentrations were more effective than each agent alone suggesting further investigations.

Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition.

Insulin-like growth factor binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates the growth of non-small cell lung cancer (NSCLC) cells through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in lung cancer metastasis is not well known. In the present study, we showed that noncytotoxic doses of adenoviral or recombinant IGFBP-3 significantly decreased the migration and invasion of H1299 and A549 NSCLC cells. Furthermore, treatment of human lung fibroblasts with recombinant IGFBP-3 suppressed their ability to stimulate the invasion of H1299 cells. Overexpression of IGFBP-3 markedly reduced lung metastasis of A549 cells in an experimental animal model system and prolonged the survival time of the animals. Urokinase-type plasminogen activator (uPA) inhibitor treatment or uPA small interfering RNA transfection of A549 and H1299 cells resulted in a significant decrease in invasion. Corresponding ELISA, Western blot, gelatin zymogram, and semiquantitative reverse transcription-PCR analyses revealed that IGFBP-3 reduced the expression of uPA mRNA through IGF-independent mechanisms. The specific role of uPA in anti-invasive activity of IGFBP-3 was further confirmed in NSCLC cells, in which uPA expression/activity was suppressed by the transfection with synthetic small interfering RNA or by the treatment with uPA inhibitor or induced by the infection with an adenoviral vector. IGFBP-3 also decreased the expression/activity of matrix metalloproteinase-2 through IGF-dependent but uPA-independent pathways. Taken together, our data suggest that IGFPB-3 effectively block uPA- and matrix metalloproteinase-2-stimulated invasion pathways, ultimately reducing lung cancer cell metastasis. Our findings indicate that IGFBP-3 may be a promising anti-invasive and antimetastatic therapeutic agent in lung cancer.

Involvement of mitochondrial and Akt signaling pathways in augmented apoptosis induced by a combination of low doses of celecoxib and N-(4-hydroxyphenyl) retinamide in premalignant human bronchial epithelial cells.

Celecoxib is being evaluated as a chemopreventive agent. However, its mechanism of action is not clear because high doses were used for in vitro studies to obtain antitumor effects. We found that celecoxib inhibited the growth of premalignant and malignant human bronchial epithelial cells with IC(50) values between 8.9 and 32.7 micromol/L, irrespective of cyclooxygenase-2 (COX-2) expression. Normal human bronchial epithelial cells were less sensitive to celecoxib. Because these concentrations were higher than those attainable in vivo (

Induction of GDF-15/NAG-1/MIC-1 in human lung carcinoma cells by retinoid-related molecules and assessment of its role in apoptosis.

Growth and Differentiation Factor-15 (GDF-15, NAG-1, MIC-1) is induced by several apoptosis-inducing agents including the retinoid-related molecule (RRM) 6-[3-(1-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437). It has been suggested that GDF-15 may be involved in the induction of apoptosis by CD437 in H460 lung cancer cells. The present study was designed to probe this hypothesis more directly. Several RRMs (CD437, ST1926 and MX3350-1) but not the retinoids all-trans- retinoic acid and 4HPR were able to induce GDF-15 in H460 cells. A similar differential effect of these retinoids was observed for the induction of p53, which has been reported to regulate GDF-15 expression. In H460 cells transfected with a neo vector control (H460-Neo), treatment with RRMs but not ATRA or 4HPR resulted in increases in p53, GDF-15 and apoptosis evidenced by poly(ADP ribose) polymerase (PARP) cleavage. In contrast, RRMs failed to increase p53 or induce apoptosis in H460 cells in which p53 was inactivated by transfection of the human papillomavirus E6-6 (H460-E6-6). The increase in GDF-15 by RRMs was also compromised in the H460-E6-6 cells. Because PARP cleavage was only evident when GDF-15 levels where elevated it appeared that GDF-15 was mediating the pro-apoptotic effects of RRMs. However, silencing of GDF-15 induction by RNA interference failed to decrease the ability of CD437 and ST1926 to induce apoptosis. These results demonstrate that GDF-15 is dispensable for the pro-apoptotic activity of CD437 and ST1926.

Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations.

Celecoxib exhibits cancer preventive and therapeutic effects in animal models and clinical trials. It presumably acts through selective inhibition of cyclooxygenase-2 (COX-2) and subsequent reduction of prostaglandin (PG) synthesis. However, the concentrations of celecoxib required for growth inhibition and apoptosis induction in vitro are higher than those needed for suppression of PGs. Moreover, those concentrations are not achievable in humans raising a controversy regarding the clinical relevance of in vitro data. We investigated the activity of celecoxib alone and in combination with the pro-apoptotic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) on growth and apoptosis of human nonsmall cell lung cancer (NSCLC) cell lines. Celecoxib inhibited growth of thirteen NSCLC cell lines with IC50 values ranging from 19 to 33 microM regardless of their COX-2 expression. Apoptosis was induced in cells with high (A549) as well as low (H1792) COX-2 levels but only at a concentration of 75 microM celecoxib. However, treatment with pharmacologically feasible concentrations of celecoxib (< or = 10 microM) in combination with 4HPR (< or = 2 microM) resulted in a marked suppression of NSCLC cell growth and colony formation. Apoptosis mediated by activation of caspase-3, cleavage of PARP and lamin A was suppressed by addition of antioxidants, suggesting that the generation of reactive oxygen species was partially involved. This study indicates, that celecoxib combined with 4HPR is more effective than treatment with either agent alone in inhibition of growth and induction of apoptosis in NSCLC cells. It suggests further investigations of this combination for lung cancer treatment.

Eicosanoid metabolism in squamous cell carcinoma cell lines derived from primary and metastatic head and neck cancer and its modulation by celecoxib.

Eicosanoid metabolism through cyclooxygenases (COXs) and lipoxygenases (LOXs) generates various lipids that play a role in squamous cell carcinogenesis. We used pairs of head and neck squamous cell carcinoma (HNSCC) cell lines derived from primary and metastatic tumors of the same patient to analyze eicosanoid metabolites by ESI-LC/MS/MS and COX/LOX expression by western immunoblotting. The effects of celecoxib on eicosanoid synthesis and HNSCC cell growth were examined. Prostaglandin E2 (PGE2) was the major metabolite in three of six cell lines. COX-2 was detected in three cell lines, which produced PGE2 (two from metastases). We found low expression of COX-1 at similar intensities for each pair of cell lines. 5-LOX was detected in all cells. Some expressed 12-LOX, 15-LOX-1, and 15-LOX-2, but there was no correlation between enzyme expression and endogenous product content. Exogenous arachidonic acid did not change the profile of eicosanoid biosynthesis. Low doses of celecoxib inhibited formation of PGE2 in UMSCC-14A cells by 84% as early as 6 hours. In contrast, 5-HETE, 12-HETE, and 15-HETE levels were increased by approximately 40-, 5- and 3-fold, respectively, with a decline to baseline levels within 24 hours. High dose celecoxib increased the 12-HETE level 2.3-fold after 3 days of incubation. Celecoxib inhibited growth of all HNSCC cell lines in a concentration-dependent manner regardless of their COX expression (IC50 values after 3 days; 33 to 62 microM). Our findings provide new informations about individual eicosanoids produced by HNSCC cells and their differential regulation by the selective COX-2 inhibitor celecoxib.

Effect of selenite combined with chemotherapeutic agents on the proliferation of human carcinoma cell lines.

Selenite is frequently used in combination with cancer chemotherapeutic agents to reduce side effects. However, the cytoprotective activity of selenite may also reduce the efficacy of chemotherapeutic drugs on tumor cells. This study was designed to examine the effects of selenite combined with cytotoxic agents used in clinical protocols [e.g., doxorubicine, docetaxel, 5-fluorouracil (5-FU), methotrexate (MTX), mafosphamide, mitomycin C, gemcitabine, etoposide, cisplatin, irinotecan, and oxaliplatin] on the proliferation of various carcinoma cell types. The data demonstrated that selenite had no marked effects on the antiproliferative activity of docetaxel, doxorubicine, 5-FU, MTX, and mafosphamide in MDA-MB-231 breast cancer cells. Likewise, no consistent changes were observed in A549 lung cancer cell proliferation when selenite was combined with cisplatin, etoposide, gemcitabine, or mitomycin C. On the other hand, selenite potentiated the cytotoxicity of 5-FU, oxaliplatin, and irinotecan in HCT116 colon cancer cells by approx 1.1-fold, 2.7-fold, and 2.6-fold, respectively. In SW620 colon cancer cells, selenite induced a 1.5-fold and 4.3-fold increase of the antiproliferative activity of 5-FU and oxaliplatin, respectively. Whereas irinotecan showed no effects on SW620 cell growth, a combination with selenite resulted in 23% inhibition. Our results indicate that selenite did not reduce the antiproliferative activity of chemotherapeutic agents in vitro. In addition, selenite was able to increase the inhibitory activity of docetaxel in A549 lung cancer cells, and of 5-FU, oxaliplatin, and irinotecan in HCT116 and SW620 colon cancer cells implying selenite is potentially useful as an adjuvant chemotherapeutic agent.