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Harris A, Morgan D, Pineles L, et al.
AbstractBackgroundThe Benefits of Universal Gloves and Gowns cluster randomized trial found varying effects on MRSA and VRE and no increase in adverse events. The aim of this study was to assess whether the intervention decreases the acquisition of antibiotic-resistant Gram-negative bacteria.MethodsSecondary analysis of 20 hospital intensive care unit, randomized trial. The intervention consisted of healthcare workers wearing gloves and gowns when entering any patient room compared to standard care. The primary composite outcome was acquisition of any antibiotic-resistant Gram-negative bacteria based on surveillance cultures.FindingsA total of 40,492 admission and discharge perianal swabs from 20,246 individual patient admissions were included in the primary outcome. For the primary outcome of acquisition of any antibiotic-resistant Gram-negative bacteria, the intervention had a RR of 0.90 (95% CI 0.71 to 1.12, p= 0.34). Effects on the secondary outcomes of individual bacteria acquisition were as follows: carbapenem-resistant Enterobacteriaceae [RR 0.86 (95% CI, 0.60 to 1.24), p=0.43], carbapenem-resistant Acinetobacter [RR 0.81 (95% CI, 0.52 to 1.27) p=0.36], carbapenem-resistant Pseudomonas [RR 0.88 (95% CI, 0.55 to 1.42) p=0.62], ESBL producing bacteria [RR 0.94, (95% CI, 0.71 to 1.24) p=0.67].InterpretationUniversal glove and gown use in the ICU was associated with a non-statistically significant decrease in acquisition of antibiotic-resistant Gram-negative bacteria. Individual hospitals should consider the intervention based on the importance of these organisms at their hospital, effect sizes, confidence intervals, and cost of instituting the intervention.Trial registrationClinicaltrials.gov identifier NCT01318213
Waterer, G., Lord, J., Hofmann, T., Jouhikainen, T.
Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, we developed a dry powder formulation suitable for inhalation (AeroVanc). Here we report a Phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In Part I, 18 healthy subjects received a single dose of 16 mg, 32 mg or 80 mg of AeroVanc. Two subjects also received a 250 mg dose of intravenous vancomycin. In Part 2 of the study, 32 mg and 80 mg AeroVanc was administered to subjects with cystic fibrosis as single doses. There were no serious side effects. A small drop in FEV1 was observed in 3 subjects with cystic fibrosis, one of whom required salbutamol. Vancomycin was rapidly absorbed after inhalation. Peak and mean plasma concentrations of vancomycin were dose proportional. The average minimum concentration of vancomycin in sputum remained above the usual MIC values for MRSA for up to 24 hours (Cmin: 32mg dose = 3.05 μg/ml, 80mg dose = 8.0 μg/ml). In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.
The FDA has authorized a new diagnostic test based on bacteriophage technology to detect methicillin-resistant Staphylococcus aureus (MRSA) colonization more quickly than traditional culture-based techniques allow.
Simonetti, O., Lucarini, G., Morroni, G., Orlando, F., Lazzarini, R., Zizzi, A., Brescini, L., Provinciali, M., Giacometti, A., Offidani, A., Cirioni, O.
Dalbavancin is an effective antibiotic widely used to treat skin infection. Our aim was to determinate the effects of dalbavancin administration on wound healing compared to vancomycin, and to elucidate if EGFR, MMP-1, MMP-9 and VEGF could be involved in its therapeutic mechanism.A mouse model of MRSA skin infection was established. Mice were treated daily with vancomycin (10mg/kg) and weekly with dalbavancin, at day 1 (20 mg/kg) and day 8 (10 mg/kg). After 14 days wounds were excised and bacterial counts were perfomed. Wound healing was assessed by histological and immunohistochemical staining, followed by protein extraction and immunoblotting.Our microbiological results confirmed that both dalbanvancin and vancomycin are effective in reducing the bacterial load in wounds. Dalbavancin had a strong effect compared with infected untreated animals and vancomycin treated group. The wounds treated with dalbavancin showed robust epidermal coverage with a reconstitution of the regular and keratinized epidermal lining and a well-organized granulation tissue with numerous blood vessels, although slightly less than in the uninfected group, while in vancomycin treated group the epithelium appeared in general still hypertrophic, the granulation tissue appears even less organized.We observed elevated EGFR and VEGF expression in both treated groups, although it was higher in dalbavancin treated mice. MMP-1 and MMP-9 were decreased in uninfected and in both treated tissue when compared with untreatd infected wounds.This study showed faster healing with dalbavancin treatment that might be associated with a higher EGFR and VEGF levels.
Jin, Y., Guo, Y., Zhan, Q., Shang, Y., Qu, D., Yu, F.
Previous studies have shown that the administration of antibiotics at sub-inhibitory concentrations stimulates biofilm formation by the majority of MRSA strains. Here, we investigated the effect of sub-inhibitory mupirocin concentrations on biofilm formation by the community-associated (CA) mupirocin-sensitive MRSA strain USA300 and highly mupirocin-resistant clinical S. aureus SA01-SA05 isolates. We found that mupirocin increased the ability of MRSA cells to attach to surfaces and form biofilms. Confocal laser scanning microscopy (CLSM) demonstrated that mupirocin treatment promoted thicker biofilm formation, which also correlated with the production of extracellular DNA (eDNA). Furthermore, RT-qPCR results revealed that this effect was largely due to the involvement of holin-/antiholin-like proteins (encoded by the cidA gene), which are responsible for modulating cell death and lysis during biofilm development. We found that cidA expression levels significantly increased 6.05-35.52 fold (P < 0.01) on mupirocin administration. We generated a cidA-deficient mutant of the USA300 S. aureus strain. Exposure of the cidA mutant to mupirocin did not result in thicker biofilm formation compared with that in the parent strain. We therefore hypothesize that the mupirocin-induced stimulation of S. aureus biofilm formation may involve the upregulation of cidA.
Cheng Wan Rong Carmen, Ong Chiou Horng, Chan Su Gin Douglas
The objective of this study is to determine if using alternative streaking patterns on the BD Kiestra™ InoqulA™ can impact colony isolation and improve turnaround time (TAT) of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacterales (CRE) screening samples.
Allan, D. S., del Carmen Parquet, M., Savage, K. A., Holbein, B. E.
MRSA opportunistic infections are a major health burden. Decolonization of hospitalized patients with mupirocin (MUP) has reduced infection incidence but has led to MUP resistance. DIBI is a developmental-stage anti-infective that sequesters bacterial iron and bolsters innate host iron withdrawal defences. Clinical isolates possessing low, high or no MUP-resistance all had similarly high susceptibilities to DIBI. Intranasal DIBI reduced nares bacterial burdens in mice to the same extent as MUP. No resistance was found following exposure to DIBI.
An efficient surface cleaning strategy would first target cleaning to surfaces that make large contributions to the risk of infections.
In this study, we used data from the literature about methicillin-resistant Staphylococcus aureus (MRSA) and developed an ordinary differential equations based mathematical model to quantify the impact of contact heterogeneity on MRSA transmission in a hypothetical 6-bed intensive care unit (ICU). The susceptible patients are divided into two types, these who are cared by the same nurse as the MRSA infected patient (Type 1) and these who are not (Type 2).
The results showed that the mean MRSA concentration on three kinds of susceptible patient nearby surfaces was significantly linearly associated with the hand-touch frequency (p
Helio S. Sader, Ronald N. Jones
Urban and Stone presented a valuable assessment of the impact of recently revised European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for ceftaroline on the ceftaroline susceptibility rates of 5,566 methicillin-resistant Staphylococcus aureus (MRSA) isolates . Their findings indicate that for the regions (Africa, Asia, Europe, Oceania, South America) included in the evaluation, MRSA isolates with a ceftaroline MIC value of >2 mg/L remain rare, and most isolates that were previously considered resistant to ceftaroline are now categorized as intermediate based on the version 8.0 of EUCAST (2018) breakpoint criteria .
Accurate determination of the efficacy of antimicrobial agents requires neutralization of residual antimicrobial activity in the samples before microbiological assessment of the number of surviving bacteria. Sodium polyanethol sulfonate (SPS) is a known neutralizer for the antimicrobial activity of aminoglycosides and polymyxins. In this study, we evaluated the ability of SPS to neutralize residual antimicrobial activity of antimicrobial peptides [SAAP-148 and pexiganan; 1% (wt/v) in PBS], antibiotics [mupirocin (Bactroban) and fusidic acid (Fucidin) in ointments; 2% (wt/wt))] and disinfectants [2% (wt/wt) silver sulfadiazine cream (SSD) and 0.5% (v/v) chlorhexidine in 70% alcohol].
Homogenates of human skin models that had been exposed to various antimicrobial agents for 1 h were pipetted on top of Methicillin-resistant Staphylococcus aureus (MRSA) on agar plates to determine whether the antimicrobial agents display residual activity.
To determine the optimal concentration of SPS for neutralization, antimicrobial agents were mixed with PBS or increasing doses of SPS in PBS (0.05–1% wt/v) and then 105 colony forming units (CFU)/mL MRSA were added. After 30 min incubation, the number of viable bacteria was assessed. Next, the in vitro efficacy of SAAP-148 against various gram-positive and gram-negative bacteria was determined using PBS or 0.05% (wt/v) SPS immediately after 30 min incubation of the mixture. Additionally, ex vivo excision wound models were inoculated with 105 CFU MRSA for 1 h and exposed to SAAP-148, pexiganan, chlorhexidine or PBS for 1 h. Subsequently, samples were homogenized in PBS or 0.05% (wt/v) SPS and the number of viable bacteria was assessed.
All tested antimicrobials displayed residual activity in tissue samples, resulting in a lower recovery of surviving bacteria on agar. SPS concentrations at ≥0.05% (wt/v) were able to neutralize the antimicrobial activity of SAAP-148, pexiganan and chlorhexidine, but not of SSD, Bactroban and Fucidin. Finally, SPS-neutralization in in vitro and ex vivo efficacy tests of SAAP-148, pexiganan and chlorhexidine against gram-positive and gram-negative bacteria resulted in significantly higher numbers of CFU compared to control samples without SPS-neutralization.
SPS was successfully used to neutralize residual activity of SAAP-148, pexiganan and chlorhexidine and this prevented an overestimation of their efficacy.
Empirical treatment of patients with cellulitis/erysipelas usually targets both streptococci and methicillin-sensitive S. aureus (MSSA). However, the recommendation to empirically cover MSSA is weak and based on low-quality evidence.
Methods and objective
A systematic review was conducted in PubMed and clinical trial registries to assess the role of S. aureus in cellulitis/erysipelas and the need for empirical MSSA coverage.
Combined microbiological and serological data, and response to penicillin monotherapy suggest that streptococci are responsible for the vast majority of cases of cellulitis/erysipelas. However, most cases are non-culturable and the specificity of microbiological and serological studies is questionable based on recent studies using molecular techniques. According to epidemiological data and three randomized controlled trials, empirical coverage of methicillin-resistant S. aureus (MRSA) is not recommended for most patients, despite the high prevalence of MRSA in many areas. If MRSA is indeed not an important cause of uncomplicated cellulitis/erysipelas, then the same may apply to MSSA. Based on indirect comparison of data from clinical studies, cure rates with penicillin monotherapy (to which most MSSA are resistant) are comparable to the cure rates reported in many studies using wider-spectrum antibiotics.
Considering the limitations of microbiological studies in identifying the pathogens responsible for cellulitis/erysipelas, treatment needs to be guided by clinical trials. Trials comparing penicillin or amoxicillin monotherapy to MSSA-covering regimens are needed to definitively answer whether empirical coverage of MSSA is needed and to identify the subset of patients that can be safely treated with penicillin or amoxicillin monotherapy.
McCurdy, S., Keedy, K., Lawrence, L., Nenninger, A., Sheets, A., Quintas, M., Cammarata, S.
Delafloxacin is a novel fluoroquinolone with activity against Gram-positive, Gram-negative and atypical pathogens, including fluoroquinolone non-susceptible MRSA. The microbiological results of a phase 3 clinical trial in community acquired pneumonia comparing delafloxacin [300 mg IV with option to switch to 450 mg orally every 12h to moxifloxacin 400 mg IV with option to switch to 400 mg orally QD] were determined. Patients from 4 continents, predominately Europe but also South America, and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 520 patients and 60.5% of these patients had a bacterial pathogen identified. Multiple diagnostic methods were employed including culture, serology, PCR, and urinary antigen. Based on baseline MIC90 values, delafloxacin exhibited at least 16-fold greater activity than moxifloxacin for Gram-positive and fastidious Gram-negative pathogens. Delafloxacin retained activity against resistant phenotypes found in S. pneumoniae (penicillin-, macrolide-, multiple-drug resistant), Haemophilus species (β-lactamase producing, macrolide-non-susceptible) and S. aureus (MRSA, fluoroquinolone-non-susceptible MSSA). The microbiological success rates were: 92.7% for S. pneumoniae (87.5% for PRSP), 92.6% for S. aureus (100% for MRSA), 100% for E. coli, 82.4% for K. pneumoniae, 100% for K. oxytoca, 100% for M. catarrhalis, 91.7% for H. influenzae, 88.6% for H. parainfluenzae, 96.7% for M. pneumoniae, 93.1% for L. pneumophila, and 100% for C. pneumoniae. There was little correlation between MIC and outcome with a high proportion of favorable outcomes observed across all delafloxacin baseline MIC values. Delafloxacin may be considered a treatment option as monotherapy for CAP in adults, where broad spectrum coverage including MRSA activity is desirable.
Rose, W. E., Bienvenida, A. M., Xiong, Y. Q., Chambers, H. F., Bayer, A. S., Ersoy, S. C.
Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) increases β-lactam susceptibility of selected MRSA strains ("NaHCO3-responsive"). This "sensitization" phenomenon translated to enhanced β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-mediated β-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. Four previously-described MRSA were used: two each exhibiting in vitro NaHCO3-responsive or NaHCO3-nonresponsive phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB±NaHCO3. Intra-SEV MRSA killing was determined over 72 hr exposures. In both "responsive" strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤ 4 mg/L) and resulted in bactericidal activity (≥ 3 log kill) in the model for both OXA and CFZ. In contrast, neither in vitro-defined non-responsive MRSA strains showed significant sensitization in the SEV model to either β-lactam. At both NaHCO3 concentrations, the fractional time-above-MIC was >50% for both CFZ and OXA in the responsive MRSA strains. Also, in RPMI+10% LB media (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against NaHCO3-responsive strains in the SEV model. Neither CFZ nor OXA exposures selected for emergence of high-level β-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.
Vu, T. T. T., Nguyen, N. T. Q., Tran, V. G., Gras, E., Mao, Y., Jung, D. H., Tkaczyk, C., Sellman, B. R., Diep, B. A.
Staphylococcus aureus is a major human pathogen, causing a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (mAb) neutralizing alpha-hemolysin or a broadly cross-reactive mAb that neutralize Panton-Valentine leukocidin, leukocidin ED and gamma-hemolysins HlgAB/HlgCB only conferred partial protection, whereas the combination of those two mAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 MRSA epidemic clone.
Zimmerman, S. M., Lafontaine, A.-A. J., Herrera, C. M., Mclean, A. B., Trent, M. S.
The threat of diminished antibiotic discovery has global healthcare in crisis. In the United States, it is estimated each year that over 2 million bacterial infections are resistant to first-line antibiotic treatments and cost in excess of 20 billion dollars. Many of these cases result from infection with the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.), which are multidrug-resistant bacteria that often cause community- and hospital-acquired infections in both healthy and immunocompromised patients. Physicians have turned to last-resort antibiotics like polymyxins to tackle these pathogens, and as a consequence, polymyxin-resistance has emerged and is spreading. Barring the discovery of new antibiotics, another route to successfully mitigate polymyxin-resistance is to identify compounds that can complement the existing arsenal of antibiotics. We recently designed and performed a large-scale robotic screen to identify 43 bioactive compounds that act synergistically with polymyxin B to inhibit growth of polymyxin-resistant Escherichia coli. Of these 43 compounds, 5 lead compounds were identified and characterized using various Gram-negative bacterial organisms to better assess their synergistic activity with polymyxin. Several of these compounds reduce polymyxin to a minimal inhibitory concentration (MIC) < 2 μg/mL against polymyxin-resistant and polymyxin-heteroresistant Gram-negative pathogens. Likewise, 4 of these compounds exhibit antimicrobial activity against Gram-positive bacteria, one of which rapidly eradicated methicillin-resistant Staphylococcus aureus (MRSA). We present multiple first-generation compounds that warrant further investigation and optimization, as they can act both synergistically with polymyxin and also as lone antimicrobials for combating ESKAPE pathogens.
Narin A. Rasheed, Nawfal R. Hussein
Methicillin-resistant Staphylococcus aureus (MRSA) is considered a leading global concern in the health sector and more recently in the community (Boyle-Vavra and Daum 2007). MRSA infections can range from simple to life threating, and can include skin and soft tissue infections and sepsis (Bhatta et al. 2016; Boyle-Vavra and Daum 2007). The gene responsible for methicillin resistance is mecA, which is carried by a DNA fragment known as staphylococcal cassette chromosome mec (SCCmec). This encodes a protein called penicillin-binding protein (PBP-2a), which inhibits the action of β-lactam antibiotics such as methicillin (Bhatta et al.
Scangarella-Oman, N. E., Ingraham, K. A., Tiffany, C. A., Tomsho, L., Van Horn, S. F., Mayhew, D. N., Perry, C. R., Ashton, T. C., Dumont, E. F., Huang, J., Brown, J. R., Miller, L. A.
A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12h [q12h], 1,000 mg q12h, and 1,000 mg every 8h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA) and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the 750-mg q12h group, 89% for the gepotidacin 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 μg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N,both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial.
The presence of nosocomial pathogens in many intensive care units poses a threat to patients and public health worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen endemic in many hospital settings. Patients who are colonized with MRSA may develop an infection that can complicate their prior illness.
A mathematical model to describe transmission dynamics of MRSA among high-risk and low-risk patients in an intensive care unit (ICU) via hands of health care workers is developed. We aim to explore the effects of the proportion of high-risk patients, the admission proportions of colonized and infected patients, the probability of developing an MRSA infection, and control strategies on MRSA prevalence among patients.
The increasing proportion of colonized and infected patients at admission, along with the higher proportion of high-risk patients in an ICU, may significantly increase MRSA prevalence. In addition, the prevalence becomes higher if patients in the high-risk group are more likely to develop an MRSA infection. Our results also suggest that additional infection prevention and control measures targeting high-risk patients may considerably help reduce MRSA prevalence as compared to those targeting low-risk patients.
The proportion of high-risk patients and the proportion of colonized and infected patients in the high-risk group at admission may play an important role on MRSA prevalence. Control strategies targeting high-risk patients may help reduce MRSA prevalence.
Staphylococcus aureus carriage is a known risk factor for staphylococcal disease. However, the carriage rates vary by country, demographic group and profession. This study aimed to determine the S. aureus carriage rate in children in Eastern Uganda, and identify S. aureus lineages that cause infection in Uganda.
Nasopharyngeal samples from 742 healthy children less than 5 years residing in the Iganga/Mayuge Health and Demographic Surveillance Site in Eastern Uganda were processed for isolation of S. aureus. Antibiotic susceptibility testing based on minimum inhibitory concentrations (MICs) was determined by the BD Phoenix™ system. Genotyping was performed by spa and SCCmec typing.
The processed samples yielded 144 S. aureus isolates (one per child) therefore, the S. aureus carriage rate in children was 19.4% (144/742). Thirty one percent (45/144) of the isolates were methicillin resistant (MRSA) yielding a carriage rate of 6.1% (45/742). All isolates were susceptible to rifampicin, vancomycin and linezolid. Moreover, all MRSA were susceptible to vancomycin, linezolid and clindamycin. Compared to methicillin susceptible S. aureus (MSSA) isolates (68.8%, 99/144), MRSA isolates were more resistant to non-beta-lactam antimicrobials –trimethoprim/sulfamethoxazole 73.3% (33/45) vs. 27.3% (27/99) [p
Jan Kluytmans, Stephan Harbarth
Staphylococcus aureus belongs to the microbiome in 20–30% of healthy humans, and has long been recognised as one of the most important human pathogens. Treatment has been hampered by the development of resistance against all β-lactam antibiotics, leading to meticillin-resistant S aureus (MRSA). MRSA was initially confined to hospitals, but since the 1990s it has also established itself in the community as so-called community-associated MRSA.1
Yasunori Iwata, Kenji Satou, Kengo Furuichi, Ikuko Yoneda, Takuhiro Matsumura, Masahiro Yutani, Yukako Fujinaga, Atsushi Hase, Hidetoshi Morita, Toshiko Ohta, Yasuko Senda, Yukiko Sakai-Takemori, Taizo Wada, Shinichi Fujita, Taito Miyake, Haruka Yasuda, Norihiko Sakai, Shinji Kitajima, Tadashi Toyama, Yasuyuki Shinozaki, Akihiro Sagara, Taro Miyagawa, Akinori Hara, Miho Shimizu, Yasutaka Kamikawa, Kazuho Ikeo, Shigeyuki Shichino, Satoshi Ueha, Takuya Nakajima, Kouji Matsushima, Shuichi Kaneko, Takashi Wada
Methicillin-resistant Staphylococcus aureus (MRSA) is a common pathogenic bacterium that causes nosocomial and community-acquired infections. Annual report of nationwide survey in Japan revealed MRSA was detected at 100% of the hospitals in 2017 (Japan Nosocomial Infections Surveillance (JANIS), 2019). Moreover, MRSA infection can cause severe illness not only in immunocompromised patients but also in healthy people. Although anti-MRSA therapeutic agents are clinically available, MRSA infection can be life threatening.
Lepak, A. J., Zhao, M., Marchillo, K., VanHecker, J., Andes, D. R.
Omadacycline is an effective therapy for community-acquired bacterial pneumonia (CABP). Given its potent activity against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA), we sought to determine the pharmacodynamic activity and target PK/PD exposures associated with therapeutic effect in the neutropenic mouse pneumonia model against 10 MSSA/MRSA strains. The area under the concentration-time curve (AUC)/MIC associated with 1-log kill was noted at 24h ELF and plasma AUC/MIC exposures of ~2 (ELF range
Thalso-Madsen, I., Torrubia, F. R., Xu, L., Petersen, A., Jensen, C., Frees, D.
Most clinically relevant methicillin resistant Staphylococcus aureus (MRSA) strains have become resistant to β-lactams antibiotics through horizontal acquisition of the mecA gene encoding PBP2a, a peptidoglycan transpeptidase with low affinity for β-lactams. The level of resistance conferred by mecA is, however, strain dependent and the mechanisms underlying this phenomenon remain poorly understood. We here show that β-lactam resistance correlates to expression of the Sle1 cell wall amidase in the fast spreading and highly virulent community-acquired MRSA USA300 clone. Sle1 is a substrate of the ClpXP protease, and while the high Sle1 levels in cells lacking ClpXP activity confer β-lactam hyper-resistance, USA300 cells lacking Sle1 are as susceptible to β-lactams as cells lacking mecA. This finding prompted us to assess the cellular roles of Sle1 in more detail, and we demonstrate that high Sle1 levels accelerate the onset of daughter cells splitting and decrease cell size. Vice versa, oxacillin decreases the Sle1 level, and imposes a cell-separation defect that is antagonized by high Sle1 levels, suggesting that high Sle1 levels increase tolerance to oxacillin by promoting cell separation. In contrast, increased oxacillin sensitivity of sle1 cells appears linked to a synthetical lethal effect on septum synthesis. In conclusion, this study demonstrates that Sle1 is a key factor in resistance to β-lactam antibiotics in the JE2 USA300 model strain, and that PBP2a is required for expression of Sle1 in JE2 cells exposed to oxacillin.
Graber C, Jones M, Goetz M, et al.
AbstractBackgroundAntimicrobial stewards may benefit from comparative data to inform interventions that promote optimal antimicrobial use in the inpatient setting.MethodsAntimicrobial stewards from eight geographically dispersed Veterans Affairs (VA) inpatient facilities participated in the development of iterative antimicrobial use visualization tools that allowed for comparison to facilities of similar complexity. The visualization tools consisted of an interactive web-based antimicrobial dashboard and, later, a standardized antimicrobial usage report updated at user-selected intervals. Following tool implementation, stewards participated in monthly learning collaboratives. The percent change in average monthly antimicrobial use [all antimicrobial agents, anti-methicillin-resistant Staphylococcus aureus agents (anti-MRSA), and anti-pseudomonal agents] was analyzed using a pre-post (1/2014-1/2016 versus 7/2016-1/2018) design with segmented regression and external comparison with uninvolved control facilities (n=118).ResultsIntervention sites demonstrated a 2.1% decrease (95% confidence interval (CI) [-5.7%, 1.6%]) in total antimicrobial use pre-post intervention, versus a 2.5% increase (95% CI [0.8%, 4.1%]) in non-intervention sites (absolute difference 4.6%, P=0.025). Anti-MRSA antimicrobial use decreased 11.3% (95% CI [-16.0%, -6.3%]) at intervention sites versus a 6.6% decrease (95% CI [-9.1%, -3.9%]) at non-intervention sites (absolute difference 4.7%, P=0.092). Anti-pseudomonal antimicrobial use decreased 3.4% (95% CI [-8.2%, 1.7%]) at intervention sites versus a 3.4% increase (95% CI [0.8%, 6.5%]) at non-intervention sites (absolute difference 7.0%, P=0.018).ConclusionsComparative data visualization tool use by stewards in a pilot implementation project at eight VA facilities was associated with significant reductions in overall antimicrobial and anti-pseudomonal use relative to uninvolved facilities.
Several reports designate the recent increase in community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) nasal carriage. Because of the scanty information regarding the nasal carriage sate of MRSA in the west of Iran, the purpose of the present study was to determine the frequency of CA-MRSA in Sanandaj city.
Swabs collected from anterior nares of 600 volunteers were analyzed for the presence of S. aureus. The isolates were further investigated for methicillin resistance by using the cefoxitin disk diffusion test, followed by PCR-amplification of the mecA gene. SCCmec types and the presence of the Panton-Valentine Leukocidin (pvl) encoding genes were determined through PCR. Finally, the antimicrobial susceptibility of the isolates was determined by the agar diffusion method.
Nasal screening identified 181 S. aureus, of which 55 isolates were MRSA. SCCmec types IV and V were detected in MRSA at frequencies of 80 and 20%, respectively. The overall frequency of pvl genes among the MRSA isolates was 14.54%. MRSA isolates were highly susceptible (98.18%) to mupirocin, gentamicin, and fusidic acid.
The high prevalence of CA-MRSA carriage in the population could pose a serious public health concern for the region. Additionally, advent of drug-resistant pvl-positive strains demands continuous surveillance on the colonization state of CA-MRSA in order to prevent dissemination of the bacterium in the community.
Morgan D, Zhan M, Goto M, et al.
AbstractBackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is a common cause of healthcare-associated infections in long-term care facilities (LTCF). The Centers for Disease Control and Prevention (CDC) recommends Contact Precautions for prevention of MRSA within acute care facilities and are being used within the United States Department of Veterans Affairs (VA) for LTCF in a modified fashion. The impact of Contact Precautions in long-term care is unknown.MethodsTo evaluate if Contact Precautions decreased MRSA acquisition in LTCF compared to Standard Precautions we performed a retrospective effectiveness study (pre-post with concurrent controls) using data from the VA healthcare system from 1/1/2011 until 12/31/2015, two years before and after a 2013 policy recommending a more aggressive form of Contact Precautions.ResultsAcross 75,414 patient admissions from 74 long-term care facilities in the United States, the overall unadjusted rate of MRSA acquisition was 2.6/1000 patient days. Patients were no more likely to acquire MRSA if they were cared for using Standard Precautions vs. Contact Precautions in multivariable discrete-time survival analysis, controlling for patient demographics, risk factors, and year of admission (Odds Ratio (OR) 0.97, 95% confidence interval (CI), 0.85-1.12, p=0.71).ConclusionsMRSA acquisition and infections were not impacted by use of active surveillance and Contact Precautions in LTCF in the VA.
There have been no reports regarding the molecular characteristics, virulence features, and antibiotic resistance profiles of Staphylococcus aureus (S. aureus) from Hainan, the southernmost province of China.
Two hundred twenty-seven S. aureus isolates, consisting of 76 methicillin-resistant S. aureus (MRSA) and 151 methicillin-susceptible S. aureus (MSSA), were collected in 2013–2014 and 2018–2019 in Hainan, and investigated for their molecular characteristics, virulence genes, antibiotic resistance profiles and main antibiotic resistance genes.
Forty sequence types (STs) including three new STs (ST5489, ST5492 and ST5493), and 79 Staphylococcal protein A (spa) types were identified based on multilocus sequence typing (MLST) and spa typing, respectively. ST398 (14.1%, 32/227) was found to be the most prevalent, and the prevalence of ST398-MSSA increased significantly from 2013 to 2014 (5.5%, 5/91) to 2018–2019 (18.4%, 25/136). Seventy-six MRSA isolates were subject to staphylococcus chromosomal cassette mec (SCCmec) typing. SCCmec-IVa was the predominant SCCmec type, and specifically, ST45-SCCmec IVa, an infrequent type in mainland China, was predominant in S. aureus from Hainan. The antibiotic resistance profiles and antibiotic resistance genes of S. aureus show distinctive features in Hainan. The resistant rates of the MRSA isolates to a variety of antibiotics were significantly higher than those of the MSSA isolates. The predominant erythromycin and tetracycline resistance genes were ermC (90.1%, 100/111) and tetK (91.8%, 78/85), respectively. Eleven virulence genes, including the Panton-Valentine leukocidin (pvl) and eta, were determined, and the frequency of eta and pvl were found to be 57.3 and 47.6%. Such high prevalence has never been seen in mainland China before.
S. aureus isolates in Hainan have unique molecular characteristics, virulence gene and antibiotic resistance profiles, and main antibiotic resistance genes which may be associated with the special geographical location of Hainan and local trends in antibiotic use.
Kang, C. K., Song, K.-H., Kim, S. E., Kim, E. S., Park, W. B., Park, K.-H., Chun, S. H., Lee, S., Cho, C. R., Kang, S. J., Oh, M.-d., Kim, Y.-S., Lee, S. H., Kwak, Y. G., Jang, H.-C., Kim, C.-J., Kim, Y. K., Bang, J.-H., Kiem, S., Kwon, K. T., Jung, Y., Kang, Y. M., Jung, S.-I., Kim, H. B., the Korea INfectious Diseases (KIND) study group
The purpose of this study was to describe and compare the duration of Staphylococcus aureus bacteremia (SAB) according to methicillin resistance and primary foci of infection. We also aimed to newly define persistent SAB considering these results. Non-duplicated episodes of SAB in patients aged ≥15 years from 14 hospitals between January 2009 and February 2018 in Korea were analyzed. The duration of SAB was defined as the number of days from the administration of a susceptible antibiotic after the onset of SAB to the last day of positive blood culture for S. aureus. SAB durations were described and compared based on methicillin resistance and the primary foci of infection. Cases in the top quartile for the duration of bacteremia under the respective clinical context were classified as newly defined persistent SAB, and its association with in-hospital mortality was evaluated. A total of 1917 cases were analyzed. The duration of SAB was longer in methicillin-resistant SAB (MRSAB, n=995) compared to methicillin-susceptible SAB (MSSAB, n=922) (days, median [interquartile range], 1 (1–3) in MSSAB vs. 1 (0–5) in MRSAB; P
Ceballos, S., Kim, C., Qian, Y., Mobashery, S., Chang, M., Torres, C.
The in vitro activities of five quinazolinone antibacterials, compounds Q1-Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (both in μg/ml) were as follows: Q1 (0.5/2), Q2 (1/4), Q3 (2/4), Q4 (0.06/0.25) and Q5 (0.125/0.5). Several strains with high MIC values for some of these compounds (from 8 to >32 μg/ml) exhibited amino-acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.
Mroue, N., Arya, A., Brown Gandt, A., Russell, C., Han, A., Gavrish, E., LaFleur, M.
It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and enterococci. ADEPs activate the ClpP protease, killing high-density, non-dividing cultures of bacteria, tolerant to approved classes of antibiotics. Acyldepsipeptide analog 4 (ADEP4) was active against a panel of drug resistant Gram-positive pathogens in MIC assays with no pre-existing resistance detected. Killing of stationary phase cultures was observed when ADEP4 was combined with multiple classes of approved antibiotics. Additionally, a hollow-fiber infection model was used to assess the effects of ADEP4 antibiotic combinations on bacterial killing and resistance development. These studies were performed on high-density cultures of methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), and vancomycin-resistant Enterococcus faecalis (VRE). None of the approved antibiotics linezolid, ampicillin, or oxacillin had bactericidal activity when tested alone under these conditions. ADEP4 initially caused killing, but regrowth of the culture was apparent within 96 hours due to resistance. Combinations of ADEP4 with linezolid or oxacillin caused substantially improved killing of MRSA and MSSA cultures respectively, and no regrowth due to resistance was observed. The combination of ADEP4 and ampicillin eradicated cultures of VRE to the limit of detection within 52 hours. These data suggest that combining ClpP activators with traditional antibiotics may be a good strategy to treat complicated Gram-positive infections.
Clarke, R. S., Bruderer, M. S., Ha, K. P., Edwards, A. M.
Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the use of SXT is limited to the treatment of low-burden, superficial S. aureus infections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. We found that mutants lacking the DNA repair complex RexAB had a modest 2-fold lower SXT MIC than wild-type strains but were killed 50-5000-fold more efficiently by the combination antibiotic at the breakpoint concentration. SXT-mediated DNA damage occurred via both thymidine limitation and the generation of reactive oxygen species, and triggered induction of the SOS response in a RexAB-dependent manner. SOS induction was associated with a 50% increase in the mutation rate, which may contribute to emergence of resistant strains during SXT therapy. In summary, this work determined that SXT caused DNA damage in S. aureus via both thymidine limitation and oxidative stress, which was repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused by S. aureus.
Mergenhagen K, Starr K, Wattengel B, et al.
AbstractBackgroundTreatment of suspected methicillin-resistant Staphylococcus aureus (MRSA) is a cornerstone of many antibiotic regimens; however, antibiotics are associated with toxicity. The Department of Veterans Affairs (VA) hospitals screen each patient on admission and transfer for MRSA nares colonization. The objective of this study was to determine the negative predictive value (NPV) of MRSA screening in the determinization of subsequent positive clinical culture for MRSA. High NPVs with MRSA nares screening maybe used as a stewardship tool for de-escalation as well as avoidance of anti-MRSA therapy.MethodsThis was a retrospective cohort study across VA medical centers nationwide from January 1, 2007 to January 1, 2018. Data from patients with MRSA nares screening upon admission or transfer were obtained from the VA Corporate Data Warehouse. Subsequent clinical cultures within 7 days of the nares swab were evaluated for presence of MRSA. Sensitivity, specificity, positive predictive values (PPVs), and NPVs were calculated for the entire cohort, as well as subgroups for specific culture sites.ResultsThis cohort yielded 561,325 clinical cultures from a variety of anatomical sites. The sensitivity and specificity for positive MRSA clinical culture were 67.4% and 81.2%, respectively. The NPV of MRSA nares screening for ruling out MRSA infection was 96.5%. The NPV for bloodstream infections was 96.5%, for intra-abdominal cultures was 98.6%, for respiratory cultures was 96.1%, for wound cultures was 93.1%, and for cultures from the urinary system was 99.2%.ConclusionGiven the high NPVs, MRSA nares screening may be a powerful stewardship tool for de-escalation and avoidance of empirical anti-MRSA therapy.
Lopes, A.-A., Yoshii, Y., Yamada, S., Nagakura, M., Kinjo, Y., Mizunoe, Y., Okuda, K.-i.
Staphylococcus aureus is responsible for numerous community outbreaks and is one of the most frequent causes of nosocomial infections with significant morbidity and mortality. While the function of lytic transglycosylases (LTs) in relation to cell division, biofilm formation, and antibiotic resistance has been determined for several bacteria, their role in S. aureus remains largely unknown. The only known LTs in S. aureus are immunodominant staphylococcal antigen A (IsaA) and Staphylococcus epidermidis D protein (SceD). Our study demonstrates that, in a strain of methicillin-resistant S. aureus (MRSA), IsaA and SceD contribute differently to biofilm formation and β-lactam resistance. Deletion of isaA, but not sceD, led to decreased biofilm formation. Additionally, in isaA-deleted strains, β-lactam resistance was significantly decreased compared to that of wild-type strains. Plasmid-based expression of mecA, a major determinant of β-lactam resistance in MRSA, in an isaA-deleted strain did not restore β-lactam resistance, demonstrating that the β-lactam susceptibility phenotype is exhibited by isaA mutant regardless of the production level of PBP2a. Overall, our results suggest that IsaA is a potential therapeutic target for MRSA infections.
Webb B, Majers J, Healy R, et al.
AbstractBackgroundAntibiotic stewardship is challenging in hematological malignancy patients.MethodsQuasi-experimental implementation study of two antimicrobial stewardship interventions in a hematological malignancy unit: 1) monthly antibiotic cycling for febrile neutropenia: cefepime (+/- metronidazole) and piperacillin-tazobactam and 2) a clinical prediction rule to guide anti-VRE therapy. We used interrupted time-series analysis (ITS) to compare antibiotic use and logistic regression to adjust observed unit-level changes in resistant infections by background community rates.Results2434 admissions spanning 3 years prior and 2 years post-implementation were included. Unadjusted carbapenem and daptomycin use decreased significantly. In ITS analysis, carbapenem use decreased by -230 DOT/1000 patient days (95% confidence interval (CI) -290 to -180), p
Watkins, R. R., Holubar, M., David, M. Z.
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.
Kim, D., Hong, J. S., Yoon, E.-J., Lee, H., Kim, Y. A., Shin, K. S., Shin, J. H., Uh, Y., Shin, J. H., Park, Y. S., Jeong, S. H.
Introduction: This study was performed to evaluate the clinical impacts of putative risk factors in patients with Staphylococcus aureus bloodstream infections (BSIs) through a prospective, multicenter, observational study.Methods: All 576 patients with S. aureus BSIs that occurred during a one-year period in six general hospitals were included in this study. Host- and pathogsen-related variables were investigated to determine risk factors for the early mortality of patients with S. aureus BSIs.Results: The all-cause mortality rate was 14.8% (85/576) during the four-week follow-up period from the initial blood culture, and 76.5% (65/85) of the mortality cases occurred within the first two weeks. One-quarter (26.8%, 152/567) of the S. aureus blood isolates carried the tst-1 gene, and most (86.2%, 131/152) of them were identified as clonal complex 5-agr type 2-methicillin-resistant S. aureus (MRSA) strains harboring staphylococcal cassette chromosome mec type II, belonging to the New York/Japan epidemic clone. A multivariable logistic regression showed that tst-1-positivity of causative S. aureus isolates was associated with an increased two-week mortality rate both in patients with S. aureus BSIs [adjusted odds ratio (aOR), 1.62; 95% confidence interval (CI), 0.90-2.88] and in patients with MRSA BSIs (aOR, 2.61; 95% CI, 1.19-6.03).Conclusions: Both host-related factors, increased Pitt bacteremia score and advanced age, as well as a pathogen-related factor, carriage of tst-1 by causative MRSA isolates, were risk factors for two-week mortality in patients with BSIs, and careful management of patients with BSIs caused by the New York/Japan epidemic clone is needed to improve clinical outcomes.
Yui Eto, K., Firth, N., Davis, A. M., Kwong, S. M., Krysiak, M., Lee, Y. T., O'Brien, F. G., Grubb, W. B., Coombs, G. W., Bond, C. S., Ramsay, J. P.
Horizontal transfer of plasmids encoding antimicrobial-resistance and virulence determinants has been instrumental in Staphylococcus aureus evolution, including the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA). In the early 1990s the first CA-MRSA isolated in Western Australia (WA), WA-5, encoded cadmium, tetracycline and penicillin-resistance genes on plasmid pWBG753 (~30 kb). WA-5 and pWBG753 appeared only briefly in WA, however, fusidic-acid-resistance plasmids related to pWBG753 were also present in the first European CA-MRSA at the time. Here we characterized a 72-kb conjugative plasmid pWBG731 present in multiresistant WA-5-like clones from the same period. pWBG731 was a cointegrant formed from pWBG753 and a pWBG749-family conjugative plasmid. pWBG731 carried mupirocin, trimethoprim, cadmium and penicillin-resistance genes. The stepwise evolution of pWBG731 likely occurred through the combined actions of IS257, IS257-dependent miniature inverted-repeat transposable elements (MITEs) and the BinL resolution system of the β-lactamase transposon Tn552. An evolutionary intermediate ~42-kb non-conjugative plasmid pWBG715, possessed the same resistance genes as pWBG731 but retained an integrated copy of the small tetracycline-resistance plasmid pT181. IS257 likely facilitated replacement of pT181 with conjugation genes on pWBG731, thus enabling autonomous transfer. Like conjugative plasmid pWBG749, pWBG731 also mobilized non-conjugative plasmids carrying oriT mimics. It seems likely that pWBG731 represents the product of multiple recombination events between the WA-5 pWBG753 plasmid and other mobile genetic elements present in indigenous CA-MSSA. The molecular evolution of pWBG731 saliently illustrates how diverse mobile genetic elements can together facilitate rapid accrual and horizontal dissemination of multiresistance in S. aureus CA-MRSA.
Popovich K, Snitkin E, Zawitz C, et al.
AbstractBackgroundJails may facilitate spread of MRSA in urban areas. We examined MRSA colonization at entrance to a large urban jail to determine if there are community transmission networks for MRSA that precede incarceration.MethodsIncarcerated males at the Cook County Jail were enrolled—with enrichment for HIV-positive subjects—within 72hours of intake. Surveillance cultures were collected to determine prevalence of MRSA colonization. Genomic analysis and epidemiologic data were used to identify community transmission networks.ResultsThere were 800 incarcerations (718 individuals) enrolled; 58% were HIV-infected. The prevalence of MRSA colonization at intake was 19%. In multivariate analysis, methamphetamine use, unstable housing, current/recent skin infection, and recent injection drug use were predictors of MRSA. Among HIV patients, recent injection drug use, current skin infection, and HIV care at outpatient Clinic A that emphasizes comprehensive care to the LGBTQ community were predictors of MRSA. 14(45%) of 31 detainees with care at Clinic A had colonization. WGS revealed that the high prevalence of MRSA in Clinic A was not due to clonal spread in the clinic but rather an intermingling of distinct community transmission networks. In contrast, genomic analysis supported spread of USA500 strains within a community network. Members of this USA500 network were more likely to be HIV-infected (p
Holland T, Davis J.
Jorgensen S, Zasowski E, Trinh T, et al.
AbstractBackgroundMounting evidence suggests the addition of a beta-lactam (BL) to daptomycin (DAP) results in synergistic in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and bolsters the innate immune response to infection. The objective of this study was to provide clinical translation to this experimental data and determine if DAP+BL combination therapy results in improved clinical outcomes compared to treatment with DAP alone in patients with MRSA bloodstream infections (BSI).MethodsThis was a retrospective, comparative cohort study conducted at two academic medical centers between 2008 and 2018. Adults with MRSA BSI treated with DAP for ≥72 hours and initiated within five days of culture collection were included. Patients who received a BL for ≥24 hours and initiated within 24 hours of DAP comprised the DAP+BL group. The primary outcome was composite clinical failure (60-day all-cause mortality and/or 60-day recurrence). Analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW).ResultsA total of 229 patients were included (72 DAP+BL and 157 DAP). In unadjusted and IPTW-adjusted analyses, DAP+BL was associated with significantly reduced odds of clinical failure (OR 0.362, 95% CI 0.164, 0.801; aOR 0.386, 95% CI 0.175, 0.853). Adjusted analyses restricted to pre-specified subgroups based on infection complexity and baseline health status, were consistent with the main analysis.ConclusionsThe addition of a BL to DAP was associated with improved clinical outcomes in patients with MRSA BSI. This study provides support to ongoing and future studies evaluating the impact of combination therapy for invasive MRSA infections.
Verma, A. K., Bauer, C., Yajjala, V. K., Bansal, S., Sun, K.
Post-influenza methicillin-resistant Staphylococcus aureus (MRSA) infection can quickly develop into severe, necrotizing pneumonia, causing over 50% mortality despite antibiotic treatments. In this study, we investigated the efficacy of antibiotic therapies and the impact of S. aureus α-toxin in a lethal model of influenza and MRSA coinfection. We demonstrate that antibiotics primarily attenuate α-toxin-induced acute lethality, even though both α-toxin-dependent and -independent mechanisms significantly contribute to animal mortality after coinfection. Furthermore, we found that protein synthesis-suppressing antibiotic linezolid has an advantageous therapeutic effect on α-toxin-induced lung damage as measured by protein leak and lactate dehydrogenase (LDH) activity. Importantly, using a Panton–Valentine Leucocidin (PVL)-negative MRSA isolate from patient sputum, we show that linezolid therapy significantly improves animal survival from post-influenza MRSA pneumonia as compared with vancomycin treatment. Rather than improved viral or bacterial control, this advantageous therapeutic effect is associated with significantly attenuated pro-inflammatory cytokine response and acute lung damage in linezolid-treated mice. Together, our findings not only establish a critical role of α-toxin in the extreme mortality of secondary MRSA pneumonia after influenza, but also provide support that linezolid could be a more effective treatment to improve disease outcome.
Volk C, Burgdorf S, Edwardson G, et al.
AbstractIntroductionPatient IL-1β and IL-10 responses early in the course of Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on choice of antimicrobial therapy, with particular interest in knowing whether the superior performance of -lactams may be linked to key cytokine signaling pathways.MethodsThree medical centers included 59 patients with SaB (47 MRSA, 12 MSSA) from 2015-2017. In the first 48 h, patients were treated with either a β-lactam (n=24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n=35), i.e. vancomycin or daptomycin (VAN/DAP). Patient sera from days 1, 3 and 7 were assayed for IL-1β and IL-10 by ELISA and compared using Mann-Whitney U.ResultsOn day 1 of presentation, IL-10 was elevated in patients with outcomes of mortality (P=0.008) and persistent bacteremia (P=0.034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 was similar at presentation prior to receiving an antibiotic. Patients treated with β-lactam had higher IL-1β on day 3 (median +5.6 pg/mL; P=0.007) and day 7 (+10.9 pg/ml; P=0.016). Ex vivo, the addition of IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting a functional significance of the host IL-1β response in SaB clearance. β-lactam treated patients had sharper declines in IL-10 than VAN/DAP treated patients at days 3 and 7.
Karau, M. J., Schmidt-Malan, S. M., Yan, Q., Greenwood-Quaintance, K. E., Mandrekar, J., Lehoux, D., Schuch, R., Cassino, C., Patel, R.
Bacteriophage-derived lysins are being developed as anti-infective agents. In an acute osteomyelitis MRSA model, rats receiving no treatment, daptomycin, execabase (CF-301) or daptomycin plus exebacase had means of 5.13, 4.09, 4.65, and 3.57 log10 cfu/gram of bone, respectively. All treated animals had fewer bacteria than untreated animals (P≤0.0001), with daptomycin plus exebacase being more active than daptomycin (P=0.0042) or exebacase (P
Elita Jauneikaite, Tricia Ferguson, Mia Mosavie, Joanne L. Fallowfield, Trish Davey, Neil Thorpe, Adrian Allsopp, Anneliese M. Shaw, Dominic Fudge, Matthew K. O’Shea, Duncan Wilson, Marina Morgan, Bruno Pichon, Angela M. Kearns, Shiranee Sriskandan, Lucy E. Lamb
Skin and soft tissue infections (SSTIs) are a serious health issue for military personnel. Of particular importance are those caused by MRSA and PVL-positive S. aureus (PVL-SA), as they have been associated with outbreaks of SSTIs. A prospective observational study was conducted in Royal Marines recruits to investigate the prevalence of PVL-SA carriage and any association with SSTIs.
Sandra Valderrama-Beltrán, Sandra Gualtero, Carlos Álvarez-Moreno, Fabian Gil, Álvaro Ruiz-Morales, José Yesid Rodríguez, Johanna Osorio, Ivan Tenorio, Carlos Gómez Quintero, Sebastián Mackenzie, María Alejandra Caro, Alberto Zhong, Gerson Arias, Indira Berrio, Ernesto Martinez, Gloria Cortés, Alejandro De la Hoz, Cesar A. Arias
Methicillin resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTIs) represent a major clinical problem in Colombia. The aim of this study was to evaluate the risk factors associated with MRSA SSTI in Colombia.
G C, B., Sahukhal, G. S., Elasri, M. O.
Staphylococcus aureus is an important human pathogen in both community and health care settings. One of the challenges with S. aureus as a pathogen is its acquisition of antibiotic resistance. Previously, we have shown that deletion of the msaABCR operon reduces cell wall thickness, resulting in decreased resistance to vancomycin in vancomycin-intermediate susceptible S. aureus (VISA). In this study, we investigated the nature of the cell wall defect in the msaABCR operon mutant in the Mu50 (VISA) and USA300 LAC methicillin-resistant Staphylococcus aureus (MRSA) strains. Results showed that msaABCR-mutant cells had decreased crosslinking in both strains. This defect is typically due to increased murein hydrolase activity and/or nonspecific processing of murein hydrolases mediated by increased protease activity in mutant cells. The defect was enhanced by a decrease in teichoic acid content in the msaABCR mutant. Therefore, we propose that deletion of the msaABCR operon results in decreased peptidoglycan crosslinking, leading to increased susceptibility towards cell wall-targeting antibiotics, such as β-lactams and vancomycin. Moreover, we also observed significantly downregulated transcription of early cell wall-synthesizing genes, supporting the finding that msaABCR-mutant cells have decreased peptidoglycan synthesis. More specifically, the msaABCR mutant in the USA300 LAC strain (MRSA) showed significantly reduced expression of the murA gene, whereas the msaABCR mutant in the Mu50 strain (VISA) showed significantly reduced expression of glmU, murA, and murD. Thus, we conclude that the msaABCR operon controls the balance between cell wall synthesis and cell wall hydrolysis, which is required for maintaining a robust cell wall and acquiring resistance to cell wall-targeting antibiotics, such as vancomycin and the β-lactams.
Methicillin-resistant Staphylococcus aureus (MRSA) is associated with significant morbidity and mortality and has resultant important economic and societal costs underscoring the need for accurate surveillance. In recent years, prevalence rates reported in East Africa have been inconsistent, sparking controversy and raising concern.
We described antimicrobial susceptibility patterns of Staphylococcus aureus isolates cultured from patients within the Internal Medicine department of the largest public healthcare facility in East and Central Africa- the Kenyatta National Hospital (KNH) in Nairobi, Kenya. Routine antimicrobial susceptibility data from non-duplicate Staphylococcus aureus isolates cultured between the years 2014–2016 from the medical wards in KNH were reviewed.
Antimicrobial susceptibility data from a total of 187 Staphylococcus aureus isolates revealed an overall MRSA prevalence of 53.4%. Isolates remained highly susceptible to linezolid, tigecycline, teicoplanin and vancomycin.
The prevalence of MRSA was found to be much higher than that reported in private tertiary facilities in the same region. Careful interrogation of antimicrobial susceptibility results is important to uproot any red herrings and reserve genuine cause for alarm, as this has a critical bearing on health and economic outcomes for a population.
Staphylococcus aureus bacteremia (SAB) is associated with significant morbidity and mortality. We sought to re-define the burden, epidemiology and mortality-associated risk factors of SAB in a large Canadian health region.
Residents (> 18 years) experiencing SAB from 2012 to 2014 were assessed. Incidence rates were calculated using civic census results. Factors associated with 30-day mortality were determined through multivariate logistic regression. Incidence and risk factors for SAB were compared to 2000–2006 data.
780 residents experienced 840 episodes of SAB (MRSA; 20%). Incidence rates increased from 23.5 to 32.0 cases/100,000 from 2012 to 2014; [IRR 1.15 (95% CI 1.07–1.23); p
Yamashita, Y., Nagaoka, K., Kimura, H., Suzuki, M., Konno, S., Fukumoto, T., Akizawa, K., Kaku, N., Morinaga, Y., Yanagihara, K.
The use of macrolides against pneumonia has been reported to improve survival, however, little is known about their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. In this study, we investigated the effect of azithromycin (AZM), and compared it with that of vancomycin (VCM) and daptomycin (DAP), in a murine model of MRSA pneumonia. Mice were infected with MRSA by intratracheal injection, and then treated with AZM, VCM or DAP. The therapeutic effect of AZM, in combination or not with the other drugs, was compared in vivo, whereas the effect of AZM on MRSA growth and toxin mRNA expression was evaluated in vitro. In vivo, the AZM-treated group showed significantly longer survival and fewer bacteria in the lungs 24 h after infection than the untreated group, as well as the other anti-MRSA drug groups. No significant decrease in cytokine levels (IL-6 and MIP-2) in bronchoalveolar lavage fluid or toxin expression levels (hla and spa) was observed following AZM treatment. In vitro, AZM suppressed growth of MRSA in late log phase, but not in stationary phase. No suppressive effect against toxin production was observed following AZM treatment in vitro. In conclusion, contrary to the situation in vitro, AZM was effective against MRSA growth in vivo in our pneumonia model, substantially improving survival. The suppressive effect on MRSA growth at the initial stage of pneumonia could underlie the potential mechanism of AZM action against MRSA pneumonia.
Dymond A, Davies H, Mealing S, et al.
AbstractBackgroundGenomic surveillance of MRSA identifies unsuspected transmission events and outbreaks. Used proactively, this could direct early and highly targeted infection control interventions to prevent ongoing spread. Here, we evaluate the cost effectiveness of this intervention in a model that compared whole genome sequencing plus current practice versus current practice alone.MethodsA UK cost-effectiveness study was conducted using an early model built from the perspective of the National Health Service (NHS) and personal social services. Effectiveness of sequencing was based on the relative reduction in total MRSA acquisitions in a cohort of hospitalised patients in the year following their index admissions. Sensitivity analysis was used to illustrate and assess the level of confidence associated with the conclusions of our economic evaluation.ResultsA cohort of 65,000 patients were ran through the model. Assuming that sequencing would result in a 90% reduction in MRSA acquisition, 290 new MRSA cases were avoided. This gave an absolute reduction of 28.8% and avoidance of two MRSA-related deaths. Base case results indicated that the use of routine, proactive MRSA sequencing would be associated with estimated cost savings of over £728,290 per annual hospitalised cohort. The impact in total QALYs was relatively modest, with sequencing leading to an additional 14.28 QALYs gained. Results were most sensitive to changes in the probability of an MRSA negative patient acquiring MRSA during their hospital admission.ConclusionsWe showed that proactive genomic surveillance of MRSA is likely to be cost-effective. Further evaluation is required in the context of a prospective study.
Specialespecifikt kursus om immundefekt og feber af ukendt årsag
28.01.2020 - 29.01.2020
International Congress on Infectious Diseases (ICID) 2020
Kuala Lumpur, Malaysia
20.02.2020 - 23.02.2020
Dansk Selskab for Intern Medicin (DSIM) årsmøde og overrækkelse af Hagedorn prisen 2020
Novo Nordisk Fonden, Tuborg Havnevej 19, 2900 Hellerup
Conference on Retroviruses and Opportunistic Infections (CROI) 2020
Boston, Massachusetts, USA
8.03.2020 - 11.03.2020
Når CROI går i fisk - med transmissioner fra CROI 2020
10.03.2020 - 11.03.2020
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
Widening the lens to ensure children who are HIV exposed are alive, HIV-free and thriving
24.01.2020Clinical Infectious Diseases Advance Access
Mortality, HIV transmission and growth in children exposed to HIV in rural Zimbabwe
24.01.2020Clinical Infectious Diseases Advance Access
RSV Antivirals: Problems and Progress
24.01.2020The Journal of Infectious Diseases Advance Access
Efficacy and safety of ceftolozane/tazobactam as therapeutic option for complicated skin and soft tissue infections by MDR/XDR Pseudomonas aeruginosa in patients with impaired renal function: a case series from a single-center experience
24.01.2020Latest Results for Infection
How to Choose Target Facilities in a Region to Implement Carbapenem-Resistant Enterobacteriaceae (CRE) Control Measures
23.01.2020Clinical Infectious Diseases Advance Access
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