Effect of antimicrobial stewardship on antimicrobial prescriptions for selected diseases of dogs in Switzerland.

BACKGROUND: Antimicrobial stewardship programs (ASPs) are important tools to foster prudent antimicrobial use. OBJECTIVE: To evaluate antimicrobial prescriptions by Swiss veterinarians before and after introduction of the online ASP AntibioticScout.ch in December 2016. ANIMALS: Dogs presented to 2 university hospitals and 14 private practices in 2016 or 2018 for acute diarrhea (AD; n = 779), urinary tract infection (UTI; n = 505), respiratory tract infection (RTI; n = 580), or wound infection (WI; n = 341). METHODS: Retrospective study. Prescriptions of antimicrobials in 2016 and 2018 were compared and their appropriateness assessed by a justification score. RESULTS: The proportion of dogs prescribed antimicrobials decreased significantly between 2016 and 2018 (74% vs 59%; P < .001). The proportion of prescriptions in complete agreement with guidelines increased significantly (48% vs 60%; P < .001) and those in complete disagreement significantly decreased (38% vs 24%; P < .001) during this time. Antimicrobial prescriptions for dogs with AD were significantly correlated with the presence of hemorrhagic diarrhea in both years, but a significantly lower proportion of dogs with hemorrhagic diarrhea were unnecessarily prescribed antimicrobials in 2018 (65% vs 36%; P < .001). In private practices, in 2018 a bacterial etiology of UTI was confirmed in 16% of dogs. Prescriptions for fluoroquinolones significantly decreased (29% vs 14%; P = .002). Prescriptions for antimicrobials decreased significantly in private practices for RTI (54% vs 31%; P < .001). CONCLUSION: Antimicrobials were used more prudently for the examined indications in 2018 compared to 2016. The study highlights the continued need for ASPs in veterinary medicine.

Antimicrobial prescriptions in cats in Switzerland before and after the introduction of an online antimicrobial stewardship tool.

BACKGROUND: Antimicrobial stewardship activities are essential to improve prudent antimicrobial use. The aim of the present study was to evaluate changes in antimicrobial prescriptions in cats after the introduction of prudent use guidelines promoted by an online antimicrobial stewardship tool (AntibioticScout.ch) in Switzerland. Data from 792 cats presented to two university hospitals and 14 private practices in 2018 were included and compared to 776 cases from 2016. Cats were diagnosed with acute upper respiratory tract disease (aURTD), feline lower urinary tract disease (FLUTD) and abscesses. Clinical history, diagnostic work-up and antimicrobial prescriptions (class, dosage, duration) were assessed. Type and proportions [95% confidence intervals] of antimicrobial prescriptions were compared between the two evaluation periods and a mixed effects logistic regression model was applied to evaluate compliance with Swiss prudent use guidelines. RESULTS: From 2016 to 2018, the proportion of antimicrobial prescription in all included cases decreased from 75.0% [71.8-78.0] to 66.7% [63.3-69.9]; this decrease was most pronounced for treatments at university hospitals (67.1% [59.5-74.0] to 49.3% [40.9-57.8]) and for cats with FLUTD (60.1% [54.6-65.4] to 48.8% [43.2-54.4]). Use of 3rd generation cephalosporins in private practices declined from 30.7% [26.5-35.1] to 22.1% [18.4-26.2], while overall use of non-potentiated aminopenicillins increased from 19.6% [16.4-23.0] to 27.8% [24.1-31.9]. In cases where antimicrobial therapy was indicated, compliance with guidelines did not increase (33.3% [26.6-40.6] to 33.5% [27.2-40.2]), neither at universities nor in private practices. On the other hand, antimicrobial treatment was more often withheld in cases with no indication for antimicrobial therapy (35.6% [30.1-41.4] to 54.0% [47.6-60.4]); this was found for private practices (26.7% [20.8-33.4] to 46.0% [38.4-53.7]) and for aURTD cases (35.0% [26.5-44.2] to 55.4% [44.7-65.8]). CONCLUSIONS: Overall proportions of antimicrobial prescription, unjustified antimicrobial therapy and, in private practices, use of 3rd generation cephalosporins decreased from 2016 to 2018 for the investigated feline diseases. However, overall compliance with Swiss prudent use guidelines was still low, implying that further efforts are required to foster prudent antimicrobial use in cats.

Antimicrobial prescriptions and adherence to prudent use guidelines for selected canine diseases in Switzerland in 2016.

BACKGROUND: Antimicrobial resistance is an increasing problem in human and veterinary medicine and is closely linked to the use of antimicrobials. The objective of this study was to describe antimicrobial prescriptions for selected canine diseases in Switzerland during 2016. METHODS: Dogs presented to two university hospitals and 14 private practices for acute diarrhoea (AD; n=371), suspected or confirmed urinary tract infections (UTIs; n=245), respiratory tract infections (RTIs; n=274) or wound infections (WIs; n=175) were included. Clinical history, diagnostic work-up and antimicrobial prescription (class, dosage and duration) were retrospectively assessed. A justification score was applied to evaluate appropriateness of antimicrobial therapy based on available national and international consensus guidelines. RESULTS: Antimicrobials were prescribed in 65 per cent of dogs with AD, 88 per cent with UTI, 62 per cent with RTI and 90 per cent with WI. The most prescribed antimicrobial classes (monotherapy and combination therapy) were potentiated aminopenicillins (59 per cent), nitroimidazoles (22 per cent), non-potentiated aminopenicillins (16 per cent) and fluoroquinolones (13 per cent). Overall, 38 per cent (95 per cent CI 0.35 to 0.41) of the prescriptions were in accordance with consensus guidelines. In dogs with AD, antimicrobial therapy was associated with the presence of haemorrhagic diarrhoea (P<0.05) and complied in 32 per cent with consensus guidelines, which recommend antimicrobial treatment only when sepsis is suspected. A bacterial aetiology was confirmed via culture and/or sediment examination in 36 per cent of dogs with suspected UTI. CONCLUSIONS: Overall, adherence to consensus guidelines was poor both, at university hospitals and private practices. Antimicrobial stewardship measures are therefore needed to improve prudent use.

Prognostic impact of polypharmacy and drug interactions in patients with advanced cancer.

The risk of potential drug-drug interactions (PDI) is poorly studied in oncology. We included 105 patients with advanced non-small-cell lung cancer (NSCLC), 100 patients with advanced breast cancer (BC) and 100 patients of the palliative care unit (PCU) receiving systemic palliative treatment between 2010 and 2015. All patients suffered from advanced incurable cancer and received basic palliative care. PDI were assessed using the hospINDEX of all drugs approved in Switzerland in combination with a specific drug interaction software. Primary study objective was to assess the prognostic impact of PDI per patient cohort using Kaplan-Meier statistics. The median number of comedications was 5 (range 0-15). Major-risk PDI were detected in 74 patients (24.3%). The number of comedications was significantly associated with PDI (p < 0.0001). Major-risk PDI increased from 14% in patients with < 4 comedications to 24% in patients with 4-7 comedications, 40% with 8-11 comedications and 67% in patients with > 11 comedications. Median overall survival (OS) was 8.6 months in NSCLC, 33 months in BC and 1.2 months in PCU patients. PDI were significantly associated with inferior OS in BC (HR = 1.32, 95% CI 1.01-1.74, p = 0.049), but not in NSCLC (HR = 1.11, 95% CI 0.84-1.47, p = 0.45) or PCU (HR = 1.12, 95% CI 0.86-1.45, p = 0.41). PDI remained significantly associated with OS in BC (HR = 1.32, p = 0.049) in the adjusted model. In conclusion, PDI are frequent in patients with advanced cancer and increased caution with polypharmacy is warranted when treating such patients.

Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia.

Evidence suggests that tumor microenvironment is critically involved in supporting survival of chronic lymphocytic leukemia (CLL) cells. However, the molecular mechanisms of this effect and the clinical significance are not fully understood. We applied a microenvironment model to explore the interaction between CLL cells and stromal cells and to elucidate the role of phosphatidylinositol 3 kinase (PI3-K)/Akt/phosphatase and tensin homolog detected on chromosome 10 (PTEN) cascade in this process and its in vivo relevance. Primary human stromal cells from bone marrow, lymph nodes, and spleen significantly inhibited spontaneous apoptosis of CLL cells. Pan-PI3-K inhibitors (LY294002, wortmannin, PI-103), isotype-specific inhibitors of p110α, p110ß, p110γ, and small interfering RNA against PI3-K and Akt1 counteracted the antiapoptotic effect of the stromal cells. Induction of apoptosis was associated with a decrease in phosphatidylinositol-3,4,5-triphosphate, PI3-K-p85, and dephosphorylation of phosphatidylinositol-dependent kinase-1 (PDK-1), Akt1, and PTEN. Freshly isolated peripheral blood mononuclear cells from patients with CLL (n = 44) showed significantly higher levels of phosphorylated Akt1, PDK-1, PTEN, and CK2 than healthy persons (n = 8). CK2 inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole, apigenin, and 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazol) decreased phosphorylation of PTEN and Akt, induced apoptosis in CLL cells, and enhanced the response to fludarabine. In conclusion, bone marrow microenvironment modulates the PI3-K/Akt/PTEN cascade and prevents apoptosis of CLL cells. Combined inhibition of PI3-K/Akt and recovery of PTEN activity may represent a novel therapeutic concept for CLL.

Double impact on p-glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells.

The development of multidrug resistance (MDR) is a major problem during cancer treatment. Drug efflux via ATP-binding cassette (ABC) transporters is the main mechanism responsible for resistance to chemotherapeutics. We have recently observed that statins enhance susceptibility to doxorubicin-induced apoptosis in human rhabdomyosarcoma cells, which is now also observed in human SH-SY5Y neuroblastoma cells. We have therefore investigated the ABC transporter activity to confirm a possible inhibition by statins in SH-SY5Y cells. Indeed, simvastatin directly inhibited dye transport at equimolar concentrations of the ABC transporter inhibitor, verapamil. Making use of the fluorescence behavior of doxorubicin the accumulation of anthracycline was monitored in real-time confocal microscopy. The intracellular doxorubicin accumulation was immediately enhanced by statins in SH-SY5Y cells and also in a MYCN-amplified neuroblastoma cell line STA-NB-10. The heavily glycosylated P-glycoprotein (ABCB1, P-gp) transporter appeared as a 180-and 140-kDa species. Atorvastatin and simvastatin reduced the 180-kDa form of P-gp, but not verapamil. Thereby the fully glycosylated species is shifted to the core glycosylated species (140 kDa), which was only seen at statin exposure times longer than 24 hr. The functional importance of glycosylation of the transporter was highlighted by exogenous application of N-glycosidase F, which was sufficient to enhance doxorubicin accumulation. Hence, these novel findings of statins' dual impact on P-gp have clinical implications. The enhanced intracellular accumulation of chemotherapeutics or other ABC transporter substrates in the presence of statins may represent a novel concept to overcome MDR in cancer therapy and improve drug safety.