Infection incidence for total hip and knee arthroplasty (THA and TKA, respectively) is between 0.2% and 5% and results in approximately 100,000 device failures per year in the United States. ...Treatment requires prolonged systemic antibiotic therapy with additional surgical revisions. As a prophylactic measure against infection, antibiotics can be incorporated into bone cement during THA and TKA to provide drug administration at the implant site. Antibiotics in bone cement are only effective if they can elute out of the cement at a concentration that is active against common organisms. There is evidence that added antibiotics may affect the cement's mechanical properties, especially at higher dosages. The purposes of this investigation were to (i) determine the mechanical properties of a commercially available bone cement with the addition of vancomycin, (ii) determine the release characteristics of vancomycin added to bone cement, and (iii) evaluate eluted vancomycin efficacy at eliminating some of the most common causative orthopedic implant pathogens. Palacos bone cement was impregnated with incrementally larger clinically relevant weight percentages of vancomycin. Vancomycin is a treatment standard for invasive gram-positive infections, and Palacos cement is one of the most commonly used bone cements. After 21 days of curing in PBS, added masses of vancomycin greater than 0.5 g per 40.0 g cement packet decreased the cement's compressive yield strength to below ISO standard. The addition of vancomycin reduced the bone cement's mechanical properties in compression more than in bending. Vancomycin eluted from Palacos with a steady rise in eluted volume up to 8 days, after which non-therapeutic elution concentrations were observed up to a 60-day end point. The eluted concentration from samples with greater than 0.25 g vancomycin per Palacos packet was sufficient to eliminate a 10
colony forming unit per mL (CFU/mL) initial inoculum of S. aureus, including methicillin-resistant S. aureus (MRSA). However, none of the tested dosages were able to fully clear a 10
CFU/mL initial inoculum of a known high biofilm producing strain of S. epidermidis. When used for infection prophylaxis at the time of THA and TKA, the findings of this study do not support the addition of more than 0.5 g vancomycin to a 40 g packet of Palacos cement due to a reduction in compression yield strength below ISO standards. Vancomycin doses up to 0.5 g were shown to elute from the bone cement matrix and are effective at treating bacterial infections of 10
CFU/mL in bacterial strains of S. aureus, but may have limited effect against high-biofilm producing strains including S. epidermidis.
(
) infections (CDI) are commonly treated with antibiotics that do not impact the dormant spore form of the pathogen. CDI-directed antibiotics, such as vancomycin and metronidazole, can destroy the ...vegetative form of
and protective microbiota. After treatment, spores can germinate into vegetative cells causing clinical disease relapse and further spore shedding. This
study compares the combination of germinants with vancomycin or omadacycline to antibiotics alone in eradicating
spores and vegetative cells. Among the four strains in this study, omadacycline minimum inhibitory concentrations (0.031-0.125 mg/L) were lower than vancomycin (1-4 mg/L). Omadacycline nor vancomycin in media alone reduced spore counts. In three of the four strains, including the epidemic ribotype 027, spore eradication with germinants was 94.8-97.4% with vancomycin and 99.4-99.8% with omadacycline (p<0.005). In ribotype 012, either antibiotic combined with germinants resulted in 100% spore eradication at 24 hours. The addition of germinants with either antibiotic did not result in significant toxin A or B production, which were below the limit of detection (<1.25 ng/mL) by 48 hours. Limiting the number of spores present in patient GI tracts at the end of therapy may be effective at preventing recurrent CDI and limiting spore shedding in the healthcare environment. These results with germinants warrant safety and efficacy evaluations in animal models.
Tigecycline is the first commercially available member of the glycylcyclines, a new class of antimicrobial agents. The glycylcyclines are derivatives of the tetracycline antibiotics, with structural ...modifications that allow for potent gram‐positive, gram‐negative, and anaerobic activity, including certain multidrug‐resistant strains. The enhanced activity can be attributed to stronger binding affinity and enhanced protection against several mechanisms of resistance that affect other antibiotic classes such as tetracyclines. Tigecycline exhibits generally bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation. In vitro activity has been demonstrated against multidrug‐resistant gram‐positive pathogens including methicillin‐resistant and glycopeptide‐intermediate and ‐resistant Staphylococcus aureus, as well as vancomycin‐resistant enterococci. Multidrug‐resistant gram‐negative pathogens, such as Acinetobacter baumannii and extended‐spectrum β‐lactamase–producing Klebsiella pneumoniae and Escherichia coli, are typically highly susceptible to tigecycline. The drug also has displayed significant activity against many clinically important anaerobic organisms. This agent demonstrates a predictable pharmacokinetic profile and minimal drug interactions, and is generally well tolerated, with nausea being the most common adverse event. It was approved in June 2005 for the treatment of complicated skin and skin structure infections (SSSIs) and complicated intraabdominal infections. Currently, a limited number of broad‐spectrum antimicrobials are available to combat multidrug‐resistant organisms. The addition of new agents is essential to limiting the spread of these pathogens and improving outcomes in patients with these types of infections. Tigecycline has demonstrated promising results in initial in vitro and clinical studies for SSSIs and complicated intraabdominal infections; however, further clinical experience will clarify its role as a broad‐spectrum agent.
Antimicrobial susceptibility testing (AST) remains the cornerstone of effective antimicrobial selection and optimization in patients. Despite recent advances in rapid pathogen identification and ...resistance marker detection with molecular diagnostics (
, qPCR, MALDI-TOF MS), phenotypic (
, microbial culture-based) AST methods - the gold standard in hospitals/clinics - remain relatively unchanged over the last few decades. Microfluidics-based phenotypic AST has been growing fast in recent years, aiming for rapid (
, turnaround time <8 h), high-throughput, and automated species identification, resistance detection, and antibiotics screening. In this pilot study, we describe the application of a multi-liquid-phase open microfluidic system, named under-oil open microfluidic systems (UOMS), to achieve a rapid phenotypic AST. UOMS provides an open microfluidics-based solution for rapid phenotypic AST (UOMS-AST) by implementing and recording a pathogen's antimicrobial activity in micro-volume testing units under an oil overlay. UOMS-AST allows free physical access (
, by standard pipetting) to the system and label-free, single-cell resolution optical access. UOMS-AST can accurately and rapidly determine antimicrobial activities including susceptibility/resistance breakpoint and minimum inhibitory concentration (MIC) from nominal sample/bacterial cells in a system aligned with clinical laboratory standards where open systems and optical microscopy are predominantly adopted. Further, we combine UOMS-AST with a cloud lab data analytic technique for real-time image analysis and report generation to provide a rapid (<4 h) sample-to-report turnaround time, shedding light on its utility as a versatile (
, low-resource setting and manual laboratory operation, or high-throughput automated system) phenotypic AST platform for hospital/clinic use.
Increased usage of daptomycin (DAP) for methicillin-resistant Staphylococcus aureus (MRSA) infections has led to emergence of DAP-resistant (DAP-R) strains, resulting in treatment failures. ...DAP-fosfomycin (Fosfo) combinations are synergistically active against MRSA, although the mechanism(s) of this interaction is not fully understood. The current study explored four unique but likely interrelated activities of DAP-Fosfo combinations: (i) synergistic killing, (ii) prevention of evolution of DAP-R, (iii) resensitization of already DAP-R subpopulations to a DAP-susceptible (DAP-S) phenotype, and (iv) perturbations of specific cell envelope phenotypes known to correlate with DAP-R in MRSA. Using an isogenic DAP-S (CB1483)/DAP-R (CB185) clinical MRSA strain pair, we demonstrated that combinations of DAP plus Fosfo (DAP+Fosfo) (i) enhanced killing of both strains
and
, (ii) increased target tissue clearances of the DAP-R strain in an
model of experimental infective endocarditis (IE), (iii) prevented emergence of DAP-R in the DAP-S parental strain both
and
, and (iv) resensitized the DAP-R strain to a DAP-S phenotype
. Phenotypically, following exposure to sub-MIC Fosfo, the DAP-S/DAP-R strain pair exhibited distinct modifications in (i) net positive surface charge (
< 0.05), (ii) quantity (
< 0.0001) and localization of cell membrane cardiolipin (CL), (iii) DAP surface binding, and (iv) membrane fluidity (
< 0.05). Furthermore, preconditioning this strain pair to DAP with or without Fosfo (DAP+/-Fosfo) sensitized these organisms to killing by the human host defense peptide LL37. These data underscore the notion that DAP-Fosfo combinations can impact MRSA clearances within multiple microenvironments, likely based on specific phenotypic adaptations.
Methicillin-resistant
(MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, ...an approved lipoglycopeptide used to treat infections due to
, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against
infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived
strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC
was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC
and 25-fold lower than the linezolid and vancomycin MIC
We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log
CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against
strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur
in both CF- and non-CF patient-derived
strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant
mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a
infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent
activity and a low resistance development potential.
Objectives This study evaluated vancomycin susceptibility and activity alone and in combination with rifampicin and tigecycline against low-biofilm- and high-biofilm-producing methicillin-resistant ...Staphylococcus aureus (MRSA) clinical isolates. Methods Forty MRSA isolates recovered from bloodstream infections were analysed. Susceptibilities were performed in planktonic and biofilm cultures by microbroth dilution. Biofilm production was determined using an adherent plate assay. Time–kill analysis was performed on six low- and six high-biofilm-producing isolates with 15 mg/L vancomycin alone and in combination with rifampicin or tigecycline at 4× MIC. Results Vancomycin susceptibility displayed a 4-fold and an 8-fold increase in the MIC50 and MIC90, respectively, in the presence of biofilm. Rifampicin and tigecycline susceptibilities also increased in biofilms, but still remained within the susceptibility breakpoints except for a tigecycline MIC90 of 1 mg/L. High biofilm production was detected in 60% of the isolates. In time–kill analysis, 15 mg/L vancomycin achieved bactericidal activity against only low-biofilm-producing strains with a 1.8 log10 cfu/mL difference in bacterial kill compared with high-biofilm-producing strains (P < 0.001). Rifampicin alone had minimal activity, resulting in resistance. Tigecycline was minimally effective and was not bactericidal, but no difference was observed in the comparison of biofilm-producing strains. Vancomycin in combination with rifampicin or tigecycline was bactericidal against all strains (mean kill 4.5 ± 0.5 log10 cfu/mL), regardless of biofilm production. Conclusions Vancomycin exposures at 15 mg/L may not be adequate in eradicating biofilm-producing S. aureus. Alternative treatments or combination therapy should be explored to optimize outcomes in biofilm-associated infections.
In response to the antimicrobial resistance crisis, pharmaceutical industry reinvested in and produced new antibiotics. Antimicrobial stewardship programs influence optimal antimicrobial use, which ...often places them at the cross-roads of resistance and treatments. We surveyed a clinical administration database of US medical centers between 2014 and 2018 for index antimicrobial utilization date of six Qualified Infectious Diseases Products (QIDP). Among 132 hospitals identified, the median time to use any agent was 398 days (range 13 to >1478 days). QIDP antibiotic use was more likely among academic medical centers (range 34%–88%) and hospitals >400 beds (range 39%–86%) compared to non-academic medical center (3–51%) and smaller and hospitals (range 0–61%). The South was quickest to use all QIDP (median 733 days), while the Northeast was longest at 1370 days. New antimicrobials have limited clinical use, which impacts manufacturers' ability to stay in the antimicrobial market and further risking a depleted antimicrobial pipeline.
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