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Open Forum Infectious Diseases May 2024Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in...
BACKGROUND
Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in immunocompromised patients with cancer are not well established.
METHODS
An antimicrobial time out, in the form of an email, was sent to physicians caring for hospitalized patients reaching 5 days of therapy for targeted antimicrobials (daptomycin, linezolid, tigecycline, vancomycin, imipenem/cilastatin, meropenem) in a comprehensive cancer center. Physicians were to discontinue the antimicrobial if unnecessary or document a rationale for continuation. This is a quasi-experimental, interrupted time series analysis assessing antimicrobial use during the following times: period 1 (before time-out: January 2007-June 2010) and period 2 (after time-out: July 2010-March/2015). The primary antimicrobial consumption metric was mean duration of therapy. Days of therapy per 1000 patient-days were also assessed.
RESULTS
Implementation of the time-out was associated with a significant decrease in mean duration of therapy for the following antimicrobials; daptomycin: -0.89 days (95% confidence interval [CI], -1.38 to -.41); linezolid: -0.89 days (95% CI, -1.27 to -.52); meropenem: -0.97 days (95% CI, -1.39 to -.56); tigecycline: -1.41 days (95% CI, -2.19 to -.63); < .001 for each comparison. Days of therapy/1000 patient-days decreased significantly for meropenem (-43.49; 95% CI, -58.61 to -28.37; < .001), tigecycline (-35.47; 95% CI, -44.94 to -26.00; < .001), and daptomycin (-9.47; 95% CI, -15.25 to -3.68; = .002).
DISCUSSION
A passive day 5 time-out was associated with reduction in targeted antibiotic use in a cancer center and could potentially be successfully adopted to several settings and electronic health records.
PubMed: 38798895
DOI: 10.1093/ofid/ofae235 -
International Journal of Infectious... May 2024This study conducted a network meta-analysis comparing linezolid, teicoplanin, daptomycin, tigecycline, and ceftaroline fosamil with vancomycin for treating MRSA-related...
OBJECTIVES
This study conducted a network meta-analysis comparing linezolid, teicoplanin, daptomycin, tigecycline, and ceftaroline fosamil with vancomycin for treating MRSA-related diseases, addressing the lack of comprehensive evaluations in existing research on antibiotic therapy for MRSA infections.
METHODS
We systematically searched databases including PubMed, Embase, Web of Science, the Cochrane Librar up to August 22, 2023. All eligible randomized controlled trials of the six antibiotics were included in the NMA, and their effectiveness and safety were compared across various MRSA-related diseases. Categorical data were used for the odds ratio (OR), and continuous data were used for mean difference (SMD). The surface under the cumulative ranking (SUCRA) was employed to evaluate the incidence rate.
RESULTS
According to SUCRA results, daptomycin was the most effective treatment (73.0%) in bloodstream infections. In pulmonary infections and skin and soft tissue infections, linezolid out-performed other antibiotics in effectiveness rate (90.6% and 86.3%), microbial killing rate (93.3% and 93.1%). Vancomycin showed lower adverse reactions than teicoplanin, with less hepatotoxicity compared to linezolid and tigecycline. Linezolid had higher thrombocytopenia risk but lower nephrotoxicity risk than others. Vancomycin was less effective in microbial killing rates than linezolid across various infections.
CONCLUSIONS
The present research suggests that in pulmonary infections and skin and soft tissue infections, linezolid may be a better option for treating MRSA-related diseases. However, caution is warranted due to the association of linezolid with thrombocytopenia.
TRIAL REGISTRATION
Our study protocol was registered with the International Prospective Register of SystematicReviews (PROSPERO); Registration number: CRD42024535142.
PubMed: 38789000
DOI: 10.1016/j.ijid.2024.107109 -
Frontiers in Pharmacology 2024Daptomycin is gaining prominence for the treatment of methicillin-resistant infections. However, the dosage selection for daptomycin in critically ill patients remains...
Daptomycin is gaining prominence for the treatment of methicillin-resistant infections. However, the dosage selection for daptomycin in critically ill patients remains uncertain, especially in Chinese patients. This study aimed to establish the population pharmacokinetics of daptomycin in critically ill patients, optimize clinical administration plans, and recommend appropriate dosage for critically ill patients in China. The study included 64 critically ill patients. Blood samples were collected at the designated times. The blood daptomycin concentration was determined using validated liquid chromatography-tandem mass spectrometry. A nonlinear mixed-effects model was applied for the population pharmacokinetic analysis and Monte Carlo simulations of daptomycin. The results showed a two-compartment population pharmacokinetic model of daptomycin in critically ill adult Han Chinese patients. Monte Carlo simulations revealed that a daily dose of 400 mg of daptomycin was insufficient for the majority of critically ill adult patients to achieve the anti-infective target. For critically ill adult patients with normal renal function (creatinine clearance rate >90 mL/min), the probability of achieving the target only reached 90% when the daily dose was increased to 700 mg. For patients undergoing continuous renal replacement therapy (CRRT), 24 h administration of 500 mg met the pharmacodynamic goals and did not exceed the safety threshold in most patients. Therefore, considering its efficacy and safety, intravenous daptomycin doses are best scaled according to creatinine clearance, and an increased dose is recommended for critically ill patients with hyperrenalism. For patients receiving CRRT, medication is recommended at 24 h intervals.
PubMed: 38756382
DOI: 10.3389/fphar.2024.1378872 -
MSphere May 2024Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistant . In the rare...
UNLABELLED
Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistant . In the rare event of failed daptomycin therapy, the source of resistance is often attributable to mutations directly within the membrane phospholipid biosynthetic pathway of or in the regulatory systems that control cell envelope response and membrane homeostasis. Here we describe the structural changes to the cell envelope in a daptomycin-resistant isolate of strain N315 that has acquired mutations in the genes most commonly reported associated with daptomycin resistance: , , and . In addition to the decreased phosphatidylglycerol (PG) levels that are the hallmark of daptomycin resistance, the mutant with high-level daptomycin resistance had increased branched-chain fatty acids (BCFAs) in its membrane lipids, increased membrane fluidity, and increased cell wall thickness. However, the successful utilization of isotope-labeled straight-chain fatty acids (SCFAs) in lipid synthesis suggested that the aberrant BCFA:SCFA ratio arose from upstream alteration in fatty acid synthesis rather than a structural preference in PgsA. Transcriptomics studies revealed that expression of pyruvate dehydrogenase () was suppressed in the daptomycin-resistant isolate, which is known to increase BCFA levels. While complementation with an additional copy of had no effect, complementation of the mutation resulted in increased PG formation, reduction in cell wall thickness, restoration of normal BCFA levels, and increased daptomycin susceptibility. Collectively, these results demonstrate that contributes to daptomycin resistance through its influence on membrane fluidity and cell wall thickness, in addition to phosphatidylglycerol levels.
IMPORTANCE
The cationic lipopeptide antimicrobial daptomycin has become an essential tool for combating infections with that display reduced susceptibility to β-lactams or vancomycin. Since daptomycin's activity is based on interaction with the negatively charged membrane of , routes to daptomycin-resistance occur through mutations in the lipid biosynthetic pathway surrounding phosphatidylglycerols and the regulatory systems that control cell envelope homeostasis. Therefore, there are many avenues to achieve daptomycin resistance and several different, and sometimes contradictory, phenotypes of daptomycin-resistant , including both increased and decreased cell wall thickness and membrane fluidity. This study is significant because it demonstrates the unexpected influence of a lipid biosynthesis gene, , on membrane fluidity and cell wall thickness in with high-level daptomycin resistance.
PubMed: 38752757
DOI: 10.1128/msphere.00115-24 -
Experimental and Clinical... Apr 2024Tigecycline is a parenteral glycycline antibiotic that is used to treat severe infections caused by susceptible organisms, butitis also associated with hepatotoxicity....
Tigecycline is a parenteral glycycline antibiotic that is used to treat severe infections caused by susceptible organisms, butitis also associated with hepatotoxicity. We present 2 similar patients with hepatic steatosis possibly associated with early tigecycline after transplant. In the first case, a 61-year-old woman underwent liver transplant for acute severe hepatitis; 6 days posttransplant, because of nonroutine resistant fever, the patient received tigecycline combined with daptomycin. Retransplant was applied to the patient on day 12 posttransplant because of acute liver failure secondary to hepatic vein thrombosis. After retransplant, biochemical levels gradually increased, exceeding the upper limit of normal. In liver biopsy, the patient had macrovesicular steatosis in 70% to 80% ofthe parenchyma. In the second case, a 53-yearold woman underwent liver transplant for liver cirrhosis. Tigecycline was added to the treatment because of recurrent fever on day 6 after transplant, with treatment also comprising piperacillin-tazobactam and meropenem. On day 15 of the patient's tigecycline treatment, her liver function tests were elevated. In liver biopsy, the patient had 30% to 40% macrovesicular steatosis and canalicular cholestasis in the parenchyma, especially in zone 3. Reports of hepatic steatosis associated with early tigecycline after transplant are quite new to the literature.
Topics: Humans; Tigecycline; Female; Middle Aged; Liver Transplantation; Anti-Bacterial Agents; Fatty Liver; Treatment Outcome; Biopsy; Minocycline
PubMed: 38742325
DOI: 10.6002/ect.2023.0227 -
Cureus Apr 2024Lemierre-like syndrome is a rare, systemic sequelae following a persistent oropharyngeal infection, leading to septic thrombophlebitis of the internal jugular vein...
Lemierre-like syndrome is a rare, systemic sequelae following a persistent oropharyngeal infection, leading to septic thrombophlebitis of the internal jugular vein (IJV). Lemierre syndrome is caused by the obligate anaerobic organism , innate to the oropharyngeal tract. Lemierre-like syndrome is due to infections caused by other organisms, including methicillin-resistant (MRSA). We are reporting a case of a five-month-old male who presented with one week of fever that was not alleviated by acetaminophen, bilateral otitis media, and left-sided cervical lymphadenopathy not alleviated with medical therapy. The patient's clinical course continued to deteriorate as he developed respiratory distress that progressed to acute respiratory failure requiring mechanical ventilation support. Extensive laboratory investigation ruled out the causes of primary and secondary immunodeficiencies. Blood cultures were positive for MRSA, and he was treated initially with vancomycin, then switched to linezolid per ENT recommendations, and ultimately needed daptomycin and ceftaroline therapy. A computed tomography (CT) scan of the neck and chest showed deep neck space infection, bilateral loculated pleural empyema, and mediastinitis. The patient required a decortication video-assisted thoracoscopic surgery (VATS), multiple drains, and a mediastinal washout to control the MRSA infection. This report emphasizes that the rapid progression and spread of septic thrombus can become detrimental to a patient's recovery and survival; therefore, it should be recognized early and treated promptly.
PubMed: 38741847
DOI: 10.7759/cureus.58192 -
Open Forum Infectious Diseases May 2024Daptomycin use for gram-positive infections has increased. This cost minimization analysis aimed to determine cost and/or time savings of daptomycin over vancomycin. The...
Daptomycin use for gram-positive infections has increased. This cost minimization analysis aimed to determine cost and/or time savings of daptomycin over vancomycin. The estimated hospital cost savings was US$166.41 per patient, and pharmacist time saved of almost 20 minutes per patient. Daptomycin has the potential to save both time and money.
PubMed: 38737432
DOI: 10.1093/ofid/ofae217 -
Cureus Apr 2024The use of probiotics to improve bacterial flora and achieve control of diarrheal episodes is a common practice in outpatients and hospitalized patients. In most cases,...
The use of probiotics to improve bacterial flora and achieve control of diarrheal episodes is a common practice in outpatients and hospitalized patients. In most cases, related adverse events are few and not life-threatening. However, cases of bacteremia associated with the use of these substances have been described, mainly in the pediatric population in which their prescription is more common. Cases of bacteremia and sepsis have also been documented in immunocompetent and immunocompromised adult patients following the use of probiotics. We present the report of two patients who, in the context of diarrhea, received probiotics with spores during their stay in the intensive care unit. They subsequently developed sepsis and blood-culture-documented bacteremia. Both patients were treated with daptomycin as the final treatment regimen.
PubMed: 38721227
DOI: 10.7759/cureus.57853 -
Microbiology Spectrum May 2024Membrane fluidity and thickness have emerged as crucial factors for the activity of and resistance to several antimicrobials. However, the lack of tools to study...
UNLABELLED
Membrane fluidity and thickness have emerged as crucial factors for the activity of and resistance to several antimicrobials. However, the lack of tools to study membrane fluidity and, in particular, thickness in living bacteria limits our understanding of this interplay. The histidine kinase/phosphatase DesK is a molecular sensor that directly detects membrane thickness. It controls activity of DesR, which regulates expression of the lipid desaturase Des, known for its role in cold adaptation and daptomycin susceptibility. We hypothesized that this property could be exploited to develop biosensors and reporters for antibiotic-induced changes in membrane fluidity and thickness. To test this, we designed three assays based on the system: activation of the promoter as reporter for membrane thickening, localization of DesK-GFP(green-fluorescent protein) as proxy for rigidified membrane domains, and antibiotic sensitivity of , , and deletion mutants as readout for the importance of membrane rigidification/thickening under the tested condition. While we could not confirm the suitability of the system as reporter for antibiotic-induced changes in membrane thickness, we did observe that expression is only activated by mild temperature shocks, likely due to partitioning of the sensor DesK into fluid membrane domains upon phase separation, precluding effective thickness sensing under harsh cold shock and antibiotic stress conditions. Similarly, we did not observe any sensitivity of the deletion mutants to either temperature or antibiotic stress, raising the question to what extent the system contributes to fluidity adaptation under these conditions.
IMPORTANCE
The des system is a prime model for direct molecular membrane thickness sensor and, as such, has been well studied . Our study shows that our understanding of its function and its importance under temperature and antibiotic stress is still very limited. Specifically, our results suggest that (i) the system senses very subtle membrane fluidity changes that escape detection by established fluidity reporters like laurdan; (ii) membrane thickness sensing by DesK is impaired by phase separation due to partitioning of the protein into the fluid phase; and (iii) fluidity adaptations by Des are too subtle to elicit growth defects under rigidifying conditions, raising the question of how much the system contributes to adaptation of overall membrane fluidity.
PubMed: 38717171
DOI: 10.1128/spectrum.03925-23 -
Brain Communications 2024New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal... (Review)
Review
New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal meningitis in order to identify treatments with the most potential to progress to clinical trials. Studies testing therapy adjunctive to antibiotics in animal models of pneumococcal meningitis were included. A literature search was performed using Medline, Embase and Scopus for studies published from 1990 up to 17 February 2023. Two investigators screened studies for inclusion and independently extracted data. Treatment effect was assessed on the clinical parameters disease severity, hearing loss and cognitive impairment and the biological parameters inflammation, brain injury and bacterial load. Adjunctive treatments were evaluated by their effect on these outcomes and the quality, number and size of studies that investigated the treatments. Risk of bias was assessed with the SYRCLE risk of bias tool. A total of 58 of 2462 identified studies were included, which used 2703 experimental animals. Disease modelling was performed in rats (29 studies), rabbits (13 studies), mice (12 studies), gerbils (3 studies) or both rats and mice (1 study). Meningitis was induced by injection of into the subarachnoid space. Randomization of experimental groups was performed in 37 of 58 studies (64%) and 12 studies (12%) were investigator-blinded. Overall, 54 treatment regimens using 46 adjunctive drugs were evaluated: most commonly dexamethasone (16 studies), daptomycin (5 studies), complement component 5 (C5; 3 studies) antibody and Mn(III)tetrakis(4-benzoicacid)porphyrin chloride (MnTBAP; 3 studies). The most frequently evaluated outcome parameters were inflammation [32 studies (55%)] and brain injury [32 studies (55%)], followed by disease severity [30 studies (52%)], hearing loss [24 studies (41%)], bacterial load [18 studies (31%)] and cognitive impairment [9 studies (16%)]. Adjunctive therapy that improved clinical outcomes in multiple studies was dexamethasone (6 studies), C5 antibodies (3 studies) and daptomycin (3 studies). HMGB1 inhibitors, matrix metalloproteinase inhibitors, neurotrophins, antioxidants and paquinimod also improved clinical parameters but only in single or small studies. Evaluating the treatment effect of adjunctive therapy was complicated by study heterogeneity regarding the animal models used and outcomes reported. In conclusion, 24 of 54 treatment regimens (44%) tested improved clinically relevant outcomes in experimental pneumococcal meningitis but few were tested in multiple well-designed studies. The most promising new adjunctive treatments are with C5 antibodies or daptomycin, suggesting that these drugs could be tested in clinical trials.
PubMed: 38707710
DOI: 10.1093/braincomms/fcae131