An in vitro study of the susceptibilities and growth dynamics of common ocular pathogens using five fluoroquinolones

Bacteria are responsible for up to 70% of all ocular infections including conjunctivitis, keratitis and endophthalmitis. If left untreated, a reduction of visual acuity, and in severe cases, sight loss, is possible. Treatment usually consists of a topically applied antibacterial preparation for patients with superficial infections. With intraocular infections, topical administration is augmented with systemic treatment or local instillation. While several types of drugs are available for ocular therapy, the fluoroquinolone class of antimicrobials is especially effective. This is due in part to their broad-spectrum of activity and low toxicity. However, as with any globally prescribed antimicrobial agent, bacterial resistance is an issue. Over the past 10 years there has been a decline in the effectiveness of older fluoroquinolones (ciprofloxacin and ofloxacin) in treating Gram-positive and, to a lesser extent, certain Gram-negative infections. In response to the declining activity of ciprofloxacin and ofloxacin, newer fluoroquinolones have been developed such as levofloxacin (L-isomer of ofloxacin), and more recently, gatifloxacin and moxifloxacin. In order to ensure the most potent drugs are being used to treat the most serious types of infection, studies need to be done to assess the activity of the current antimicrobial arsenal against pertinent infecting organisms. Three different types of experiments can be done to achieve this. In vitro potency can be tested two ways. The first is minimum inhibitory concentration (MIC). This test defines the concentration of antimicrobial drug that prevents growth of bacteria when tested against an inoculum of approximately 105 colony forming units (CFU)/ml. The second is the mutant prevention concentration (MPC), which is the amount of drug needed to inhibit a first step resistant mutant. This is a relatively new approach to measuring fluoroquinolone potency; like MIC it is not a measure of kill. A separate set of experiments are needed to assess in vitro killing. Kill curves measure the ability of an antimicrobial agent to reduce/kill a bacterial population over a period of 24 hours.Because bacterial loads can vary greatly in in vivo infections, kill curves were conducted on a series of four inoculum sizes ranging from 106 to 109 cfu/ml. Some of the most common ocular pathogens are Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. Mycobacterium fortuitum and Mycobacterium chelonae, while much less commonly associated with ocular disease, are capable of causing vision-threatening infections. As a result, the above six organisms were used to test the in vitro potency of ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and gatifloxacin.Both MIC and MPC testing found both gatifloxacin and moxifloxacin to be 4-8-fold more potent in vitro against the Gram-positive organisms than the older fluoroquinolones with an average potency rank order of moxifloxacin = gatifloxacin > levofloxacin > ofloxacin = ciprofloxacin. The Gram-negative results, however, revealed that the older fluoroquinolones are still the most potent of the fluoroquinolones tested with an average potency rank order of ciprofloxacin > ofloxacin = levofloxacin > gatifloxacin = moxifloxacin. Kill curve results showed a significant difference in the rate of killing between the MIC and MPC drug concentrations. At the MIC drug concentration there was generally only a noticeable reduction in viable cells following 24 hours of drug exposure and in many cases this was followed by a period of bacterial re-growth. At the MPC drug concentration, a significant bacterial count reduction was often observed as early as 4 to 6 hours for both S. pneumoniae and H. influenzae. Surprisingly, there was little difference between the five fluoroquinolones in their rates of and amount of bacterial reduction.Because of high in vitro resistance rates in drugs like penicillin, the fluoroquinolones are an important broad-spectrum alternative. Consequently, it is imperative that measures are taken to maintain the efficacy of this class. One approach is to ensure that the most potent drug is being used to eradicate possible resistant sub-populations present in in vivo infections. The data from these experiments suggest that the new fluoroquinolones gatifloxacin and moxifloxacin are much more potent (in vitro) than older fluoroquinolones against Gram-positive bacteria. With Gram-negative pathogens, however, ciprofloxacin remains the most potent agent in vitro

Appendectomy versus non-operative treatment for acute uncomplicated appendicitis in children: Study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Background Appendectomy is considered the gold standard treatment for acute appendicitis. Recently the need for surgery has been challenged in both adults and children. In children there is growing clinician, patient and parental interest in non-operative treatment of acute appendicitis with antibiotics as opposed to surgery. To date no multicentre randomised controlled trials that are appropriately powered to determine efficacy of nonoperative treatment (antibiotics) for acute appendicitis in children compared with surgery (appendectomy) have been performed. Methods Multicentre, international, randomised controlled trial with a non-inferiority design. Children (age 5–16 years) with a clinical and/or radiological diagnosis of acute uncomplicated appendicitis will be randomised (1:1 ratio) to receive either laparoscopic appendectomy or treatment with intravenous (minimum 12 hours) followed by oral antibiotics (total course 10 days). Allocation to groups will be stratified by gender, duration of symptoms (≫ or \u3c48 hours) and centre. Children in both treatment groups will follow a standardised treatment pathway. Primary outcome is treatment failure defined as additional intervention related to appendicitis requiring general anaesthesia within 1 year of randomisation (including recurrent appendicitis) or negative appendectomy. Important secondary outcomes will be reported and a cost-effectiveness analysis will be performed. The primary outcome will be analysed on a non-inferiority basis using a 20% non-inferiority margin. Planned sample size is 978 children. Discussion The APPY trial will be the first multicentre randomised trial comparing non-operative treatment with appendectomy for acute uncomplicated appendicitis in children. The results of this trial have the potential to revolutionise the treatment of this common gastrointestinal emergency. The randomised design will limit the effect of bias on outcomes seen in other studies. Trial registration number clinicaltrials.gov:NCT02687464. Registered on Jan 13th 2016

Long-term outcome of isolated mitral valve repair versus replacement for degenerative mitral regurgitation in propensity-matched patientsCentral MessagePerspective

Objective: This study was performed to investigate the long-term outcomes in patients with degenerative mitral regurgitation (MR) undergoing mitral valve repair (MVr) versus mitral valve replacement (MVR) without concomitant surgeries. Methods: The study cohort comprised 1493 patients with degenerative MR who were treated with isolated mitral valve surgery between January 2000 and December 2017 in a large multicenter (5 hospitals) registry of the Province of British Columbia, Canada, including 991 with repair and 502 with replacement. A propensity-matched comparison and risk-adjusted model were used to analyze the outcomes. Results: After propensity matching (415 matched pairs), the 30-day mortalities were 2.4% and 3.6% in the MVr and MVR groups respectively (odds ratio [OR], 1.500; 95% confidence interval [CI], 0.674-3.339; P = .32). The MVR group had significantly greater rates of prolonged inotrope usage >24 hours (P = .024), prolonged ventilation (P = .039), and blood transfusion (P = .023). The respective 1-, 5-, 10-, and 15-year survival rates were 95.7%, 88.8%, 71.4%, and 53.3% in the MVr group, and 93.0%, 81.6%, 61.3%, and 46.0% in the MVR group (hazard ratio [HR], 1.355; 95% CI, 1.105-1.661; P = .004). A multivariable analysis revealed that MVR was an independent risk factor for 30-day mortality (OR, 2.270; 95% CI, 1.089-4.732; P = .029) and long-term mortality (HR, 1.417; 95% CI, 1.161-1.729; P < .001). The HR of MVR over MVr remained consistently greater than 1.0 across all ages. Conclusions: MVr is associated with lower postoperative morbidity and better long-term survival compared with MVR in patients undergoing isolated mitral valve surgery for degenerative MR. The benefit of MVr appears age-independent

Prophylactic Cranial Irradiation Revisited: Cost-effectiveness and Quality of Life in Small-cell Lung Cancer

PURPOSE: To investigate the therapeutic usefulness and cost-effectiveness of prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer (SCLC) who had achieved a complete remission. METHODS: A retrospective chart review was undertaken of all patients diagnosed in Saskatchewan with SCLC between 1987 and 1998 inclusive. Patients who achieved a complete remission were divided into two groups, depending on whether they underwent PCI (PCI+ and PCI-, respectively). The quality-of-life-adjusted survival was estimated by the Q-TWiST method (quality time without symptoms and toxicity). The mean incremental costs per month of incremental OS were calculated in a cost-effectiveness analysis. RESULTS: Among the 98 complete remission patients, the median OS for PCI+ and PCI- patients was 20.0 and 19.0 months, respectively (p \u3e 0.05, nonsignificant). The median disease-free survival was 14.7 and 10.0 months, respectively (p \u3c 0.05). The difference in the mean Q-TWiST survival was significant (p \u3c 0.01). The mean marginal cost was $18,834/PCI+ patient and$17,885/PCI- patient (p \u3e 0.05, nonsignificant). The cost-effectiveness ratio was $70/mo of incremental OS if u(tox) and u(rel) (the utility coefficients to reflect the value of time in health states of toxicity and relapse) were assumed to be 1.0. CONCLUSION: PCI is a cost-effective treatment that improves the quality-of-life-adjusted survival for patients with a complete remission of SCLC