Empirical Monotherapy Research Articles

World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a serious public health problem, compromising the management and control of gonorrhoea globally. Resistance in N. gonorrhoeae to ceftriaxone, the last option for first-line empirical monotherapy of gonorrhoea, has been reported from many countries globally, and sporadic failures to cure especially pharyngeal gonorrhoea with ceftriaxone monotherapy and dual antimicrobial therapies (ceftriaxone plus azithromycin or doxycycline) have been confirmed in several countries. In 2018, the first gonococcal isolates with ceftriaxone resistance plus high-level azithromycin resistance were identified in England and Australia. The World Health Organization (WHO) Global Gonococcal Antimicrobial Surveillance Program (GASP) is essential to monitor AMR trends, identify emerging AMR and provide evidence for refinements of treatment guidelines and public health policy globally. Herein we describe the WHO GASP data from 67 countries in 2015-16, confirmed gonorrhoea treatment failures with ceftriaxone with or without azithromycin or doxycycline, and international collaborative actions and research efforts essential for the effective management and control of gonorrhoea. In most countries, resistance to ciprofloxacin is exceedingly high, azithromycin resistance is present and decreased susceptibility or resistance to ceftriaxone has emerged. Enhanced global collaborative actions are crucial for the control of gonorrhoea, including improved prevention, early diagnosis, treatment of index patient and partner (including test-of-cure), improved and expanded AMR surveillance (including surveillance of antimicrobial use and treatment failures), increased knowledge of correct antimicrobial use and the pharmacokinetics and pharmacodynamics of antimicrobials and effective drug regulations and prescription policies (including antimicrobial stewardship). Ultimately, rapid, accurate and affordable point-of-care diagnostic tests (ideally also predicting AMR and/or susceptibility), new therapeutic antimicrobials and, the only sustainable solution, gonococcal vaccine(s) are imperative.

1881. Empiric Pseudomonal Monotherapy vs. Combination Therapy for Community-Onset Pneumonia in Older Adults

BackgroundPatients with pseudomonal pneumonia have a poor prognosis; therefore, IDSA guidelines recommend empiric antipseudomonal combination therapy when Pseudomonas is suspected, at least until treatment can be adjusted based on susceptibilities. However, combination antipseudomonal therapy is controversial. This study compared all-cause 30-day mortality in older patients who received antipseudomonal monotherapy (PMT) or antipseudomonal combination therapy (PCT) for the treatment of community-onset pneumonia.MethodsThis population-based cohort study used data from over 150 Veteran Health Administration hospitals. Patients were classified as low, medium, or high risk of drug-resistant pathogens according to a published rule. Patients were assigned to PCT or PMT groups based on antibiotics received in the first 48 hours of hospital admission. Separate multivariable logistic regression models were constructed to determine whether the choice of PCT or PMT was associated with 30-day mortality, after accounting for divergent baseline characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) were calculated for the overall, low, medium, and high-risk groups.ResultsOf the 31,027 patients who met study criteria, 23% received PCT and 77% received PMT. Patients belonged to low (59%), medium (24%), and high (18%) risk groups. 30-day mortality was 18% overall, and increased among the groups: low (13%), medium (21%), and high (36%). Patient age (median of 78 years), race (>80% white), and sex (>98% male) were similar for patients receiving PCT and PMT. The unadjusted mortality difference between PCT and PMT was most pronounced in the low-risk group (18% vs. 8%, 10% absolute risk difference), followed by the medium (24% vs. 18%, 6% difference) and high (39% vs. 33%, 6% difference) risk groups. PCT was associated with higher 30-day mortality than PMT overall (aOR, 1.54; 95% CI, 1.43–1.66), and in all three groups: low (aOR, 1.69; 95% CI, 1.50–1.89), medium (aOR, 1.30; 95% CI, 1.14–1.48), and high (aOR, 1.21; 95% CI, 1.04–1.40).ConclusionOlder adults who received empiric combination antipseudomonal therapy for community-onset pneumonia fared worse than those who received monotherapy. Empiric combination antipseudomonal therapy should not be routinely offered to all patients suspected of having pseudomonal pneumonia.Disclosures All authors: No reported disclosures.

Assessment of Initial Febrile Neutropenia Management in Hospitalized Cancer Patients at a Community Cancer Center

Fever may be the only sign of an underlying infection in neutropenic cancer patients. Unrecognized fever and untreated infections can lead to progressive sepsis and possibly death. The importance of early recognition, timely antibiotics, and treatment is crucial to favorable outcomes. The primary objective of this study was to evaluate the treatment of adult cancer patients with febrile neutropenia for compliance with National Comprehensive Cancer Network (NCCN) febrile neutropenia guidelines at our institution, UCHealth Memorial Hospital. Secondary objectives were to examine antibiotic selection, culture results, time to antibiotics, all-cause mortality, and length of hospital stay. This was a single-center, retrospective chart review of hospitalized neutropenic patients undergoing active chemotherapy. Neutropenia and fever were defined based on NCCN Guidelines. A total of 223 neutropenic patients were hospitalized between October 15, 2015, and December 31, 2016. Overall, 16 patients met the inclusion criteria for chemotherapy-induced neutropenia with fever. Compliance with the NCCN guideline standards was seen in seven (43.8%) patients. Antibiotics administered within 60 minutes of presentation was the lowest standard with adherence in eight (50%) patients. Empiric monotherapy antibiotic regimens were initiated in 11 (68.8%) patients; eight (50%) received cefepime and three (18.8%) received meropenem. At our institution, full compliance with the NCCN febrile neutropenia guidelines is not optimal. This study demonstrates the need for process improvement initiatives, including the addition of an electronic health record alert to flag patients undergoing active chemotherapy. It also warrants promoting the use of our institution's emergency department febrile neutropenia treatment pathway to providers to improve overall compliance.

Benzylpenicillin versus wide-spectrum beta-lactam antibiotics as empirical treatment of Haemophilus influenzae-associated lower respiratory tract infections in adults; a retrospective propensity score-matched study

There is consensus that definitive therapy for infections with H. influenzae should include antimicrobial agents with clinical breakpoints against the bacterium. In Scandinavia, benzylpenicillin is the recommended empirical treatment for community-acquired pneumonia (CAP) except in very severe cases. However, the effect of benzylpenicillin on H. influenzae infections has been debated. The aim of this study was to compare the outcomes of patients given benzylpenicillin with patients given wide-spectrum beta-lactams (WSBL) as empirical treatment of lower respiratory tract H. influenzae infections requiring hospital care. We identified 481 adults hospitalized with lower respiratory tract infection by H. influenzae, bacteremic and non-bacteremic. Overall, 30-day mortality was 9% (42/481). Thirty-day mortality, 30-day readmission rates, and early clinical response rates were compared in patients receiving benzylpenicillin (n = 199) and a WSBL (n = 213) as empirical monotherapy. After adjusting for potential confounders, empirical benzylpenicillin treatment was not associated with higher 30-day mortality neither in a multivariate logistic regression (aOR 2.03 for WSBL compared to benzylpenicillin, 95% CI 0.91–4.50, p = 0.082), nor in a propensity score-matched analysis (aOR 2.14, 95% CI 0.93–4.92, p = 0.075). Readmission rates did not significantly differ between the study groups, but early clinical response rates were significantly higher in the WSBL group (aOR 2.28, 95% CI 1.21–4.31, p = 0.011), albeit still high in both groups (84 vs 81%). In conclusion, despite early clinical response rates being slightly lower for benzylpenicillin compared to WSBL, we found no support for increased mortality or readmission rates in patients empirically treated with benzylpenicillin for lower respiratory tract infections by H. influenzae.

Efficacy of sulbactam-cefoperazone as empirical monotherapy for febrile neutropenic children wıth solid tumors and lymphoma.

e22516Background: Febrile neutropenia (FEN) is one of the major causes of morbidity and mortality in patients with cancer. The clinical effectiveness of sulbactam-cefoperazone (SC) was demonstrated...

Management of fever and neutropenia in children with cancer: A survey of Australian and New Zealand practice.

Variation in the management of fever and neutropenia (FN) in children is well described. The aim of this study was to explore the current management of FN across Australia and New Zealand and highlight areas for improvement. A practice survey was administered to paediatric health-care providers via four clinical and research networks. Using three clinical case vignettes, we explored risk stratification, empiric antibiotics, initial investigations, intravenous-oral switch, ambulatory management and antibiotic duration in children with cancer and FN. A response was received from 104 participants from 16 different hospitals. FN guideline compliance was rated as moderate or poor by 24% of respondents, and seven different fever definitions were described. There was little variation in the selected empiric monotherapy and dual-therapy regimens, and almost all respondents recommended first-dose antibiotics within 1 h. However, 27 different empiric antibiotic combinations were selected for beta-lactam allergy. An incorrect risk status was assigned to the low-risk case by 27% of respondents and to the high-risk case by 41%. Compared to current practice, significantly more respondents would manage the low-risk case in the ambulatory setting provided adequate resources were in place (43 vs. 85%, P < 0.0001). There was variation in the use of empiric glycopeptides as well as use of aminoglycosides beyond 48 h. Although the antibiotics selected for empiric management of FN are appropriate and consistent, variation and inaccuracies exist in risk stratification, the selection of monotherapy over dual therapy, empiric antibiotics chosen for beta-lactam allergy, use of glycopeptides and duration of aminoglycosides.

Eggerthella lenta Bloodstream Infections Are Associated With Increased Mortality Following Empiric Piperacillin-Tazobactam (TZP) Monotherapy: A Population-based Cohort Study.

Eggerthella lenta is a anaerobic gram-positive bacilli associated with polymicrobial intraabdominal infections. Recently, E. lenta was recognized as an important cause of anaerobic bloodstream infections (BSIs) associated with high mortality. Eggerthella lenta has been reported to have high minimal inhibitory concentrations (MICs) to piperacillin-tazobactam (TZP), a broad-spectrum antibiotic with anaerobic coverage commonly used in multiple centers for empiric treatment of abdominal sepsis. We describe a retrospective population-based analysis of invasive E. lenta infections from 2009 through 2015. A logistic regression analysis for 30-day mortality risk factors was conducted. We identified 107 E. lenta infections, 95 (89%) were BSIs, 11 (10%) skin and soft tissue infections, and 1 intraabdominal abscess. Polymicrobial infections were found in 40%; 72% of isolates were from a gastrointestinal source, most commonly appendicitis (33%) of which two-thirds were perforated. TZP MIC50 and MIC90 for E. lenta isolates were 32 μg/mL and 64 μg/mL, respectively. The overall 30-day mortality for BSI was 23% and was independently associated with empiric TZP monotherapy (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.2-16; P = .02) and intensive care unit stay (OR, 6.2; 95% CI, 1.4-27.3; P = .01). Thirty-day mortality rates were significantly influenced by the use of different TZP MIC breakpoints. Our results demonstrate the increased recognition of E. lenta as an anaerobic opportunistic pathogen and highlight the need for improved empiric antimicrobial guidelines and TZP MIC breakpoints with better correlation to clinical outcomes to guide appropriate management of invasive E. lenta infections.

Antibiotic resistance and NG-MAST sequence types of Neisseria gonorrhoeae isolates in Poland compared to the world.

Gonorrhoea is one of the most common sexually transmitted infections and in 2012, the World Health Organization estimated about 78 million of new global urogenital cases among adults per year. The main concern during the latest decade has been the emergence and spread of multidrug-resistant strains of Neisseria gonorrhoeae. Resistance has emerged internationally to the extended-spectrum cephalosporins, ceftriaxone and cefixime, which are the last remaining options for empiric first-line monotherapy of gonorrhoea. In Poland, the levels of resistance to ciprofloxacin, benzylpenicillin and tetracycline are high, and the prevalence of azithromycin resistance has increased. However, no resistance to ceftriaxone has been identified. The currently spread multidrug-resistant strains frequently represent epidemic clones. The present paper reviews and describes the antimicrobial resistance and N. gonorrhoeae multiantigen sequence typing (NG-MAST) sequence types of N. gonorrhoeae strains spreading in Poland compared to the world.

Phenotypic and genotypic characteristics of ESBL and AmpC producing organisms associated with bacteraemia in Ho Chi Minh City, Vietnam

BackgroundBroad-spectrum antimicrobials are commonly used as empirical therapy for infections of presumed bacterial origin. Increasing resistance to these antimicrobial agents has prompted the need for alternative therapies and more effective surveillance. Better surveillance leads to more informed and improved delivery of therapeutic interventions, potentially leading to better treatment outcomes.MethodsWe screened 1017 Gram negative bacteria (excluding Pseudomonas spp. and Acinetobacter spp.) isolated between 2011 and 2013 from positive blood cultures for susceptibility against third generation cephalosporins, ESBL and/or AmpC production, and associated ESBL/AmpC genes, at the Hospital for Tropical Diseases in Ho Chi Minh City.ResultsPhenotypic screening found that 304/1017 (30%) organisms were resistance to third generation cephalosporins; 172/1017 (16.9%) of isolates exhibited ESBL activity, 6.2% (63/1017) had AmpC activity, and 0.5% (5/1017) had both ESBL and AmpC activity. E. coli and Aeromonas spp. were the most common organisms associated with ESBL and AmpC phenotypes, respectively. Nearly half of the AmpC producers harboured an ESBL gene. There was no significant difference (p > 0.05) between the antimicrobial resistance phenotypes of the organisms associated with community and hospital-acquired infections.ConclusionAmpC and ESBL producing organisms were commonly associated with bloodstream infections in this setting, with antimicrobial resistant organisms being equally distributed between infections originating from the community and healthcare settings. Aeromonas spp., which was associated with bloodstream infections in cirrhotic/hepatitis patients, were the most abundant AmpC producing organism. We conclude that empirical monotherapy with third generation cephalosporins may not be optimum in this setting.

Influence of empirical double-active combination antimicrobial therapy compared with active monotherapy on mortality in patients with septic shock: a propensity score-adjusted and matched analysis.

To evaluate the influence on mortality of empirical double-active combination antimicrobial therapy (DACT) compared with active monotherapy (AM) in septic shock patients. A retrospective study was performed of monomicrobial septic shock patients admitted to a university centre during 2010-15. A propensity score (PS) was calculated using a logistic regression model taking the assigned therapy as the dependent variable, and used as a covariate in multivariate analysis predicting 7, 15 and 30 day mortality and for matching patients who received DACT or AM. Multivariate models comprising the assigned therapy group and the PS were built for specific patient subgroups. Five-hundred and seventy-six patients with monomicrobial septic shock who received active empirical antimicrobial therapy were included. Of these, 340 received AM and 236 DACT. No difference in 7, 15 and 30 day all-cause mortality was found between groups either in the PS-adjusted multivariate logistic regression analysis or in the PS-matched cohorts. However, in patients with neutropenia, DACT was independently associated with a better outcome at 15 (OR 0.29, 95% CI 0.09-0.92) and 30 (OR 0.25, 95% CI 0.08-0.79) days, while in patients with Pseudomonas aeruginosa infection DACT was associated with lower 7 (OR 0.12, 95% CI 0.02-0.7) and 30 day (OR 0.26, 95% CI 0.08-0.92) mortality. All-cause mortality at 7, 15 and 30 days was similar in patients with monomicrobial septic shock receiving empirical double-active combination therapy and active monotherapy. However, a beneficial influence of empirical double-active combination on mortality in patients with neutropenia and those with P. aeruginosa infection is worthy of further study.

In Vitro Activity of Sitafloxacin and Additional Newer Generation Fluoroquinolones Against Ciprofloxacin-Resistant Neisseria gonorrhoeae Isolates.

Emergence of antimicrobial resistance in Neisseria gonorrhoeae is a major public health concern globally, and new antimicrobials for treatment of gonorrhea are imperative. In this study, the in vitro activity of sitafloxacin, a fluoroquinolone mainly used for respiratory tract or urogenital infections in Japan, and additional newer generation fluoroquinolones were determined against ciprofloxacin-resistant N. gonorrhoeae isolates. Minimum inhibitory concentrations (MICs) of ciprofloxacin, levofloxacin, moxifloxacin, sitafloxacin, pazufloxacin, and tosufloxacin against 47 N. gonorrhoeae isolates cultured in 2009 in Japan were determined by agar dilution method. The quinolone resistance-determining region (QRDR) of gyrA and parC was sequenced. The in vitro potency of sitafloxacin was substantially higher compared with all other tested fluoroquinolones. The MICs of sitafloxacin ranged from 0.03 to 0.5 mg/L for 35 ciprofloxacin-resistant N. gonorrhoeae isolates (ciprofloxacin MICs from 2 to 32 mg/L). No identified mutations in GyrA and ParC QRDR resulted in higher sitafloxacin MIC than 0.5 mg/L. Sitafloxacin had a high activity against N. gonorrhoeae isolates, including strains with mutations in DNA gyrase and topoisomerase IV, resulting in high-level resistance to ciprofloxacin and all other newer generation fluoroquinolones examined. However, it was still to a lower extent affected by GyrA and ParC QRDR mutations resulting in sitafloxacin MICs of up to 0.5 mg/L. This indicates that sitafloxacin should not be considered for empirical first-line monotherapy of gonorrhea. However, sitafloxacin could be valuable in a dual antimicrobial therapy and for cases with ceftriaxone resistance or allergy.

Impact of initial empirical antifungal agents on the outcome of critically ill patients with invasive candidiasis: analysis of the China-SCAN study

The effect of different empirical antifungal agents on the clinical outcome of critically ill patients with invasive candidiasis (IC) has not been fully elucidated. In this study, 136 patients with proven IC who received empirical therapy in the China-SCAN multicentre study were retrospectively analysed. Initial empirical antifungal monotherapy consisted of a triazole [fluconazole (n = 61), voriconazole (n = 20) or itraconazole (n = 12)] or an echinocandin (n = 43). Hospital mortality as the primary outcome and global responses (clinical and microbiological) were assessed. The results indicated that rates of hospital mortality (P = 0.006) and intensive care unit (ICU) mortality (P = 0.011) were significantly lower in patients treated with an echinocandin compared with those receiving fluconazole, voriconazole or itraconazole. Multivariate regression analysis indicated that the type of antifungal agent used in empirical therapy was an independent predictor of hospital mortality (P = 0.033). Initial empirical echinocandin treatment was associated with decreased hospital mortality compared with fluconazole [odds ratio (OR) = 0.22, 95% confidence interval (CI) 0.06–0.85; P = 0.028], voriconazole (OR = 0.11, 95% CI 0.02–0.56; P = 0.008) or itraconazole (OR = 0.12, 95% CI 0.02–0.72; P = 0.020). Similar findings were observed for the clinical success endpoint. This study demonstrated that the initial empirical antifungal agent was an independent predictor of hospital mortality in critically ill patients with IC. Empirical therapy with an echinocandin was associated with decreased hospital mortality and greater clinical success than empirical therapy with fluconazole, voriconazole or itraconazole.

Clinical Pharmacology of Ceftazidime in Neonates: Effects and Pharmacokinetics

Ceftazidime is a valuable third-generation bactericidal cephalosporin. Ceftazidime inhibits the biosynthesis of bacterial cell peptidoglycan, causing inhibition of bacterial growth or cell lyses and death. Common nosocomial gram-negative organisms susceptible to ceftazidime include Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, and Providencia stuartii. Good activity remains against other gram-negative species including Salmonella, Shigella, and Neisseria species. Ceftazidime is widely distributed in most body tissues and fluids including respiratory secretion, ascitic fluid and cerebrospinal fluid. Ceftazidime is administered parenterally, is completely absorbed after intramuscular injection, and peak drug concentrations generally occur within 3 hours of intramuscular injection. Ceftazidime is not absorbed when taken by mouth. Ceftazidime half-life is 4 to 10 hours at birth, but half this in infants more than a week old. In premature infants, the distribution volume and the clearance of ceftazidime range from 292+44 to 366+130 ml/kg and from 27.8+5.8 to 60.8+8.3 ml/h/kg, respectively. Ceftazidime binds to plasma proteins at 10% to 17%. No ceftazidime metabolites have been identified and this drug is excreted by renal elimination. The dose of ceftazidime is 25 mg/kg once-daily in the first week of life. Ceftazidime crosses the placenta freely, but there is no evidence of teratogenicity. As empirical ceftazidime monotherapy may not be appropriate for the treatment of neonatal sepsis, the addition of ampicillin, to cover against enterococci and Listeria monocytogenes, seems prudent in these neonatal patients. The aim of this study is to review the effects of ceftazidime in neonates.

Penicillin treatment for patients with Community-Acquired Pneumonia in Denmark: a retrospective cohort study

BackgroundCommunity-acquired pneumonia (CAP) is a severe infection, with high mortality. Antibiotic strategies for CAP differ across Europe.The objective of the study was to describe the epidemiology of CAP in Denmark and evaluate the prognosis of patients empirically treated with penicillin-G/V monotherapy.MethodsRetrospective cohort study including hospitalized patients with x-ray confirmed CAP. We calculated the population-based incidence, reviewed types of empiric antibiotics and duration of antibiotic treatment. We evaluated the association between mortality and treatment with empiric penicillin-G/V using logistic regression analysis.ResultsWe included 1320 patients. The incidence of hospitalized CAP was 3.1/1000 inhabitants. Median age was 71 years (IQR; 58–81) and in-hospital mortality was 8%. Median duration of antibiotic treatment was 10 days (IQR; 8–12). In total 45% were treated with penicillin-G/V as empiric monotherapy and they did not have a higher mortality compared to patients treated with broader-spectrum antibiotics (OR 0.92, CI 95% 0.55–1.53).ConclusionThe duration of treatment exceeded recommendations in European guidelines. Empiric monotherapy with penicillin-G/V was commonly used and not associated with increased mortality in patients with mild to moderate pneumonia. Our results are in agreement with current conservative antibiotic strategy as outlined in the Danish guidelines.

Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents.

This is an updated version of the original Cochrane review originally published in 2003, Issue 3, and updated in 2005, Issue 4.Absence seizures are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with typical absence seizures. To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other. We searched the Cochrane Epilepsy Group's Specialized Register (1 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1 September 2016), MEDLINE (Ovid, 1946 to 1 September 2016), ClinicalTrials.gov (1 September 2016) and the WHO International Clinical Trials Registry Platform ICTRP (1 September 2016). Previously we searched Embase (1988 to March 2005) and SCOPUS (1823 to 31 March 2014). No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine; or placebo. Outcome measures were: (1) proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test; and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). Eight small trials were found (three of them not included in the previous version of the review). Six of them were of poor methodological quality and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from randomised controlled trials to support a specific effect on absence seizures for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in children with newly diagnosed childhood absence epilepsy found that at 12 months, the freedom-from-failure rates for ethosuximide and valproic acid (VPA) were similar and were higher than the rate for lamotrigine. The frequency of treatment failures due to lack of seizure control (P < 0.001) and intolerable adverse events (P < 0.037) was significantly different among the treatment groups, with the largest proportion of lack of seizure control in the lamotrigine cohort, and the largest proportion of adverse events in the VPA group. Overall, this large study demonstrates the superior effectiveness of ethosuximide and VPA compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with absence seizures. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.

Antimicrobial combination treatment including ciprofloxacin decreased the mortality rate of Pseudomonas aeruginosa bacteraemia: a retrospective cohort study

Ineffective antimicrobial therapy of Pseudomonas aeruginosa bacteraemia increases mortality. Recent studies have proposed the use of antimicrobial combination therapy composed of a beta-lactam with either ciprofloxacin or tobramycin. To determine if combination therapy correlates to lower mortality and is superior compared to monotherapy, we investigated the effect of antimicrobial treatment regimens on 30-day mortality in a cohort with Pseudomonas aeruginosa bacteraemia. All cases of P. aeruginosa bacteraemia (n = 292) in southwest Skåne County, Sweden (years 2005–2010, adult population 361,112) and the whole county (2011–2012, 966,130) were identified. Available medical and microbiological records for persons aged 18 years or more were reviewed (n = 235). Antimicrobial therapy was defined as empiric at admission or definitive after culture results and was correlated to 30-day mortality in a multivariate regression model. The incidence and mortality rates were 8.0 per 100,000 adults and 22.9% (67/292), respectively. As expected, multiple comorbidities and high age were associated with mortality. Adequate empiric or definitive antipseudomonal treatment was associated with lower mortality than other antimicrobial alternatives (empiric p = 0.02, adj. p = 0.03; definitive p < 0.001, adj. p = 0.007). No difference in mortality was seen between empiric antipseudomonal monotherapy or empiric combination therapy. However, definitive combination therapy including ciprofloxacin correlated to lower mortality than monotherapy (p = 0.006, adj. p = 0.003), whereas combinations including tobramycin did not. Our results underline the importance of adequate antipseudomonal treatment. These data also suggest that P. aeruginosa bacteraemia should be treated with an antimicrobial combination including ciprofloxacin when susceptible.

Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

Empiric therapy decisions are predicated on knowledge of both the epidemiology and antimicrobial susceptibility of the probable infecting pathogen(s). The objective of this study was to evaluate the microbial distribution and phenotypic profiles of nosocomial respiratory isolates collected from multiple US hospitals and assess the clinical utility of various monotherapy and combination regimens. Hospitals provided consecutive non-duplicate adult inpatients Gram-negative nosocomial respiratory isolates from cultures received ≥48 h after hospital admission. Minimum inhibitory concentrations (MICs) for 12 antimicrobials were determined using broth microdilution methods. An antibiogram was constructed for monotherapy regimens as well as combinations inclusive of either tobramycin (TOB) or ciprofloxacin (CIP). Six hospitals provided 518 nosocomial respiratory isolates. P. aeruginosa (PSA) comprised 28% of the population followed by Klebsiella pneumoniae (13%), Enterobacter spp. (13%), S. maltophilia (9%), S. marcesens (6%), A. baumannii (6%), and others (18%). When considering monotherapy for the Enterobacteriaceae & PSA ceftolozane/tazobactam (C/T) provided the highest (87%) percent susceptibility (%S) followed by meropenem (MEM), CIP, cefepime (FEP), ceftazidime (CAZ) and piperacillin-tazobactam (TZP) at 71-85%S. The addition of TOB > CIP improved the probability that the antimicrobial combination would provide ≥1 active agent. PSA was the predominant nosocomial respiratory pathogen; however, the Enterobacteriaceae comprised an additional 53% in this survey. When considering empiric β-lactam monotherapy therapy for the entire spectrum of pathogens C/T provided the highest (78%) %S followed by MEM, FEP and TZP. The addition of either TOB > CIP to these β-lactams enhances the likelihood that an active agent would be selected when considering empirical therapy choices for nosocomial respiratory tract infections.

Tree-structured survival analysis of patients with Pseudomonas aeruginosa bacteremia: A multicenter observational cohort study

This study aimed to construct a prediction algorithm, which is readily applicable in the clinical setting, to determine the mortality rate for patients with P. aeruginosa bacteremia. A multicenter observational cohort study was performed retrospectively in seven university-affiliated hospitals in Korea from March 2012 to February 2015. In total, 264 adult patients with monomicrobial P. aeruginosa bacteremia were included in the analyses. Among the predictors independently associated with 30-day mortality in the Cox regression model, Pitt bacteremia score >2 and high-risk source of bacteremia were identified as critical nodes in the tree-structured survival analysis. Particularly, the empirical combination therapy was not associated with any survival benefit in the Cox regression model compared to the empirical monotherapy. This study suggests that determining the infection source and evaluating the clinical severity are critical to predict the clinical outcome in patients with P. aeruginosa bacteremia.

Time-kill curve analysis and pharmacodynamic modelling for in vitro evaluation of antimicrobials against Neisseria gonorrhoeae.

BackgroundGonorrhoea is a sexually transmitted infection caused by the Gram-negative bacterium Neisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic models describing the relationship between the concentration of antimicrobials and the minimum growth rate of the bacteria provide more detailed information than the MIC only.ResultsIn this study, a novel standardised in vitro time-kill curve assay was developed. The assay was validated using five World Health Organization N. gonorrhoeae reference strains and a range of ciprofloxacin concentrations below and above the MIC. Then the activity of nine antimicrobials with different target mechanisms was examined against a highly antimicrobial susceptible clinical strain isolated in 1964. The experimental time-kill curves were analysed and quantified with a previously established pharmacodynamic model. First, the bacterial growth rates at each antimicrobial concentration were estimated with linear regression. Second, we fitted the model to the growth rates, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. A gradual decrease of bactericidal effects from ciprofloxacin to spectinomycin and gentamicin was found. The beta-lactams ceftriaxone, cefixime and benzylpenicillin showed bactericidal and time-dependent properties. Chloramphenicol and tetracycline were purely bacteriostatic as they fully inhibited the growth but did not kill the bacteria. We also tested ciprofloxacin resistant strains and found higher pharmacodynamic MICs (zMIC) in the resistant strains and attenuated bactericidal effects at concentrations above the zMIC.ConclusionsN. gonorrhoeae time-kill curve experiments analysed with a pharmacodynamic model have potential for in vitro evaluation of new and existing antimicrobials. The pharmacodynamic parameters based on a wide range of concentrations below and above the MIC provide information that could support improving future dosing strategies to treat gonorrhoea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-016-0838-9) contains supplementary material, which is available to authorized users.

In silico trials using Monte Carlo simulation to evaluate ciprofloxacin and levofloxacin dosing in critically ill patients receiving prolonged intermittent renal replacement therapy

Prolonged intermittent renal replacement therapy (PIRRT) is a growing option to treat acute kidney injury in critically ill patients, but absent pharmacokinetic data challenge optimal drug dosing. Inappropriate antibiotic dosing can cause widespread bacterial resistance and decreased antibiotic utility. The purpose of this study was to evaluate probability of target attainment (PTA) of various ciprofloxacin and levofloxacin regimens in critically ill patients receiving PIRRT, utilizing Monte Carlo simulation (MCS). The models incorporated published body weights and pharmacokinetic parameters (volume of distribution, non-renal clearance, and extraction coefficients) and their associated variability and ranges. Four different PIRRT effluent/duration combinations (4 L/h × 10 h or 5 L/h × 8 h in hemodialysis or hemofiltration, respectively) occurring at the beginning or 14-16 h after drug administration were modeled. MCS predicted drug disposition during the first 72 h in 5000 virtual patients for each dosing regimen. Desired pharmacodynamic targets to calculate PTA were the 24-h area under the curve/minimum inhibitory concentration (AUC24h:MIC) of ≥125 and ≥50 for Gram-negative and Gram-positive infections, respectively. The “successful” doses were the ones with PTA of ~90 % in all PIRRT settings. No conventional, FDA-approved regimens attained ~90 % of PTA for Gram-negative infection with Pseudomonas aeruginosa at the MIC of 1 and 2 mg/L for ciprofloxacin and levofloxacin, respectively. The successful doses (ciprofloxacin 1200 mg loading dose, 800 mg q12h, and levofloxacin 2000 mg loading dose, 1000 mg q24h post-PIRRT) greatly exceed the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg loading dose and 500 mg q24h post-PIRRT successfully attained PTA ~90 % at the MIC of 1 mg/L for Streptococcus pneumoniae. Ciprofloxacin and levofloxacin cannot be recommended as empiric monotherapy for serious Gram-negative infections in patients receiving PIRRT due to suboptimal efficacy. This MCS prediction supports rational dosing decisions to treat infected patients receiving PIRRT and should be used until clinical pharmacokinetic trials are conducted in this population.