Efficacy of daptomycin in complicated skin and skin-structure infections due to methicillin-sensitive and ‐resistant Staphylococcus aureus : results from the CORE Registry

ABSTRACT

Objective: To characterize postmarketing clinical experience with daptomycin in treating complicated skin and skin-structure infections (cSSSIs) due to cultureconfirmed MRSA and MSSA in real-life prescribing situations.

Research design and methods: The Cubicin Outcomes Registry and Experience 2004 (CORE 2004) is a multicenter observational registry involving 45 separate institutions, designed to characterize infection types, pathogens, and outcomes of patients who were treated with daptomycin. A subset analysis of the CORE 2004 data was conducted to characterize patients with cSSSI due to culture-confirmed MRSA and MSSA, but without bacteremia, endocarditis, osteomyelitis, or other significant infectious processes. Clinical information, including patient demographics, antibiotic treatments, and clinical outcome, was analyzed. Adverse event data were not collected in CORE 2004.

Main outcome measure: Clinical success (cured or improved) or failure was assessed at the end of daptomycin treatment.

Results: A total of 165 patients were identified, including 145 patients (87.9%) with MRSA and 20 patients (12.1%) with MSSA infections. Most patients received daptomycin at a dosage of 4–6?mg/kg intravenously and at a frequency of once every 24?h. Daptomycin dosing frequency was adjusted to once every 48?h or thrice weekly in all seven patients who had received hemodialysis. Prior antibiotic therapy had been administered to 121/163 (74.2%) patients and concomitant antibiotic therapy to 65/165 (39.4%) of patients. Clinical success was achieved with daptomycin in 89.1% of patients overall, including 89.7% and 85.0% of those with MRSA and MSSA, respectively. Among patients with a successful outcome, the total days of daptomycin therapy (median days: MRSA = 13.0, MSSA = 11.0) and the days to clinical response (median days: MRSA = 3.5, MSSA = 2.0) were not significantly different for MRSA and MSSA patients (p = 0.27 and p = 0.15 respectively, median test).

Conclusions: Given the limitations of this registry which include its retrospective nature; limited numbers of MSSA patients; and lack of specific information on adverse events, type and duration of prior antibiotic therapy, timing and duration of concomitant antibiotic therapy, concomitant surgical interventions, and possible on-therapy dosing adjustments), daptomycin appeared effective in postmarketing clinical practice in the treatment of cSSSI caused by MRSA and MSSA.     

Efficacy and safety of ceftazidime–avibactam versus imipenem–cilastatin in the treatment of complicated urinary tract infections,including acute pyelonephritis,in hospitalized adults: results of a prospective,investigator-blinded,randomized study

Abstract

Objectives:

The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to compare the efficacy and safety of ceftazidime–avibactam and imipenem–cilastatin in hospitalized adults with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens.     

Guillain-Barré syndrome complicated by myocarditis

Guillain-Barré syndrome (GBS) is an autoimmune disease affecting the peripheral nerves, and is frequently associated with triggering events several weeks prior to the onset of symptoms. We report the case of a 68-year-old female who was diagnosed with GBS and subsequently developed myocarditis. She was treated with inotropic support and intravenous immunoglobulin (IVIG), and her condition improved. This presentation of GBS complicated by myocarditis is very rare. We examined the literature regarding this association.     

Which fluoroquinolones are suitable for the treatment of urinary tract infections?

A number of fluoroquinolone agents are now available for clinical use and even more under development. Whether these compounds are equally effective and thus interchangeable in the treatment of urinary tract infection (UTI) has to be answered by comparing their antimicrobial activity against uropathogens, the pharmacokinetic and pharmacodynamic parameters and outcome of statistically meaningful clinical studies. Whereas almost all fluoroquinolones give equivalent results with short term therapy of acute uncomplicated cystitis in women, for patients with complicated UTI, only those compounds at the appropriate dosage regimen should be chosen for empiric therapy, which would exhibit sufficiently high urinary bactericidal activity against Gram-negative as well as Gram-positive uropathogens. When considering antibacterial activity, pharmacokinetic and pharmacodynamic properties as well as the results of the published clinical studies, a dosage of 500 mg ciprofloxacin twice daily, 500 mg levofloxacin once daily, or 400 mg gatifloxacin once daily may be comparable dosage regimens in the treatment of severe complicated UTI. In the case of ciprofloxacin (750 mg twice daily) and levofloxacin (500 mg twice daily), the dose could even be increased in UTI caused by less susceptible uropathogens, such as Pseudomonas aeruginosa.     

Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections

Enterobacter cloacae is a major nosocomial pathogen that causes serious infections, including bloodstream infections (BSIs). The clinical significance of extended-spectrum β-lactamase (ESBL) production in E. cloacae is not well established. A multicentre, retrospective, cohort study was conducted to identify clinical characteristics of patients with E. cloacae BSI. ESBL production was confirmed by genotypic methods. A total of 159 patients with E. cloacae BSI were identified at three medical centres in north-eastern USA. Amongst them, 16 patients (10.1%) harboured ESBL-producing E. cloacae. Independent risk factors for ESBL production included admission from a nursing home, the presence of a gastrostomy tube and history of transplant. For the outcome analysis, 15 consecutive patients who had ESBL-producing E. cloacae BSI prior to the study were included. Amongst the 31 patients with ESBL-producing E. cloacae, 8, 9, 4 and 2 patients received a carbapenem, cefepime, piperacillin/tazobactam and ciprofloxacin, respectively, as initial therapy. All patients who received a carbapenem (n=8) were alive at 28 days, whereas 7 (38.9%) of 18 patients who received a non-carbapenem antibiotic did not survive (P=0.06). Clinical failure at 96 h was observed in 2 (25.0%) of 8 patients who received a carbapenem and in 14 (77.8%) of 18 patients who received a non-carbapenem antibiotic (P=0.03). Pulsed-field gel electrophoresis showed little clonality amongst the study isolates. The majority of isolates produced SHV-type ESBL, whereas two isolates produced CTX-M-type ESBL. Initial therapy with a carbapenem appears to be associated with improved clinical outcome in BSI due to ESBL-producing E. cloacae.     

Evaluation of an alternative extended-infusion piperacillin–tazobactam dosing strategy for the treatment of gram-negative infections

Introduction To enhance the probability of pharmacodynamic target attainment, piperacillin–tazobactam can be administered as either a continuous or extended-infusion dosage regimen for the treatment of gram-negative infections. Four hour extended-infusions of piperacillin–tazobactam 3.375 g administered intravenously (IV) every 8 h have been widely studied as an alternative to conventional, intermittent dosage regimens with largely favorable outcomes. Objective To assess the clinical and economic impact of a novel 3-h extended-infusion piperacillin–tazobactam dosing strategy for the treatment of gram-negative infections. Setting 433-bed community hospital in Lexington, KY. Methods Retrospective cohort study before and after the implementation of an alternative dosing protocol using a 3-h infusion of piperacillin–tazobactam 3.375 g IV every 6 h. Main outcome measures The primary outcome was in-hospital mortality. Secondary outcomes include length of stay, ICU length of stay, 30-day all-cause hospital readmissions, total cost per admission, complications, and a composite of in-hospital mortality and readmission within 30 days of discharge. Results Readmission within 30 days of hospital discharge was significantly reduced in the extended-infusion arm (1.2 vs. 13.7 %, P = 0.002). A composite endpoint of death or readmission was lower among patients who received the extended-infusion dosing regimen [OR_adj 0.20; 95 % CI (0.07–0.57)]. However this was likely driven by reductions in readmission. Conclusion An alternative regimen of extended-infusion piperacillin–tazobactam resulted in a significant reduction in 30-day all-cause hospital readmission. These results indicate that 3-h infusions of piperacillin–tazobactam 3.375 g IV every 6 h may represent a clinically effective alternative to other commonly used regimens and results in fewer readmissions within 30 days.     

Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis

The clinical advantages of prolonged (extended/continuous) infusion remain controversial. Previous studies and reviews have failed to show consistent clinical benefits of extending the infusion time. This meta-analysis sought to determine whether prolonged β-lactam infusions were associated with a reduction in mortality and improvement in clinical success. A search of PubMed, EMBASE and The Cochrane Library for randomised controlled trials (RCTs) and observational studies comparing prolonged infusion with intermittent bolus administration of the same antibiotic in hospitalised adult patients was conducted. Primary outcomes evaluated were mortality and clinical success. A total of 29 studies with 2206 patients (18 RCTs and 11 observational studies) were included in the meta-analysis. Compared with intermittent boluses, use of prolonged infusion appeared to be associated with a significant reduction in mortality [pooled relative risk (RR) = 0.66, 95% confidence interval (CI) 0.53–0.83] and improvement in clinical success (RR = 1.12, 95% CI 1.03–1.21). Statistically significant benefit was supported by non-randomised studies (mortality, RR = 0.57, 95% CI 0.43–0.76; clinical success, RR = 1.34, 95% CI 1.02–1.76) but not by RCTs (mortality, RR = 0.83, 95% CI 0.57–1.21; clinical success, RR = 1.05, 95% CI 0.99–1.12). The positive results from observational studies, especially in the face of increasing antibiotic resistance, serve to justify the imperative need to conduct a large-scale, well-designed, multicentre RCT involving critically ill patients infected with high minimum inhibitory concentration pathogens to clearly substantiate this benefit.     

Management of fungal infections in neutropenic patients: more doubts than certainties?

An evidence based approach to prophylaxis and therapy of invasive fungal infections depends on the knowledge of epidemiology and of risk factors for these infections, as well as on the appreciation of merits and limitation of the available clinical trials. A progressive increase in the incidence of systemic fungal infections, most often caused by Candida and Aspergillus, in patients with cancer and neutropenia has been observed in recent years. This increase of systemic fungal infections recognizes a multifactorial origin, including host defense impairment and type of underlying disease. The various combinations of these different risk factors make the patients affected by systemic fungal infections a non-homogeneous population and, therefore, the transferability of the results of many clinical trials from one population to another is difficult. Clinical trials on prophylaxis and treatment of systemic fungal infections moreover have many limitations: they are often of small size, are frequently non-comparative, enrol population at different risk for infection, use different criteria to define success or failure of therapy. These limitations make the interpretation of the trial results difficult. As randomised clinical trials and metanalysis are considered the most valuable sources of information on new treatments, it dearly appears that the mentioned difficulties in interpreting available data from the literature may expose patients to an increased risk of receiving an inappropriate or non-optimal treatment. Better designed studies are needed to clarify the many controversial questions in antifungal prophylaxis and therapy.     

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.     

Does mycophenolate mofetil increase the incidence of infections in renal transplant recipients?

The aim of this study was to investigate infectious complications in renal transplant recipients (RTRs) receiving mycophenolate mofetil (MMF) for prevention of acute transplant rejection. A group of RTRs (n = 47) receiving 1.0-2.0 g/day of MMF with cyclosporine A (CsA) and prednisolone to maintain immunosuppression was compared with a group (n = 47) taking triple immunosuppressive therapy including azathioprine. In both groups the etiology and incidence of infections were evaluated. During 2 years post-transplant, various infections developed in 72.3% of patients who received MMF and in 93.6% of those who received azathioprine. The incidence of viral infections was 53.2% in the MMF group and 59.6% in the azathioprine group and the incidence of bacterial infection was 55.3% and 70.2%, respectively There were two cases of active tuberculosis in the azathioprine group and one in the MMF group. MMF 1.0-2.0 g/day does not increase infection rates in RTRs compared with azathioprine.     

Biosensor diagnosis of urinary tract infections: a path to better treatment?

Urinary tract infection (UTI) is among the most common bacterial infections and poses a significant healthcare burden. The standard culture-based diagnosis of UTI has a typical delay of two to three days. In the absence of definitive microbiological diagnosis at the point of care, physicians frequently initiate empirical broad-spectrum antibiotic treatment, and this has contributed to the emergence of resistant pathogens. Biosensors are emerging as a powerful diagnostic platform for infectious diseases. Paralleling how blood glucose sensors revolutionized the management of diabetes, and how pregnancy tests are now conducted in the home, biosensors are poised to improve UTI diagnosis significantly. Biosensors are amenable to integration with microfluidic technology for point-of-care (POC) applications. This review focuses on promising biosensor technology for UTI diagnosis, including pathogen identification and antimicrobial susceptibility testing, and hurdles to be surpassed in the translation of biosensor technology from bench to bedside.     

Resistance of uropathogens in symptomatic urinary tract infections in León, Nicaragua

Management of urinary tract infections (UTI) in Central America and especially Nicaragua, is complicated by the lack of knowledge about the antibiotic resistance of uropathogens. We conducted a prevalence study to gain more insight into the aetiology, bacterial resistance and risk factors for symptomatic UTI in the region of León, Nicaragua. In 2002, all consecutive patients with UTI symptoms and pyuria >/=10 WBC/hpf were admitted to the study. Positive cultures from midstream urine specimens were defined as >/=10(5) cfu/ml of a single uropathogen. Susceptibility tests were performed with disc diffusion tests using the Kirby-Bauer method and broth microdilution using National Committee for Clinical Laboratory Standards criteria both in León and a reference laboratory in Utrecht. A positive culture was present in 62 of 208 study subjects (30%). Escherichia coli (56%), Klebsiella spp. (18%) and Enterobacter spp. (11%) were the most frequent pathogens isolated. Presence of cystocele, incontinence and increasing age were risk factors for bacterial UTI. E. coli was least resistant to ceftriaxone, amikacin and nitrofurantoin (>90% susceptible). We observed high resistance rates in E. coli to amoxicillin (82%, MIC(90) 128 mg/l), trimethoprim-sulphamethoxazole (TMP-SMX) (64%, MIC(90) 32 mg/l), cephalothin (58%, MIC(90), 32 mg/l), ciprofloxacin (30%; MIC(90), 32 mg/l), amoxicillin/clavulanate (21%, MIC(90) 8 mg/l) and gentamicin (12%, MIC(90) 2 mg/l). Our results suggests that community acquired uropathogens in Nicaragua are highly resistant to many antimicrobial agents. The use of amoxicillin, trimethoprim-sulphamethoxazole and cephalothin against uropathogens needs to be reconsidered. High quinolone resistance rates among E. coli in Nicaragua gives cause for great concern.     

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections

ABSTRACT

Objective: To compare safety data with levofloxacin 500?mg and 750?mg from clinical trials for the treatment of respiratory infections.

Methods: We compared adverse event data for levofloxacin 500?mg and 750?mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy.

Results: Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500?mg and in 45.5% (519/1141) of those treated with 750?mg (?p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) (?p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in ≥ 2% of patients.

Conclusions: Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750?mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.     

Antibiotics for treatment of infections caused by MRSA and elimination of MRSA carriage. What are the choices?

The widespread appearance of methicillin resistant Staphylococcus aureus (MRSA) has significantly undermined the efficacy of currently available antibiotic therapies as strains tend to be multi-resistant. Clinicians are therefore faced with a restricted choice in effective anti-MRSA therapies for infection or elimination of carriage. MRSA remain uniformly susceptible to glycopeptides vancomycin and teicoplanin which remain drugs of choice in treatment of infections. Centres with a high incidence of MRSA should use glycopeptides as empirical monotherapies against these organisms. The low toxicity of teicoplanin makes it an alternative for patients unable to tolerate vancomycin. Only mupirocin is truly effective for use as a topical agent in elimination of MRSA colonisation. For systemic use developmental glycopeptides such as daptomycin, MDL 63246, and LY191145 show better in vitro activity than vancomycin. New cephalosporins TOC-39 and FK-037 show promising anti-MRSA potential with low MICs, as does carbapenem BO-2727 which has a high in vitro activity. Whether the new cephalosporins and carbapenems with good in vitro and/or in vivo activities against MRSA will be clinically effective remains to be determined. New fluoroquinolones levofloxacin, temafloxacin and sparfloxacin have enhanced in vitro anti-MRSA activity, although the emergence of resistance, and subsequent cross resistance to related compounds during therapy is a problem. BAY 12-8039, DV-7751 and CS-940 are developmental fluoroquinolones with better in vitro activity and lower spontaneous mutation rates than related compounds. Co-trimoxazole shows good in vivo anti-MRSA activity, comparable to vancomycin, however, severe infections do not respond well and many strains are resistant to this drug. Rifampicin has excellent bactericidal activity but rapidly emerging resistance undermines its use as a monotherapy. Its use in a combination therapy offers limited potential as an alternative. Arbekacin shows good in vitro activity against many MRSA isolates, although resistance to related aminoglycosides is a problem. Streptogramins, virginiamicin and RP 59500 (dalfopristin/quinupristin), and the everninomicin SCH 27899, show excellent activity in vitro and in vivo activity against MRSA and real future potential as alternative agents to vancomycin. Azeleic acid and ramoplanin show future potential as agents for topical use against MRSA. In conclusion only vancomycin as a systemic agent and mupirocin as a topical agent, offer sufficient reliability for use against MSRA. Alternatives to glycopeptides and mupirocin rest with the development of new drugs from several classes of compounds.     

Do viral infections mimic bacterial sepsis? The role of microvascular permeability: A review of mechanisms and methods

A dysregulated immune response and functional immunosuppression have been considered the major mechanisms of the bacterial sepsis syndrome. More recently, the loss of endothelial barrier function and resultant microvascular leak have been found to be a key determinant of the pathogenesis of bacterial sepsis. Whether a similar paradigm applies to systemic viral syndromes is not known. Answering this question has far-reaching implications for the development of future anti-viral therapeutic strategies. In this review, we provide an overview of the structure and function of the endothelium and how its barrier integrity is compromised in bacterial sepsis. The various in vitro and in vivo methodologies available to investigate vascular leak are reviewed. Emphasis is placed on the advantages and limitations of cell culture techniques, which represent the most commonly used methods. Within this context, we appraise recent studies of three viruses - hantavirus, human herpes virus 8 and dengue virus - that suggest microvascular leak may play a role in the pathogenesis of these viral infections. We conclude with a discussion of how endothelial barrier breakdown may occur in other viral infections such as H5N1 avian influenza virus.     

The management of urinary infections: what have we learned in the past decade?

User-friendly, cost-effective practices to manage urinary infection should become routine. The vast majority of inflections are relatively easy to treat and many of these can be prevented with appropriate interventions. Additional research is urgently needed to compare various clinical strategies and determine which is most acceptable to patients at a reasonable cost with satisfactory health outcomes.