Fluoroquinolone-based versus β-lactam-based regimens for complicated intra-abdominal infections: a meta-analysis of randomised controlled trials

Complicated intra-abdominal infections (cIAIs) are common and confer significant morbidity, mortality and costs. In this era of evolving antimicrobial resistance, selection of appropriate empirical antimicrobials is paramount. This systematic review and meta-analysis of randomised controlled trials compared the effectiveness and safety of fluoroquinolone (FQ)-based versus β-lactam (BL)-based regimens for the treatment of patients with cIAIs. Primary outcomes were treatment success in the clinically evaluable (CE) population and all-cause mortality in the intention-to-treat (ITT) population. Subgroup analyses were performed based on specific antimicrobials, infection source and isolated pathogens. Seven trials (4125 patients) were included. FQ-based regimens included moxifloxacin (four studies) or ciprofloxacin/metronidazole (three studies); BL-based regimens were ceftriaxone/metronidazole (three studies), carbapenems (two studies) or piperacillin/tazobactam (two studies). There was no difference in effectiveness in the CE (2883 patients; RR = 1.00, 95% CI 0.95–1.04) or ITT populations (3055 patients; RR = 0.97, 95% CI 0.94–1.01). Mortality (3614 patients; RR = 1.04, 95% CI 0.75–1.43) and treatment-related adverse events (2801 patients; RR = 0.97, 95% CI 0.70–1.33) were also similar. On subset analysis, moxifloxacin was slightly less effective than BLs in the CE (1934 patients; RR = 0.96, 95% CI 0.93–0.99) and ITT populations (1743 patients; RR = 0.94, 95% CI 0.91–0.98). Although FQ- and BL-based regimens appear equally effective and safe for the treatment of cIAIs, limited data suggest slightly inferior results with moxifloxacin. Selection of empirical coverage should be based on local bacterial epidemiology and patterns of resistance as well as antimicrobial stewardship protocols.     

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation

Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrails.gov identifier: NCT00326287].     

Comparison of hospitalization rates in patients with community-acquired pneumonia treated with telithromycin for 5 or 7 days or clarithromycin for 10 days

SUMMARY

Aims: To compare the impact on hospitalization rates and the clinical efficacy of oral telithromycin and clarithromycin treatment in patients with community-acquired pneumonia (CAP).

Methods: A total of 581 patients with CAP were enrolled in this randomized, double-blind, parallel-group, multinational study, of whom 575 were evaluated for healthcare resource utilization from a payer perspective (intent to treat [ITT] population). Patients received telithromycin 800?mg once daily for 5 (n?=?193) or 7 (n?=?195) days, or clarithromycin 500?mg once daily for 10days (n?=?187). The primary efficacy endpoint was clinical outcome at test of cure (Days 17–24) in the per-protocol population. Frequency of CAP-related hospitalizations, physician visits/tests/procedures, and additional respiratory tract infection-related antibacterial use were compared by treatment group (ITT) up to late post-therapy (Days 31-36). Study investigators blinded to treatment assessed whether hospital admissions were CAP-related or not. CAP-related

hospitalization costs (US$) for telithromycin and clarithromycin were compared.

Results: Clinical cure rates were similar in patients who received clarithromycin for 10days and telithromycin for 5 or 7 days: 91.8% (134/146), 89.3% (142/159), and 88.8% (143/161), respectively, and both 5- and 7-day telithromycin were statistically equivalent to clarithromycin (difference: ?2.5 and ?3.0%, respectively; 95% CI: ?9.7, 4.7 and ?10.2, 4.3, respectively). There were 7 CAP-related hospital admissions among clarithromycin patients vs 3 (p?=?0.283) and 1 (p?=?0.021) admissions among 5- and 7-day telithromycin patients, respectively. The number of hospital days/100 patients was 40.1 for clarithromycin vs 17.1 and 7.2 for 5- and 7-day telithromycin, respectively. Projected hospitalization costs/100 patients were $86205 for clarithromycin vs $37930 (difference: ?26446; 95% CI: ?66654; 13762) and $16 091 (difference: ?37847; 95% CI: ?77953; 2259) for 5- and 7-day telithromycin, respectively.

Conclusions: Data from this study demonstrate that telithromycin 800?mg once daily for 5 or 7 days is an effective treatment for CAP, and that telithromycin treatment of CAP may be associated with fewer hospital days and potentially lower hospitalization costs than clarithromycin treatment.     

A cost-minimisation analysis comparing moxifloxacin with levofloxacin plus ceftriaxone for the treatment of patients with community-acquired pneumonia in Germany: results from the MOTIV trial

ABSTRACT

Objective: This study presents a cost-minimisation analysis of moxifloxacin compared to combination treatment with levofloxacin and ceftriaxone in patients hospitalised with community-acquired pneumonia (CAP) in Germany.

Research design and methods: In the MOTIV study, 738 adult patients with CAP requiring hospitalisation and initial parenteral antibiotic therapy were randomised to sequential IV/oral therapy with either moxifloxacin (n?=?368), or levofloxacin and ceftriaxone (n?=?365). The primary effectiveness endpoint was the proportion of patients demonstrating clinical improvement 5–7 days after the completion of study treatment. Subgroup analysis considered patients with severe CAP according to pneumonia severity index (PSI) risk class IV and V, microbiologically proven infection, a history of chronic obstructive pulmonary disease, and a history of cardiovascular disease. The analysis included the cost of study medication, hospital stay, readmission and inpatient procedures and diagnostics. Event frequency in the study was multiplied by German unit costs to estimate per-patient expenditure. The analysis was conducted from a hospital perspective. Sensitivity analysis investigated the effect of costing from an insurer perspective.

Results: No significant difference was found in the percentage of successfully treated patients. Average per patient cost was €2190 for the moxifloxacin group, and €2619 for the levofloxacin + ceftriaxone group (difference –€430, 95% CI: –€138, –€740; p?<?0.05). Variability in total costs was wide, with some patients accruing up to €18?000. Medication cost was significantly lower with moxifloxacin than levofloxacin + ceftriaxone (–€470, 95% CI: –€522, –€421), and accounted for between 15 and 30% of total costs.

Conclusions: In this analysis of patients hospitalised with CAP in Germany, treatment with moxifloxacin was significantly less costly than treatment with levofloxacin and ceftriaxone.     

Effectiveness and safety of direct oral anticoagulants in atrial fibrillation patients switched from vitamin K antagonists: A systematic review and meta‐analysis

A substantial proportion of atrial fibrillation patients initiating direct oral anticoagulants (DOAC) are vitamin K antagonists (VKA)‐experienced, for example switchers from VKA to DOAC. With this study, we aimed to summarize available evidence on the effectiveness and safety of DOAC vs VKA in real‐life VKA‐experienced atrial fibrillation patients. We searched EMBASE, MEDLINE and Cochrane Library systematically for English‐language studies indexed any time before October 2018. We included studies of VKA‐experienced atrial fibrillation patients initiating DOAC therapy, with continued VKA therapy as comparator. Outcomes included arterial thromboembolism and bleeding. When appropriate, meta‐analysis was performed by calculating pooled, weighted and adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Eight cohort studies comparing VKA‐experienced DOAC (dabigatran or rivaroxaban) users with continued VKA users were included. When comparing DOAC to VKA, an increased risk of ischaemic stroke and myocardial infarction was found for dabigatran (pooled aHR of 1.61 [95% CI 1.19‐2.19, I² = 65%] and 1.29 [95% CI 1.10‐1.52, I² = 0%], respectively), but not for rivaroxaban. The use of dabigatran in VKA‐experienced users was associated with an increased risk of gastrointestinal bleeding (pooled aHR 1.63 [95% CI 1.36‐1.94, I² = 30%]), but a decreased risk of intracranial bleeding (pooled aHR 0.45 [95% CI 0.32‐0.64, I² = 0%]). In conclusion, the use of dabigatran in prior VKA users in clinical practice was associated with a slightly increased risk of arterial thromboembolism and gastrointestinal bleeding, but a decreased risk of intracranial bleeding. Importantly, observational studies of real‐life VKA‐experienced oral anticoagulant users may be confounded by the reason for switching.     

Sorafenib versus cytotoxic chemotherapy for patients with advanced hepatocellular carcinoma: a retrospective,single-institution study

Background Prior to the 2008 advent of sorafenib, traditional cytotoxic agents were the therapeutic mainstay for patients with advanced hepatocellular carcinoma (HCC). We thus undertook a clinical study of sorafinib and conventional cytotoxic therapy for HCC, comparing efficacy and safety. Methods From January, 2002 to December, 2009, 173 patients with unresectable HCC were reviewed retrospectively. Among them, 44 (25.4%) had been treated with sorafenib, and the remainder had received cytotoxic therapy (CTX). We evaluated objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity profiles. Results Median OS of sorafinib was 23.0 weeks (95% CI, 8.1–37.9) vs 43.6 weeks (95% CI, 34.0–53.2) for CTX. Likewise, median PFS was 11.1 weeks (95% CI, 6.5–15.8) vs 12.4 weeks (95% CI, 8.1–16.7) for sorafenib and CTX, respectively. Neither parameter differed significantly (OS, p = 0.105; PFS, p = 0.496). ORR and disease control rate for sorafenib were 2.3% and 52.3% vs 6.2% and 43.4% for CTX. CTX-treated patients experienced more Grade 3/4 neutropenia (19.7% vs 0% for sorafenib), while sorafenib therapy was more often linked to dermatologic toxicities (all grades), such as hand-foot skin reaction, rash, and pruritus. Conclusion Although sorafenib has become the treatment of choice for advanced HCC, there are still unsettled issues regarding the optimal use of sorafenib. Our analysis indicates that conventional CTX can be another option of treatment for advanced HCC. To improve clinical outcomes, further prospective investigations which define the role of CTX are needed.     

Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomised controlled clinical trial

Assessment of efficacy of therapeutic plasma exchange (TPE) following life-threatening COVID-19. This was an open-label, randomised clinical trial of ICU patients with life-threatening COVID-19 (positive RT-qPCR plus ARDS, sepsis, organ failure, hyperinflammation). Study was terminated after 87/120 patients enrolled. Standard treatment plus TPE (n = 43) versus standard treatment (n = 44), and stratified by PaO₂/FiO₂ ratio (>150 vs. ≤150), were compared. Primary outcomes were 35-day mortality and TPE safety. Secondary outcomes were association between TPE and mortality, improvement in SOFA score, change in inflammatory biomarkers, days on mechanical ventilation (MV), and ICU length of stay (LOS). Eighty-seven patients [median age 49 (IQR 34–63) years; 82.8% male] were randomised (44 standard care; 43 standard care plus TPE). Days on MV (P = 0.007) and ICU LOS (P = 0.02) were lower in the TPE group. 35-Day mortality was non-significantly lower in the TPE group (20.9% vs. 34.1%; Kaplan-Meier, P = 0.582). TPE was associated with increased lymphocytes and ADAMTS-13 activity and decreased serum lactate, lactate dehydrogenase, ferritin, d-dimers and interleukin-6. Multivariable regression analysis provided several predictors of 35-day mortality: PaO₂/FiO₂ ratio (HR, 0.98, 95% CI 0.96–1.00; P = 0.02]; ADAMTS-13 activity (HR, 0.89, 95% CI 0.82–0.98; P = 0.01); pulmonary embolism (HR, 3.57, 95% CI 1.43–8.92; P = 0.007). Post-hoc analysis revealed a significant reduction in SOFA score for TPE patients (P < 0.05). In critically-ill COVID-19 patients, addition of TPE to standard ICU therapy was associated with faster clinical recovery and no increased 35-day mortality.     

HLA‐A*24:02 is associated with metronidazole‐induced cutaneous adverse drug reactions in Han Chinese individuals: A pilot case‐control study with both HLA gene and T cell receptor repertoire analysis

Metronidazole, a widely used drug for the treatment of infections with anaerobic and facultative anaerobic bacteria and protozoa, can frequently cause metronidazole‐induced cutaneous adverse reactions (McADRs). The aim of the present study was to investigate the association between human leucocyte antigen (HLA) alleles and McADRs in a Chinese Han population. The frequency of HLA‐B*24:02 carriers among the McADR patients was 73.3%, which was significantly higher than that of the population controls (32.16%, OR = 5.80, 95% CI = [1.80‐18.72], Pc = 0.004) and of the metronidazole‐tolerant patients (26.67%, OR = 7.56, 95% CI = [2.02‐28.35], Pc = 0.004). Molecular docking showed that metronidazole and one of its major metabolites had the potential to bind in the HLA groove and that there was a relatively stable binding state of the HLA‐B*24:02‐metronidazole/the metabolite complex. The CDR3 repertoires of both T cell receptor (TCR)Vα and Vβ of the patients showed a significantly skewed or an oligoclonal distribution. The TCRVβ CDR3 of the patients shared a similar motif, “CASSxxxxxxQxF.” The current study demonstrated that both the HLA‐A*24:02 allele and TCR are involved in the pathogenesis of McADRs.     

β-lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis

BackgroundCombining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice.ObjectiveTo determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy.MethodsA systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity.ResultsFour randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63–1.08, P = 0.10, I² 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64–0.99, P = 0.04, I² 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83–2.09, P = 0.40, I² 0%).ConclusionsThe existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.     

Determination of tranexamic acid in cosmetic products by high-performance liquid chromatography coupled with barrel plating nickel electrode

Tranexamic acid (TA) is an important reagent in cosmetic skin-whitening formulation and a drug for the inhibition of plasminogen to plasmin in blood. Since there is no chromophore in tranexamic acid molecule to enable direct analysis by UV–visible absorption spectrophotometry, derivatization is thus required by excluding use of UV or fluorescence detection. We report here a relatively simple electrochemical TA detection method by using a barrel plating nickel electrode. Chromatographic separation was performed on a Hamilton PRP-X100 anion-exchange column (150 mm × 4.1 mm i.d., 10 μm particle size) with a (85:15, v/v) mixture of 0.1 mol l⁻¹ NaOH and acetonitrile as mobile phase and pumped at a flow rate of 0.9 ml min⁻¹. By detecting at +0.55 V vs. Ag/AgCl, the calibration plot was linear in the concentration window of 3–1000 ppm with regression coefficient and detection limit (S/N = 3) of 0.9993 and 0.13 ppm (0.84 μmol l⁻¹), respectively. Successive injections (n = 10) of 50 ppm tranexamic acid showed a R.S.D. value of only 0.3% indicating good reproducibility of the proposed system. The method was successfully applied to the analysis of the content of tranexamic acid in cosmetic products and proved to be suitable for rapid and reliable quality control.     

Cadmium level in seminal plasma may affect the pregnancy rate for patients undergoing infertility evaluation and treatment

This study evaluated the relationship between pregnancy rate and semen cadmium concentration. This prospective and nonrandomized clinical study analyzed 341 male partners of infertile couples undergoing infertility evaluation and management. Semen samples were collected to analyze semen quality and cadmium concentrations. The main outcome was pregnancy during 60-day infertility treatment. Simple linear regression analysis revealed an association between semen cadmium concentration NS sperm count (r = −0.150, P = 0.0416) in nonsmoking subjects (n = 184). In both smokers and nonsmokers, semen cadmium concentrations were significantly higher in non-pregnant patients than in pregnant patients. In nonsmokers, Cox multi-variable fertility ratio analysis demonstrated an association between semen cadmium concentration and fertility (fertility ratio of log semen cadmium = 0.24; 95% confidence intervals (CI) = 0.12–0.47, P < 0.0001) after adjusting for related variables. Each tenfold increase in semen cadmium concentration was associated with a 4.17-fold increase in infertility ratio in nonsmoking patients. In smokers, Cox multi-variable fertility ratio analysis demonstrated that sperm count and semen cadmium concentration are associated with fertility (fertility ratio of log semen cadmium = 0.17; 95% CI = 0.04–0.63, P = 0.0085) after adjusting for related variables. In smokers, each tenfold increase in semen cadmium concentration was associated with a 5.88-fold increase in infertility ratio. In conclusion, low levels of cadmium accumulation in semen may contribute to male infertility by reducing sperm quality.     

Measurement of Adult Antimicrobial Drug Use in Tertiary Care Hospital Using Defined Daily Dose and Days of Therapy

Widespread overuse and inappropriate use of antimicrobial drugs continues to fuel an increase in antimicrobial resistance and leads to consequent treatment complications and increased healthcare costs. In the present study we aimed to describe antimicrobial drug consumption and predictors and to identify potential targets for antimicrobial stewardship. This was a prospective observational study conducted at adult medicine wards of tertiary care teaching hospital over the period of five months. Antimicrobial drug consumption was measured using days of therapy per 1000 patient days and defined daily dose per 1000 patient days. Additionally, predictors of multiple antimicrobial prescribing were also analyzed. Seven hundred thirty patients were screened and 550 enrolled, receiving 1,512 courses of antimicrobial therapy, mainly intravenously (66%). Most frequently prescribed agents were artesunate (13%), ceftriaxone (11%) and metronidazole (10.5%). Overall consumption was 1,533 days of therapy per 1000 patient days and was mainly attributed to antibiotics (98.3%) for empirical therapy (50%). Median days of antimicrobial drugs prescribing were 3 (inter quartile range 2-5). Most commonly consumed antimicrobials were ceftriaxone (31%, 248.8 g) and artesunate (26%, 29 g). Antimicrobials contributed to 72.5% expense of the total incurred. Multivariate analysis reveals that younger patients (≥45 years) (odds ratio: 1.59, 95% CI 1.14-2.21) were more likely and absence of comorbidities (odds ratio: 0.58, 95% CI 0.42-0.79) and shorter hospital stay (≥6 days)(odds ratio: 0.44, 95% CI 0.32-0.60) were associated with less likelihood of prescribing multiple antimicrobial drugs. Estimating antimicrobial drugs use by defined daily dose method will remain open to criticism because the prescribed dosage is not often in agreement with the “usual” daily dose, which depends on location of and susceptibility of pathogenic organisms and metabolic status of the patient.     

Randomised clinical trial: a comparative study of 10-day sequential therapy with 7-day standard triple therapy for Helicobacter pylori infection in naïve patients

Aliment Pharmacol Ther 2012; 35: 56–65

Summary

Background The eradication rates following standard triple therapy for Helicobacter pylori infection are declining worldwide. Recent studies have shown that sequential therapy for H. pylori infection yields high cure rates. Aim To compare the efficacy and tolerability of a sequential regimen as first‐line treatment of H. pylori infection with a standard triple regimen. Methods A total of 348 naïve H. pylori‐infected patients from six hospitals in Korea were assigned randomly to standard triple or sequential therapy groups. Standard triple therapy consisted of 20 mg of rabeprazole, 1 g of amoxicillin and 500 mg of clarithromycin, twice daily for 7 days. Sequential therapy consisted of a 5‐day dual therapy (20 mg of rabeprazole and 1 g of amoxicillin, twice daily) followed by a 5‐day triple therapy (20 mg of rabeprazole, 500 mg of clarithromycin, and 500 mg of metronidazole, twice daily). Results The intention‐to‐treat (ITT) and per‐protocol (PP) eradication rates were 62.2% (95% CI 54.8–69.6%) and 76.0% (95% CI 68.5–83.5%) in the standard triple group, and 77.8% (95% CI 71.4–84.2%) and 87.9% (95% CI 82.3–93.5%) in the sequential group, respectively. The eradication rate was significantly higher in the sequential group compared with the standard triple group in both the ITT and PP populations (P = 0.002 and P = 0.013 respectively), whereas the incidence of adverse events was similar. Conclusions Ten‐day sequential therapy is more effective and equally tolerated for eradication of H. pylori infection compared with standard triple therapy. Sequential therapy may have a role as first‐line treatment for H. pylori infection.     

Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients

It is unclear whether the effectiveness of polymyxins depends on the site of infection, the responsible pathogen, dosage, and monotherapy vs. combination therapy. We investigated colistin therapy in a large, retrospective, single-centre, cohort study. Primary analysis outcomes were infection outcome, survival and nephrotoxicity. Over a 7-year period (October 2000 to October 2007), 258 patients received intravenous (i.v.) colistin for at least 72 h for microbiologically documented multidrug-resistant Gram-negative bacterial infections, comprising 170 (65.9%) Acinetobacter baumannii, 68 (26.4%) Pseudomonas aeruginosa, 18 (7.0%) Klebsiella pneumoniae, 1 (0.4%) Stenotrophomonas maltophilia and 1 (0.4%) Enterobacter cloacae. Cure of infection occurred in 79.1% of patients, nephrotoxicity in 10% and hospital survival in 65.1%. In the multivariate analysis, independent predictors of survival were colistin average daily dose [adjusted odds ratio (aOR) = 1.22, 95% confidence interval (CI) 1.05–1.42] and cure of infection (aOR = 9, 95% CI 3.6–23.1), whilst the proportion of creatinine change (aOR = 0.21, 95% CI 0.1–0.45), Acute Physiology and Chronic Health Evaluation (APACHE) II score (aOR = 0.89, 95% CI 0.84–0.95) and haematological disease (aOR = 0.23, 95% CI 0.08–0.66) were associated with mortality. Effectiveness of colistin was not dependent on the type of pathogen. No independent predictors for nephrotoxicity were observed. The findings of the largest cohort study to date on i.v. colistin show that colistin is a valuable antibiotic with acceptable nephrotoxicity and considerable effectiveness that depends on the daily dosage and infection site.     

Triple nucleoside treatment with abacavir plus the lamivudine/ zidovudine combination tablet (COM) compared to indinavir/COM in antiretroviral therapy-naïve adults: results of a 48-week open-label,equivalence trial (CNA3014)

SUMMARY

Objective: An equivalence (non-inferiority) trial comparing antiviral response, tolerability, and adherence with a triple nucleoside regimen containing abacavir 300?mg (ABC) plus a lamivudine 150-mg/zidovudine 300-mg combination tablet (COM) twice daily vs. a regimen containing the protease inhibitor indinavir (IDV) 800?mg three times daily plus COM twice daily (IDV/COM) in antiretroviral-naïve, HIV-infected patients.

Methods: Adult patients with plasma HIV-1 RNA levels ≥ 5000?copies/mL and CD4+ cell counts ≥ 100?cells/mm³ were randomized to receive open-label ABC/COM (n = 169) or IDV/COM (n = 173) for 48?weeks. The intent-to-treat (ITT) population was the primary population evaluated. ITT: switch/missing equals failure (ITT: S/M = F) and as-treated (AT) analyses were used for assessing the proportion of patients achieving plasma HIV-1 RNA level < 400 and < 50?copies/mL at each clinic visit. In the ITT: S/M = F analysis, patients who switched treatment or had missing values were considered treatment failures; the AT analysis examined virologic data only while patients received study treatment. ABC/COM was considered equivalent (non-inferior) to IDV/COM if the lower limit of the 95% confidence intervals (CIs) about the difference in proportions of ABC/COM- vs. IDV/COM-treated patients attaining plasma HIV-1 RNA < 400?copies/mL exceeded –15% at week 48.

Results: The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80?log₁₀?copies/mL and CD4+ cell count was 315?cells/mm³. ABC/COM met the criterion of equivalence to IDV/COM. In the ITT: S/M = F analysis at Week 48, a greater proportion of ABC/COM-treated patients achieved HIV-1 RNA < 400?copies/mL (66% [109/164] vs. 50% [82/165]; treatment difference 16.6%, 95% CI (6.0, 27.2), p = 0.002) and HIV-1 RNA < 50?copies/mL (60% [99/164] vs. 50% [83/165]; treatment difference 9.6%, 95% CI [–1.1, 20.2]), whereas the AT analysis showed similar proportions achieving these endpoints (< 400?copies/mL: 85 vs. 83%; < 50?copies/mL: 79 vs 81%). Comparable proportions of patients with screening HIV-1 RNA values > 100?000?copies/mL achieved HIV-1 RNA < 400?copies/mL (ABC/COM: 60% [35/58]; IDV/COM: 51% [33/65]; treatment difference 9.6%, 95% CI [–7.9, 27.1]; ITT: S/M = F analysis). A significantly greater proportion taking ABC/COM were ≥ 95% adherent (72% [109/151] vs. 45% [70/154] with IDV/COM, p < 0.001). Median increases from baseline in CD4+ cell counts were similar in the two treatment groups (+148 vs. +152?cells/mm³). Significantly more patients on IDV/COM reported drug-related adverse events (87% [142/165] vs. 65% [108/164] with ABC/COM, p < 0.001), similar proportions discontinued treatment due to adverse events (13 vs. 10%), and a slightly greater proportion in the ABC/COM group reported serious adverse events (13 vs. 8%). About half of the latter comprised suspected ABC-related hypersensitivity reactions (overall rate, 6%). Most adverse events were gastrointestinal in nature in both treatment groups.

Conclusion: ABC/COM was at least equivalent to IDV/COM over 48?weeks in the treatment of antiretroviral-naïve patients. ABC/COM was associated with a significantly higher adherence rate and lower incidence of drug-related adverse events than IDV/COM. The study was limited in that it was not powered to determine equivalence of treatments within high vs. low viral load strata, adherence was not monitored electronically, and bias could not be ruled out due to the open-label study design.     

Ertapenem monotherapy versus combination therapy with ceftriaxone plus metronidazole for treatment of complicated intra-abdominal infections in adults

The efficacy and safety of intravenous (IV) ertapenem, 1 and 1.5 g once a day, for treatment of adults with complicated intra-abdominal infection were compared with those of IV ceftriaxone 2 g once a day plus IV metronidazole 500 mg every 8 h. After at least 3 days of IV therapy and satisfactory clinical response, patients could be switched to oral ciprofloxacin plus metronidazole. Fifty-nine patients were randomized to receive ertapenem 1 g and 51 to receive ertapenem 1.5 g; 55 patients were randomized to each comparator group. At the test of cure, 4-6 weeks post therapy, in the 1 g cohort, 84% (26/31) of patients treated with ertapenem and 85% (35/41) with comparator therapy had a favourable clinical and microbiological assessment. Success rates in the 1.5 g cohort were 83% (22/29) and 77% (24/31) in the ertapenem and comparator groups, respectively. Drug-related adverse events were generally similar in both treatment groups. Ertapenem 1 or 1.5 g once a day followed by optional oral therapy appeared similar to combined therapy with ceftriaxone plus metronidazole with the same optional oral switch for treatment of complicated intra-abdominal infections in adults. Although not compared directly in a randomized fashion, the efficacy and safety profiles of ertapenem 1 and 1.5 g appeared comparable. Ertapenem was generally well tolerated and had an overall safety profile similar to ceftriaxone plus metronidazole.     

A randomised,cross-over study comparing injection site pain with subcutaneous epoetin beta and subcutaneous darbepoetin alfa in patients with chronic kidney disease*

ABSTRACT

Objective: To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease.

Research design and methods: This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30?μg or weekly sc epoetin beta 6000?IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10?cm ungraduated visual analogue scale (0?=?no pain, 10?=?worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed.

Trial registration: http://clinicaltrials.gov/(NCT00377481).

Results: All randomised patients (N?=?48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score?=?2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p?<?0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p?<?0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p?<?0.001); 25% of patients reported no preference.

Conclusions: Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful.     

Ertapenem: a review of its use in the treatment of bacterial infections

The Group 1, 1 beta-methyl carbapenem ertapenem (Invanz) is approved for parenteral use in patients with complicated intra-abdominal infection (cIAI), community-acquired pneumonia (CAP) and acute pelvic infection caused by susceptible strains of certain designated organisms in both the US and the EU. Additional approved indications in the US include complicated skin and skin structure infection (cSSSI) and complicated urinary tract infection (cUTI). Ertapenem is approved for use in adults in both the US and the EU and in paediatric patients aged >or=3 months in the US.Ertapenem has a broad spectrum of in vitro activity against Gram-negative pathogens, including extended-spectrum beta-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae, Gram-positive pathogens and anaerobic pathogens. It has similar efficacy to comparator antibacterials such as piperacillin/tazobactam in cSSSI (including diabetic foot infection), cIAI and acute pelvic infection and ceftriaxone with or without metronidazole in cIAI, cUTI and CAP. The drug has also shown efficacy in the treatment of paediatric patients with complicated community-acquired bacterial infections. Ertapenem has a convenient once-daily administration schedule and is generally well tolerated. Thus, ertapenem is an important option for the empirical treatment of complicated community-acquired bacterial infections in hospitalised patients.     

Risk for Delirium Tremens in Patients with Alcohol Withdrawal Syndrome

To determine the characteristics associated with an increased risk for delirium tremens (DT) we performed a case-control study at the detoxification units of two hospitals. Cases met DSM-IV criteria for DT. For each case (n = 15), 3 controls (n = 45) were chosen. Eligibility criteria were applied equally to cases and controls. Cases were more likely than controls to report a prior complicated withdrawal (DT or alcohol withdrawal seizure) (53 vs. 27%, OR 3.1, 95% CI 0.94–10.55), have a systolic blood pressure greater than 145 mm Hg on admission (60 vs. 27%, OR 4.1, 95% CI 1.21–14.06), and have comorbidity scores of at least 1 (60 vs. 18%, OR 6.9, 95% CI 1.92–25.08). Zero cases (0%) and 15 (33%) controls had no prior complicated withdrawals and no adverse clinical features (systolic blood pressure >145 or comorbidity score >1). Compared to this group, the odds of being a case and having both prior complicated withdrawal and at least 1 adverse clinical feature was 44.8 (95% CI 4.36–460). Elevated blood pressure, prior complicated alcohol withdrawal and medical comorbidity, alone and in combination, are associated with an increased risk of delirium tremens.     

Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis

Aliment Pharmacol Ther 2012; 35: 66–75

Summary

Background Thiazolidinediones (TZDs) have been used in the treatment of non‐alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically. Aim To conduct a meta‐analysis of randomised, placebo‐controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH. Methods Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters. Results Four good quality RPCTs derived from three continents were included. The meta‐analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33–3.36), 2.58 (95% CI, 1.68–3.97) and 3.39 (95% CI, 2.19–5.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03–14.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.02–2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment. Conclusions Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo‐controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis.