An update on emerging therapies for urinary tract infections.

INTRODUCTION: Urinary tract infections (UTIs) are the most common healthcare-acquired infections, and are associated with high morbidity and mortality. Worldwide use of antibiotics has led to a significant rise in resistant uropathogens emanating from both hospitals and communities. The huge concern of multidrug resistance (MDR) has led the Food and Drug Administration (FDA) to encourage drug companies to invest in the development of new antibiotics. Area covered: In this review we summarized data on already approved antibiotics, and selected emerging therapies that are currently in phase II and III trials with emphasis on complicated urinary tract infections (cUTIs). We performed our search using PubMed, ClinicalTrials.gov, Google Scholar and Pharmaprojects. Expert opinion: Efficacious antimicrobials are needed to overcome MDR organisms. There are several dugs in initial and later stages of development, but most of them lack full spectrum of activity against some Gram-negative organisms, particularly against MDR Pseudomonas aeruginosa. Better understanding of the pathogenesis of UTI and genetic engineering of pathogens can provide new drugs to combat resistance in the future.

A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination With Oral Rifampin Compared With Standard-of-Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction.

BACKGROUND: Fusidic acid (FA) has been used for decades for bone infection, including prosthetic joint infection (PJI), often in combination with rifampin (RIF). An FA/RIF pharmacokinetic interaction has not previously been described. METHODS: In a phase 2 open-label randomized study, we evaluated oral FA/RIF vs standard-of-care (SOC) intravenous antibiotics for treatment of hip or knee PJI. Outcome assessment occurred at reimplantation (week 12) for subjects with 2-stage exchange, and after 3 or 6 months of treatment for subjects with hip or knee debride and retain strategies, respectively. RESULTS: Fourteen subjects were randomized 1:1 to FA/RIF or SOC. Pharmacokinetic profiles were obtained for 6 subjects randomized to FA/RIF. FA concentrations were lower than anticipated in all subjects during the first week of therapy, and at weeks 4 and 6, blood levels continued to decline. By week 6, FA exposures were 40%-45% lower than expected. CONCLUSIONS: The sponsor elected to terminate this study due to a clearly illustrated drug-drug interaction between FA and RIF, which lowered FA levels to a degree that could influence subject outcomes. Optimization of FA exposure if used in combination with RIF should be a topic of future research. CLINICAL TRIALS REGISTRATION: NCT01756924.

Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI).

BACKGROUND: Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. METHODS: ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. FINDINGS: Of 1083 patients enrolled, 800 (73·9%), of whom 656 (82·0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76·9%] of 398 vs 275 [68·4%] of 402, 95% CI 2·3-14·6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. INTERPRETATION: Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. FUNDING: Cubist Pharmaceuticals.

Antibiotics and antiseptics for preventing infection in people receiving revision total hip and knee prostheses: a systematic review of randomized controlled trials.

BACKGROUND: Infection rates in revision (second and subsequent) major joint arthroplasty continues to be a significant issue with rates 2-3 times those of primary procedures. The effect of antibiotic and antiseptic prophylaxis on outcomes for this type of surgery has not been adequately reviewed. METHODS: A systematic search of the main databases for randomized controlled trials (RCTs) evaluating antibiotics and antiseptics was conducted to evaluate the predetermined endpoints of infection. RESULTS: There were five (5) RCTs identified that examined the effects of antibiotic and antiseptic prophylaxis on infections after revision total hip arthroplasty [THA] (total of 304 participants) and total knee arthroplasty [TKA] (total of 206 participants). For TKA, preoperative systemic intravenous (IV) antibiotic prophylaxis plus antibiotic cement may be effective in reducing the incidence of infection in revision TKA at 8+ years. These results however should be interpreted with caution due to the significant biases. For revision THA, there is no RCT evidence that antibiotics/antiseptics have any effect on the infection rate. CONCLUSIONS: There is a lack of high quality data demonstrating an effect of antibiotics or antiseptics on infection rates in revision THA/TKA. Considering the rate of infections in revisions is 2-3X that of primary procedures and; there is a consensus recommendation to use similar antibiotic and antiseptic regimens in both primary and revision procedures, there is a need for high quality studies in revision THA/TKA.

Executive Summary: 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults.

These guidelines are intended for use by infectious disease specialists, orthopedic surgeons, neurosurgeons, radiologists, and other healthcare professionals who care for patients with native vertebral osteomyelitis (NVO). They include evidence and opinion-based recommendations for the diagnosis and management of patients with NVO treated with antimicrobial therapy, with or without surgical intervention.

2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults.

These guidelines are intended for use by infectious disease specialists, orthopedic surgeons, neurosurgeons, radiologists, and other healthcare professionals who care for patients with native vertebral osteomyelitis (NVO). They include evidence and opinion-based recommendations for the diagnosis and management of patients with NVO treated with antimicrobial therapy, with or without surgical intervention.

Systematic review and meta-analysis of randomized controlled trials of antibiotics and antiseptics for preventing infection in people receiving primary total hip and knee prostheses.

Infection rates in primary (first-time) major joint arthroplasty continue to be a significant issue. The effect of antibiotic and antiseptic prophylaxis on outcomes for this type of surgery has not been adequately reviewed. A systematic search of the main databases for randomized controlled trials (RCTs) evaluating antibiotics and antiseptics was conducted to evaluate the predetermined endpoints of infection, adverse events, costs, quality of life, and concentration levels of antibiotics. A meta-analysis using pooled effect estimates and fixed-effect and random-effect models of risk ratios (RR), calculated with 95% confidence intervals (CI), was utilized. Thirty (30) RCTs examined the effects of antibiotic and antiseptic prophylaxis on infections after primary total hip arthroplasty (THA) (total of 11,597 participants) and total knee arthroplasty (TKA) (total of 6,141 participants). For THA, preoperative systemic intravenous (i.v.) antibiotic prophylaxis may be effective in reducing the incidence of infection after THA from 6 months to ≥5 years. For TKA, there is no RCT evidence that antibiotics and/or antiseptics have any effect on infection rate. Preoperative systemic antibiotic prophylaxis in primary THA may be effective at reducing infection rate. There is no evidence that timing, route of administration, or concentration levels have an effect on reducing infections, adverse events, or costs in THA or TKA. Many of the trials included in this study were published in the 1980s and 1990s. Thus, it would be important to replicate a number of them based on current patient demographics and incidence of bacterial resistance.

Short versus long course of antibiotics for catheter-associated urinary tract infections in patients with spinal cord injury: a randomized controlled noninferiority trial.

OBJECTIVE: To assess the applicability of a short-course regimen of antibiotics for managing catheter-associated urinary tract infection (CA-UTI) in patients with spinal cord injury (SCI). DESIGN: Randomized, controlled, noninferiority trial. SETTING: Medical center. PARTICIPANTS: Patients with SCI who had CA-UTI (N=61). INTERVENTIONS: Patients were randomized to receive either a 5-day regimen of antibiotics after catheter exchange (experimental group) or a 10-day regimen of antibiotics with catheter retention (control group). Noninferiority was prespecified with a margin of 10%. MAIN OUTCOME MEASURE: Clinical cure at the end of therapy. RESULTS: Of the 61 patients enrolled in this study, 6 patients were excluded because of bacteremia or absence of urinary symptoms. All patients (100%) achieved clinical cure at the end of therapy. The rates of microbiologic response were 82.1% in the experimental group and 88.9% in the control group (upper boundary 95% confidence interval (CI) for difference, 26%). The rates of resolution of pyuria were 89.3% in the experimental group and 88.9% in the control group (upper boundary 95% CI for difference, 16%). Patients in the experimental group had higher rates of CA-UTI recurrence than the control group. The rates of new CA-UTI, diarrhea, and Clostridium difficile colitis were similar in the 2 treatment arms. CONCLUSIONS: The primary endpoint of the study was met, indicating that the 5-day regimen with catheter exchange was noninferior to the 10-day regimen with catheter retention on the basis of clinical cure. Criteria for noninferiority on the basis of microbiologic response and resolution of pyuria were not met.

In vitro activity and durability of a combination of an antibiofilm and an antibiotic against vascular catheter colonization.

Catheter-associated infections can cause severe complications and even death. Effective antimicrobial modification of catheters that can prevent device colonization has the potential of preventing clinical infection. We studied in vitro the antimicrobial activities of central venous catheters impregnated with N-acetylcysteine (NAC), an antibiofilm agent, and a broad-spectrum antibiotic against a range of important clinical pathogens. NAC-levofloxacin-impregnated (NACLEV) catheters were also evaluated for their antiadherence activity. NACLEV catheters produced the most active and durable antimicrobial effect against both Gram-positive and Gram-negative isolates and significantly reduced colonization (P < 0.0001) by all tested pathogens compared to control catheters. These in vitro results suggest that this antimicrobial combination can potentially be used to combat catheter colonization and catheter-associated infection.

Chlorhexidine-Alcohol versus Povidone-Iodine for Surgical-Site Antisepsis.

BACKGROUND: Since the patient's skin is a major source of pathogens that cause surgical-site infection, optimization of preoperative skin antisepsis may decrease postoperative infections. We hypothesized that preoperative skin cleansing with chlorhexidine-alcohol is more protective against infection than is povidone-iodine. METHODS: We randomly assigned adults undergoing clean-contaminated surgery in six hospitals to preoperative skin preparation with either chlorhexidine-alcohol scrub or povidone-iodine scrub and paint. The primary outcome was any surgical-site infection within 30 days after surgery. Secondary outcomes included individual types of surgical-site infections. RESULTS: A total of 849 subjects (409 in the chlorhexidine-alcohol group and 440 in the povidone-iodine group) qualified for the intention-to-treat analysis. The overall rate of surgical-site infection was significantly lower in the chlorhexidine-alcohol group than in the povidone-iodine group (9.5% vs. 16.1%; P=0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine-alcohol was significantly more protective than povidone-iodine against both superficial incisional infections (4.2% vs. 8.6%, P=0.008) and deep incisional infections (1% vs. 3%, P=0.05) but not against organ-space infections (4.4% vs. 4.5%). Similar results were observed in the per-protocol analysis of the 813 patients who remained in the study during the 30-day follow-up period. Adverse events were similar in the two study groups. CONCLUSIONS: Preoperative cleansing of the patient's skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery. (ClinicalTrials.gov number, NCT00290290.)

Clinical significance of Staphylococcus aureus bacteriuria at a tertiary care hospital.

OBJECTIVES: Staphylococcus aureus bacteriuria has been associated with invasive S. aureus disease. The current project describes the clinical significance of S. aureus bacteriuria. METHODS: We conducted a retrospective chart review of patients who had S. aureus bacteriuria at the Michael E. DeBakey Veterans Affairs Medical Center, 2008-2010. RESULTS: A total of 326 patients were included. Invasive S. aureus disease was documented within 12 months of bacteriuria in 56 patients (22.3% of methicillin-resistant S. aureus (MRSA) cases and 8.4% of methicillin-sensitive S. aureus (MSSA), p = 0.002). Multiple logistic regression indicated that MRSA bacteriuria (odds ratio (OR) 2.91, p = 0.010), absence of symptoms suggestive of a urinary tract infection (UTI) (OR 3.21, p = 0.019), inpatient status (OR 4.72, p = 0.003), and receipt of antibiotics active against S. aureus (OR 6.41, p < 0.001) were significantly associated with the presence of invasive S. aureus disease. Seventy-seven patients (23.6%) died within 12 months of the documented S. aureus bacteriuria. Age (OR 1.02, p = 0.025), absence of pyuria (OR 2.00, p = 0.029), the presence of invasive S. aureus disease (OR 2.05, p = 0.033), and inpatient status (OR 3.62, p < 0.001) were significantly associated with death. CONCLUSIONS: S. aureus bacteriuria is associated with significant morbidity and mortality. Patients without UTI symptoms, those with MRSA bacteriuria, and those without pyuria were more to likely to have worse outcomes (invasive S. aureus disease or death). Obtaining blood cultures should be considered in these cases.

In vitro potency and in vivo efficacy of a novel bis-indole antimicrobial compound in reducing catheter colonization.

Vascular catheters coated with a novel antimicrobial agent (MBX1631) were studied for their ability to protect against bacterial colonization in vitro and in a rabbit model. MBX1631-coated catheters were significantly less likely to become colonized than control catheters both in vitro and in vivo (P < 0.001). Furthermore, device-associated infection was significantly lower in MBX1631-coated catheters than in uncoated ones (P < 0.005).

Characteristics of biofilm on tunneled cuffed hemodialysis catheters in the presence and absence of clinical infection.

BACKGROUND: Biofilm occurring on the surface of tunneled hemodialysis (HD) catheters is difficult to eradicate and often is associated with recurrent bacteremia. We studied biofilm formation on catheters from patients with and without bacteremia to identify the location of bacterial growth and measure biofilm thickness. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 76 adult HD patients; 26 had HD catheters removed for bacteremia and 50 had catheters removed for reasons other than infection. PREDICTORS: Segment of catheter, reason for catheter removal. OUTCOMES & MEASUREMENTS: Microbiological growth and biofilm thickness on the outer and luminal surfaces of extravascular and intravascular catheter segments. RESULTS: Catheter cultures were positive in 16 (62%) patients with bacteremia and 15 (30%) when the catheter was removed for non-infection-related reasons. In catheters with positive cultures, the outer surface of the extravascular segment was the most common site of bacterial growth (15/16 [94%] and 11/15 [73%] for bacteremic and nonbacteremic patients, respectively). Bacteremic patients had significantly thicker biofilm on all catheter surfaces, and in bacteremic patients, the biofilm was significantly thicker on the outer compared with the luminal surface for both extravascular (14.53 ± 6.17 vs 11.97 ± 5.01 µm; P < 0.001) and intravascular (12.21 ± 5.3 vs 9.46 ± 3.71 µm; P < 0.001) segments. Extravascular segments had significantly thicker biofilm compared with intravascular segments on both the outer (P < 0.001) and luminal (P < 0.001) surfaces. Similarly, in patients for whom the catheter was removed for non-infection-related reasons, the catheter had thicker biofilm on the outer compared with the inner surface in both extravascular (2.19 ± 2.84 vs 1.62 ± 2.33 µm; P < 0.001) and intravascular (1.92 ± 2.62 vs 1.29 ± 2.33 µm; P < 0.001) segments. Similar to catheters from bacteremic patients, the outer and luminal surfaces of the extravascular segments of the catheters had significantly thicker biofilm compared with their corresponding surfaces on the intravascular segments. LIMITATIONS: Observational study. CONCLUSIONS: The outer surface of the extravascular segment of tunneled dialysis catheters in both bacteremic and nonbacteremic HD patients has the thickest biofilm and highest microbiological yield, and biofilm is thicker in patients with bacteremia. This knowledge is important for designing preventive strategies and also in the management of patients with catheter infection.

Device-related infective endocarditis, with special consideration of implanted intravascular and cardiac devices in a predominantly male population.

BACKGROUND: The relationship between invasive medical devices and infective endocarditis (IE) has not been comprehensively assessed. We describe our experience of patients with IE, with particular attention to the role of pre-existing intravascular catheters and implanted cardiac devices in the pathogenesis. METHODS: We performed a retrospective review of hospital records over a 10-y period (1997-2007), and included patients with 'definite' or 'possible' IE as per the modified Duke criteria. The complete electronic medical record was reviewed for the presence of intravascular devices prior to the onset of IE, including intravascular catheters and implanted cardiac devices (defibrillators and pacemakers). RESULTS: We identified 155 patients with IE. Infection involved a native valve in 124 (80%) patients and a prosthetic valve in 15 (9.7%). In the remaining 16 (10.3%) patients, infection was attributed to an implanted cardiac device. The most commonly identified source of infection was a central venous catheter, accounting for 17.4% of patients, followed by an implanted cardiac device in 10.3% of patients. Staphylococcus aureus was the most commonly isolated organism in catheter-associated IE and cardiac device-associated IE (31.9% and 62.5%, respectively). Thirty-five (22.5%) patients died within 90 days. Mortality was 31.9% in patients with IE caused by methicillin-resistant S. aureus (MRSA). CONCLUSIONS: Intravascular catheters and cardiac implantable devices are common sources of infection leading to IE, and the intracardiac devices themselves often become infected, with MRSA as the predominant pathogen.

Antibiotics and antiseptics to prevent infection in cardiac rhythm management device implantation surgery.

BACKGROUND: Surgical site infections (SSIs) resulting from cardiac implantable electronic device (CIED) implantation cause significant morbidity and mortality, and are increasing at a disproportionately higher rate than the rate of CIED implantation. The prophylactic administration of antibiotics and antiseptics can reduce this infection rate. The objective of this systematic review and meta-analysis was to determine whether the prophylactic administration of antibiotics and antiseptics in patients undergoing CIED implantation reduces the incidence of SSI in randomized controlled trials. We searched the Cochrane Wounds Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL. No date or language restrictions were applied. METHODS: Two review authors independently screened papers for inclusion, assessed risk of bias, and extracted data using a data collection form. Data were pooled where appropriate. RESULTS: Fifteen studies (3,970 participants) were included in this review. For patients undergoing a CIED implant, perioperative systemic antibiotics (PSA) plus antiseptics delivered 1 hour before the procedure significantly reduced the incidence of SSI compared with no antibiotics (risk ratio [RR] 0.13; 95% confidence interval [CI] 0.05-0.36; P value < 0.00001). Furthermore, PSA plus antiseptics significantly reduced the incidence of postoperative infection compared to antibiotics delivered postoperatively (RR 0.14; 95% CI 0.03-0.60; P value 0.008). CONCLUSION: The evidence strongly suggests that antibiotic prophylaxis within 1 hour before CIED implantation is effective at reducing SSI.

Prosthetic joint infections.

Prosthetic joint infections represent a major therapeutic challenge for both healthcare providers and patients. This article reviews the predisposing factors, pathogenesis, microbiology, diagnosis, treatment, and prophylaxis of prosthetic joint infection. The most optimal management strategy should be identified on the basis of a number of considerations, including type and duration of infection, antimicrobial susceptibility of the infecting pathogen, condition of infected tissues and bone stock, patient wishes, and functional status.

Staphylococcus aureus Bacteriuria: Source, Clinical Relevance, and Management.

Staphylococcus aureus bacteriuria is a common condition with still largely undetermined clinical relevance. Although S. aureus bacteriuria can be secondary to bacteremia and systemic infection in some patients, it may predispose to bacteremia and invasive disease in others. Whereas most patients with S. aureus bacteriuria do not have symptomatic urinary tract infection, it is reportedly associated with endocarditis and other types of invasive diseases, thereby resulting in major morbidity and occasional mortality. This review summarizes and analyzes the results of previous reports of S. aureus bacteriuria and assesses the clinical relevance and management of this increasingly recognized entity.

Nonstaphylococcal infections of cardiac implantable electronic devices.

BACKGROUND: Along with the rising use of cardiac implantable electronic devices (CIEDs), there has been a disproportional increase in the number of infections of such devices. Little is known about nonstaphylococcal CIED-related infections, which make up approximately 10% to 30% of all CIED infections. METHODS AND RESULTS: A retrospective review of hospital records of patients admitted with a CIED-related infection was conducted in 4 academic hospitals in Houston, Tex, between 2002 and 2009. Of the 504 identified patients with CIED-related infection, 80 (16%) had a nonstaphylococcal infection and were the focus of this study. The mean duration of CIED placement before infection was 109+/-27 weeks, whereas 44% had their device previously manipulated within a mean of 29.5+/-6 weeks. The mean duration of clinical symptoms before admission was 48+/-12.8 days. Furthermore, 13 patients (16%) presented with CIED-related endocarditis. Although not described in prior reports, we identified 3 definite and 2 suspected cases of secondary Gram-negative bacteria seeding of the CIED. Inappropriate antimicrobial coverage was provided in approximately 50% of the cases with a mean period of 2.1 days. The overall mortality rate was 4%. CONCLUSIONS: Nonstaphylococcal CIED-related infections are prevalent and diverse with a relatively low virulence and mortality rate. Because nonstaphylococcal organisms are capable of secondarily seeding the CIED, a high suspicion for CIED-related infection is warranted in patients with bloodstream infection. In patients with suspected CIED infection, adequate Gram-positive and Gram-negative antibacterial coverage should be administered until microbiological data become available.