Antimicrobial and resource utilization with T2 magnetic resonance for rapid diagnosis of bloodstream infections: systematic review with meta-analysis of controlled studies.

Objectives: To compare antimicrobial and resource utilization with T2 Magnetic Resonance (T2MR) versus blood culture (BC) in patients with suspected bloodstream infection.Methods: We systematically searched MEDLINE, EMBASE, and CENTRAL for randomized trials or observational controlled studies of patients with suspected bloodstream infection receiving a diagnosis with T2MR or BC. Using an inverse variance meta-analysis model, we reported mortality using the risk ratio (RR) and the remaining outcomes as the mean difference (MD).Results: Fourteen studies were included in the meta-analysis. Time to detection (MD = -81 hours; p < 0.001) and time to species identification (MD = -77 hours; p < 0.001) were faster with T2MR. Patients testing positive on T2MR received targeted antimicrobial therapy faster (-42 hours; p < 0.001) and patients testing negative on T2MR were de-escalated from empirical therapy faster (-7 hours; p = 0.02) vs. BC. Length of intensive care unit stay (MD = -5.0 days; p = 0.03) and hospital stay (MD = -4.8 days; p = 0.03) were shorter with T2MR. Mortality rates were comparable between T2MR and BC (28.9% vs. 29.9%, RR = 1.02, p = 0.86).Conclusion: Utilization of T2MR for identification of bloodstream pathogens provides faster time to detection, faster transition to targeted microbial therapy, faster de-escalation of empirical therapy, shorter ICU and hospital stay, and with comparable mortality rate versus BC.

In vitro interaction of fluconazole and trimethoprim-sulfamethoxazole against Candida auris using ETEST and checkerboard methods.

Candida auris was discovered in 2009 and has rapidly emerged as a serious public health threat with cases reported in over 20 countries worldwide. As of May 8, 2020, the Centers for Disease Control and Prevention reported a total of 1122 US cases. C. auris is often multidrug resistant, leaving few options for treatment. Sulfonamides are known to inhibit a bacterial enzyme involved in folate synthesis and may also inhibit yeast organisms by a similar mechanism. The combination of trimethoprim and sulfamethoxazole is more commonly used than either drug alone. The objective of this study was to evaluate the combination of fluconazole and trimethoprim-sulfamethoxazole against C. auris Minimum inhibitory concentrations (MICs) of fluconazole and trimethoprim-sulfamethoxazole were determined by ETEST and broth microdilution for 11 Cauris strains. Fluconazole MICs (µg/mL) were 4->256 by ETEST and 2->256 by broth microdilution (73% resistant); trimethoprim-sulfamethoxazole MICs were >32 by ETEST and 32->128 by broth microdilution (no interpretive guidelines for C. auris). Using our MIC: MIC ETEST method and a checkerboard method, we investigated the interaction of fluconazole and trimethoprim-sulfamethoxazole against all isolates. These interactions were analyzed by calculating the summation fractional inhibitory concentration with synergyof ≤0.5, additivity of >0.5-1.0, indifference of >1-4, and antagonism of >4. The combination of fluconazole and trimethoprim-sulfamethoxazole revealed synergy with three (27%) and additivity with one (9%) isolate. Indifference was found for the remaining seven (64%) isolates. With the checkerboard method, synergy was seen in 1/11 (9%) isolates with fluconazole (½ MIC) plus trimethoprim-sulfamethoxazole (1/64 MIC); additivity, in 7/11 (64%) isolates with fluconazole (1/8 MIC-1×MIC) plus trimethoprim-sulfamethoxazole (1/128 MIC-½ MIC); and indifference in 3/11 (27%) isolates. Regardless, in vitro interactions may or may not correlate with clinical outcomes. Synergy testing with additional drug combinations and isolates should be performed.

Evaluation of the in vitro interaction of fosfomycin and meropenem against metallo-ß-lactamase-producing Pseudomonas aeruginosa using Etest and time-kill assay.

Pseudomonas aeruginosa is a nosocomial pathogen containing various resistance mechanisms. Among them, metallo-ß-lactamase (MBL)-producing Pseudomonas are difficult to treat. Fosfomycin is an older antibiotic that has recently seen increased usage due to its activity against a broad spectrum of multidrug-resistant organisms. Our aim was to evaluate the combination of fosfomycin and meropenem against 20 MBL-producing P. aeruginosa (100% meropenem-resistant and 20% fosfomycin-resistant) using both an Etest minimal inhibitory concentration (MIC): MIC method and time-kill assay. MICs for fosfomycin and meropenem were determined by Etest and by broth microdilution method for the latter. The combination demonstrated synergy by Etest in 3/20 (15%) isolates and 5/20 (25%) isolates by time-kill assay. Results from the Etest method and time-kill assay were in agreement for 14/20 (70%) of isolates. No antagonism was found. Comparing both methods, Etest MIC: MIC method may be useful to rapidly evaluate other antimicrobial combinations.

Performance of the T2Bacteria Panel for Diagnosing Bloodstream Infections: A Diagnostic Accuracy Study.

Background: Blood cultures, the gold standard for diagnosing bloodstream infections (BSIs), are insensitive and limited by prolonged time to results. The T2Bacteria Panel (T2 Biosystems) is a direct-from-blood, nonculture test that identifies the most common ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli). Objective: To assess performance of the T2Bacteria Panel in diagnosing suspected BSIs in adults. Design: Prospective patient enrollment (8 December 2015 through 4 August 2017). Setting: Eleven U.S. hospitals. Patients: 1427 patients for whom blood cultures were ordered as standard of care. Intervention: Paired blood culture and T2Bacteria testing. Measurements: Performance of T2Bacteria compared with a single set of blood cultures in diagnosing proven, probable, and possible BSIs caused by T2Bacteria-targeted organisms. Results: Blood culture and T2Bacteria results were positive for targeted bacteria in 3% (39 of 1427) and 13% (181 of 1427) of patients, respectively. Mean times from start of blood culture incubation to positivity and species identification were 38.5 (SD, 32.8) and 71.7 (SD, 39.3) hours, respectively. Mean times to species identification with T2Bacteria were 3.61 (SD, 0.2) to 7.70 (SD, 1.38) hours, depending on the number of samples tested. Per-patient sensitivity and specificity of T2Bacteria for proven BSIs were 90% (95% CI, 76% to 96%) and 90% (CI, 88% to 91%), respectively; the negative predictive value was 99.7% (1242 of 1246). The rate of negative blood cultures with a positive T2Bacteria result was 10% (146 of 1427); 60% (88 of 146) of such results were associated with probable (n = 62) or possible (n = 26) BSIs. If probable BSIs and both probable and possible BSIs were assumed to be true positives missed by blood culture, per-patient specificity of T2Bacteria was 94% and 96%, respectively. Limitation: Low prevalence of positive blood cultures, collection of a single set of culture specimens, and inability of T2Bacteria to detect nontargeted pathogens. Conclusion: The T2Bacteria Panel rapidly and accurately diagnoses BSIs caused by 5 common bacteria. Primary Funding Source: T2 Biosystems.

Synergistic effect between nisin and polymyxin B against pandrug-resistant and extensively drug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is an opportunistic pathogen predominantly associated with nosocomial infections. The World Health Organization's data on antibiotic-resistant 'priority pathogens' reports carbapenem-resistant A. baumannii as a pathogen which is in critical need of research and development of new antimicrobials. Emerging resistance against polymyxins, last-resort drugs for carbapenem-resistant A. baumannii, increases the need for new therapeutic approaches such as synergistic combinations. Nisin, an antibacterial peptide produced by the Gram-positive bacteria L. lactis, is a US Food and Drug Administration approved food preservative with bactericidal action predominantly against other Gram-positive bacteria. A 2008 study reported that topical nisin was effective against staphylococcal mastitis in humans. Additionally, nisin has shown activity against Gram-negative bacteria in combination with antimicrobials such as polymyxin B. A recent in vitro study reported that nisin and polymyxin B exhibited synergistic activity against one isolate each of A. baumannii, Acinetobacter lwoffii and Acinetobacter calcoaceticus using time-kill assay and checkerboard technique. We evaluated the synergistic potential of nisin and polymyxin B against 15 unique clinical A. baumannii isolates using time-kill assay. Three of eight (38%) extensively drug-resistant and six of seven (86%) pandrug-resistant A. baumannii isolates showed synergy with one or more combinations of nisin and polymyxin B. The synergy seen with the use of lower concentrations of polymyxin B may help in reducing the dose-dependent side effects. Additional studies involving pharmacokinetics and pharmacodynamics of nisin are required to explore clinical possibilities.

In vitro synergy with fluconazole plus doxycycline or tigecycline against clinical Candida glabrata isolates.

Candida species, traditionally viewed as opportunistic agents, are increasingly seen as a cause of infection in hospitalized patients. Treatment options are limited to a few classes of drugs. Increased resistance, especially by Candida glabrata, is problematic. We investigated the interaction between fluconazole and doxycycline or tigecycline, using clinically unique blood culture C. glabrata isolates. Eighteen isolates were screened using an Etest® MIC:MIC synergy method. With the doxycycline plus fluconazole combination, 28% of isolates showed synergy; tigecycline plus fluconazole showed 94% synergy. No antagonism was seen. The mechanisms of these interactions are unclear. Further research is warranted to assess clinical utility.

In vitro Synergistic Activity of Caspofungin Plus Polymyxin B Against Fluconazole-Resistant Candida glabrata.

BACKGROUND: Candida species account for most invasive fungal infections, and the emergence of fluconazole and caspofungin resistance is problematic. Overcoming resistance with synergism between 2 drugs may be useful. In a 2013 in vitro study, caspofungin plus colistin (polymyxin E) was found to act synergistically against fluconazole-resistant and susceptible Candida albicans isolates. The purpose of our study was to extend this finding by evaluating caspofungin plus polymyxin B for in vitro synergy against fluconazole-resistant Candida glabrata isolates. MATERIALS AND METHODS: A total of 7 fluconazole-resistant C. glabrata bloodstream infection isolates were obtained from 2010-2011. Of these, 2 isolates were also resistant to caspofungin. Minimum inhibitory concentrations (MICs) for caspofungin and polymyxin B were determined by Etest and broth microdilution. Clinical and Laboratory Standards Institute breakpoints were used for fluconazole and caspofungin MIC interpretations. No interpretive guidelines exist for testing polymyxin B against C. glabrata. Synergy testing with caspofungin (1 × MIC) and polymyxin B (½MIC) was performed using a modified bacterial Etest synergy method and time-kill assay. RESULTS: With the Etest synergy method, 4 out of 7 isolates showed in vitro synergy and 1 out of 7 showed additivity. The remaining isolates (both caspofungin resistant) showed indifference. Using the time-kill assay, 1 out of 7 isolates showed synergy, 1 showed additivity and the remaining 5 (including both caspofungin-resistant isolates) showed indifference. CONCLUSIONS: Caspofungin susceptibility may be required for synergism between caspofungin and polymyxin B. Further synergy testing with caspofungin plus polymyxin B and additional fluconazole-resistant C. glabrata isolates should be performed. In vitro synergy/additivity may or may not correlate with in vivo benefit.

Tuberculous Otomastoiditis.

Tuberculous otitis media and mastoiditis, or tuberculous otomastoiditis, is a rare but well-described infectious process occasionally affecting individuals in the United States but more frequently seen in countries where tuberculosis is endemic. Infection may be primary and occur through mucus aspirated through the Eustachian tube. Alternatively, organisms may secondarily infect the nasopharynx when expectorated from the lungs and, less frequently, may be hematogenously spread. Chronic otorrhea and hearing loss are common symptoms, and extensive perforation of the tympanic membranes and facial nerve paralysis are routinely described. Diagnosis is made by direct culture of Mycobacterium tuberculosis, although more recently, molecular techniques have been used. Successful treatment of tuberculous otomastoiditis routinely involves surgical intervention combined with prolonged antituberculosis therapy.

Update on the emerging role of telavancin in hospital-acquired infections.

Telavancin is a lipoglycopeptide that has activity against Gram-positive aerobic and anaerobic bacteria. It has activity against methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus and non-Van-A strains of vancomycin-resistant enterococci. It has been approved by the US Food and Drug Administration (FDA) for complicated skin and skin structure infections and hospital-acquired pneumonia. There is a need for more clinical studies to determine the role of telavancin in treating bacteremia and prosthetic device infections. In this review, we discuss the published data on the use of telavancin in treating hospital-acquired infections and provide an update on new research.

Comparison of 3 Etest(®) methods and time-kill assay for determination of antimicrobial synergy against carbapenemase-producing Klebsiella species.

Increasing global antibiotic resistance has resulted in more use of antibiotic combinations. There is a lack of a gold standard for in vitro testing of these combinations for synergy or antagonism. Time-kill assay (TKA) may be used but is labor intensive and not practical for clinical use. Etest® synergy methods are more rapid and easier to perform, but there is no agreement regarding which method is best. We tested 31 clinical genetically unique Klebsiella pneumoniae carbapenemase-producing Klebsiella isolates with the combination of meropenem and polymyxin B by TKA and 3 Etest methods, each in triplicate: Method 1, MIC:MIC; Method 2, direct overlay; and Method 3, cross. Overall, testing with Etest synergy methods showed the following agreement with TKA: Method 1: 25/31 (80.6%), Method 2: 7/31 (22.6%), and Method 3: 8/31 (25.8%). The MIC:MIC method had the highest agreement (80.6%, κ = 0.59, P < 0.001) and should be evaluated more extensively.

In Vitro Synergy of Telavancin and Rifampin Against Enterococcus faecium Resistant to Both Linezolid and Vancomycin.

BACKGROUND: An emerging pathogen is Enterococcus faecium resistant to both linezolid and vancomycin (LRVRE). Antimicrobial combinations may be required for therapy and need to be evaluated. The combination of daptomycin and rifampin has demonstrated good in vitro activity against gram-positive bacteria, including E faecium. Telavancin, a newer lipoglycopeptide, has shown in vitro activity against E faecium. We evaluated the combination of telavancin and rifampin and compared the results to the combination of daptomycin and rifampin used previously on the same isolates. METHODS: Twenty-four genetically unique (by pulsed-field gel electrophoresis), clinical LRVRE isolates were collected in the United States from 2001-2004. Etest minimal inhibitory concentrations (MICs) (µg/mL) were 0.064-8 for telavancin, 1-4 for daptomycin, and 0.012 to >32 for rifampin. In vitro synergy testing was performed in triplicate by an Etest MIC:MIC ratio method, and summation fractional inhibitory concentration (ΣFIC) was calculated: synergy ≤0.5; indifference >0.5-4; and antagonism >4. RESULTS: The Etest method showed synergy (ΣFICs of 0.1-0.5) with telavancin + rifampin in 20/24 (83%) isolates and indifference (ΣFICs of 0.6-0.8) in 4/24 (17%) isolates. Similarly, the daptomycin + rifampin combination showed synergy (ΣFICs of 0.1-0.5) in 21/24 (88%) isolates and indifference (ΣFICs of 0.6-1.0) in 3/24 (12%) isolates by the Etest method. No antagonism was found. CONCLUSIONS: In vitro synergy with both combinations (rifampin + telavancin or daptomycin) was 83% and 88%, respectively, by Etest against these LRVRE isolates. Although both daptomycin and telavancin in combination with rifampin showed a high incidence of synergistic activity, further in vitro synergy testing with this combination should be performed against additional E faecium isolates. In vitro synergy may or may not translate into in vivo effectiveness.

IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults.

Evidence-based guidelines for the diagnosis and initial management of suspected acute bacterial rhinosinusitis in adults and children were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America comprising clinicians and investigators representing internal medicine, pediatrics, emergency medicine, otolaryngology, public health, epidemiology, and adult and pediatric infectious disease specialties. Recommendations for diagnosis, laboratory investigation, and empiric antimicrobial and adjunctive therapy were developed.

Detection of synergy using the combination of polymyxin B with either meropenem or rifampin against carbapenemase-producing Klebsiella pneumoniae.

Polymyxin B (PB) plus meropenem (MER) or rifampin (RIF) was tested by Etest® method and time-kill assay (TKA) against 14 genetically unique clinical Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. PB + MER: Etest, 43% synergy; TKA, 64% synergy. Concordance between methods was 79%. For PB + RIF: Etest, 21% synergy; TKA, 100% synergy. Concordance between methods was 21%.

In vitro synergistic/additive activity of levofloxacin with meropenem against Stenotrophomonas maltophilia.

Synergy testing of levofloxacin and meropenem by Etest and time-kill assay (TKA) was performed against 30 genetically unique clinical Stenotrophomonas maltophilia isolates. Synergy was demonstrated in 18/30 (60%) isolates by Etest and in 13/30 (43%) by TKA; the remaining isolates were indifferent. Methods showed agreement for 25/30 (83%) of isolates.

In vitro antibacterial activity of tigecycline against resistant Gram-negative bacilli and enterococci by time-kill assay.

This time-kill study was performed with 65 genetically unique clinical isolates of Gram-negative bacilli and enterococci to further define the antibacterial activity of tigecycline. To our knowledge, this is the largest published time-kill study evaluating tigecycline activity to date. Isolates evaluated were 10 meropenem-resistant Acinetobacter baumannii; 15 Escherichia coli, including 10 extended-spectrum beta-lactamase (ESBL) producers; 15 Klebsiella pneumoniae, including 10 ESBL producers; 20 vancomycin-resistant Enterococcus faecium (VRE), including 10 that were linezolid resistant; and 5 vancomycin-susceptible Enterococcus faecalis. Time-kill testing was performed using tigecycline concentrations of 1x, 2x, and 4x MIC with colony-forming units (CFU) per milliliter determined at 0, 4, 8, 12, 24, 36, and 48 h. Tigecycline MICs (microg/mL) were < or =1 for E. coli and K. pneumoniae, regardless of the isolates' ESBL production; A. baumannii, 0.06 to 4; 9/10 (90%) were < or =2; E. faecalis < or =0.12; and VRE < or =0.25, regardless of linezolid susceptibility. In the time-kill assay, tigecycline significantly inhibited bacterial growth when compared with the growth control. The reduction in growth was <3 log(10) CFU/mL for all isolates, indicative of a bacteriostatic effect.

The detection of synergy between meropenem and polymyxin B against meropenem-resistant Acinetobacter baumannii using Etest and time-kill assay.

Time-kill assay and Etest testing for synergy of meropenem (MER) (1x MIC) plus polymyxin B (1/4, 1/2, and 1x MIC) were performed against 8 genetically unique MER-resistant clinical Acinetobacter baumannii isolates. Time-kill assay demonstrated synergy for all isolates, whereas Etest showed synergy in 5 isolates and indifference in 3.

In vitro testing of daptomycin plus rifampin against methicillin-resistant Staphylococcus aureus resistant to rifampin.

OBJECTIVE: To test for synergy between daptomycin (DAP) and rifampin (RIF) against RIF-resistant methicillin-resistant Staphylococcus aureus (MRSA) isolates. METHODS: Synergy testing using time-kill assay (TKA) was performed on 6 clinically, and genetically unique RIF-resistant MRSA isolates. The isolates were identified out of 489 (1.2%) samples collected during April 2003 to August 2006, from patients at the Ochsner Medical Center in New Orleans, Louisiana, United States of America. RESULTS: Synergy testing of DAP plus RIF by TKA showed that 5 isolates were indifferent, but one isolate was antagonistic. CONCLUSION: Our in vitro study failed to demonstrate synergy between DAP plus RIF, against our RIF-resistant MRSA isolates. Clinical failure of this combination should prompt the clinician to consider antagonism, as one of the potential causes.

Tigecycline in critical care.

The emergence and spread of multidrug resistance in many pathogenic bacterial species is increasing at an alarming rate, especially with hospital-acquired infections in the critical care setting. Deaths associated with hospital-acquired infections have exceeded the number attributable to several of the top 10 leading causes of death reported in the United States. The emerging resistance limits the use of older antibiotics. Tigecycline is a new agent, and this article explores its role in the treatment of adults in the critical care setting.

Study of common functional genetic polymorphisms of FCGR2A, 3A and 3B genes and the risk for cryptococcosis in HIV-uninfected patients.

A pilot candidate gene association study was conducted to investigate the role of three common functional genetic polymorphisms of the low-affinity Fc gamma receptors, FCGR2A (131H/R), FCGR3A (158F/V) and FCGR3B (NA1/NA2) in Cryptococcus neoformans infections in individuals not infected with HIV. The FCGR2A 131RR and FCGR3A 158VV genotypes were over-represented [OR: 1.67 (1.05-2.63) and 2.04 (1.06-4.00), respectively] whereas the FCGR3B NA2NA2 was under-represented in patients with cryptococcosis (28% vs. 40% in controls). An analysis of haplotypes showed a significant difference in distribution between cases and controls overall and in Caucasians.