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Microbiology Spectrum Jun 2024Methicillin-resistant (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of...
Methicillin-resistant (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC) for all isolates tested and lowered daptomycin IC below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin ICs were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce ICs and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC. These analyses rationalize further evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.
PubMed: 38916355
DOI: 10.1128/spectrum.00976-24 -
Microbiology Spectrum Jun 2024The incidence of heterogeneous vancomycin-intermediate (hVISA) infection is increasing and is associated with vancomycin treatment failures. However, studies...
The incidence of heterogeneous vancomycin-intermediate (hVISA) infection is increasing and is associated with vancomycin treatment failures. However, studies investigating the risk factors for treatment failure in hVISA infection are limited. Patients with hVISA bacteremia treated with vancomycin over 7 days between August 2008 and June 2020 were enrolled in this study. Clinical and microbiological characteristics were compared between vancomycin treatment failure and success groups to identify the risk factors for vancomycin treatment failure. Among the 180 patients with hVISA bacteremia, 102 patients treated with vancomycin over 7 days were included. Vancomycin treatment failed in 80 (78%) patients. Patients in the vancomycin treatment failure group were older ( < 0.001) and more frequently had solid cancer ( = 0.04) than those in the vancomycin treatment success group. Solid organ transplantation (SOT) was more frequent ( < 0.001) in the vancomycin treatment success group. The Charlson comorbidity index ( = 0.01) and Acute Physiology and Chronic Health Evaluation II scores ( < 0.001) were higher in the vancomycin treatment failure group. In multivariate analysis, independent risk factors for vancomycin treatment failure were old age and severity of bacteremia. SOT and vancomycin minimal inhibitory concentration (MIC) ≤ 1.0 mg/L using the broth microdilution (BMD) method were associated with successful vancomycin treatment. Old age and infection severity were independent risk factors for vancomycin treatment failure. Vancomycin MIC using the BMD method is an important risk factor for vancomycin treatment failure, and its use should be considered in hVISA bacteremia.IMPORTANCEIn this study, we assessed the clinical and microbiological characteristics of heterogeneous vancomycin-intermediated (hVISA) bacteremia and identified risk factors for vancomycin treatment failure. We found that advanced age and severity of infection were independent risk factors for vancomycin treatment failure. On the other hand, solid organ transplantation and a low vancomycin minimal inhibitory concentration were associated with successful vancomycin treatment. This study highlights the importance of vancomycin minimal inhibitory concentration in hVISA bacteremia.
PubMed: 38916352
DOI: 10.1128/spectrum.00333-24 -
Microbiology Spectrum Jun 2024Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience...
Mechanisms of gastrointestinal toxicity in neuromyelitis optica spectrum disorder patients treated with mycophenolate mofetil: insights from a mouse model and human study.
UNLABELLED
Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial β-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The β-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF.
IMPORTANCE
Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.
PubMed: 38916339
DOI: 10.1128/spectrum.04307-23 -
Microbiology Spectrum Jun 2024is a leading cause of healthcare-associated infections globally. Vancomycin-resistant (VRSA), those with high-level resistance [minimum inhibitory concentration (MIC)...
UNLABELLED
is a leading cause of healthcare-associated infections globally. Vancomycin-resistant (VRSA), those with high-level resistance [minimum inhibitory concentration (MIC) of 16-32 µg/mL vancomycin], are uncommon, whereas vancomycin-intermediate (VISA; MIC of 4-8 µg/mL), are isolated more frequently and develop during long-term and/or repeated use of the antibiotic. VISA can be difficult to eradicate and infections may persist. Our knowledge of mechanisms that underlie the development of VISA is incomplete. We used a genomics approach to investigate the VISA phenotype in three prominent lineages. All VISA clinical isolates tested had increased cell wall thickness compared with vancomycin-susceptible strains. Growth rates of clonal complex (CC) 5, CC8, and CC45 clinical isolates were reduced in 2 µg/mL vancomycin compared to media alone. Culture in 2 and 4 µg/mL vancomycin sequentially for two weeks reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin in a majority of CC5, CC8, and CC45 isolates tested. We identified alleles reported previously to contribute to the VISA phenotype, but unexpectedly, these alleles were unique to each CC. A subtherapeutic concentration of vancomycin elicited changes in the VISA transcriptome-common and unique-among the three CCs tested. Multiple genes, including those encoding a glycerate kinase, an M50 family metallopeptidase, and an uncharacterized membrane protein, were upregulated among all three lineages and not reported previously as associated with VISA. Although there are lineage-specific changes in DNA sequence, our findings suggest changes in the VISA transcriptome constitute a general response to stress that confers reduced susceptibility to multiple antibiotics.
IMPORTANCE
Our understanding of the mechanisms that underlie the development of vancomycin-intermediate (VISA) is incomplete. To provide a more comprehensive view of this process, we compared genome sequences of clonal complex (CC) 5, CC8, and CC45 VISA clinical isolates and measured changes in the transcriptomes of these isolates during culture with a subtherapeutic concentration of vancomycin. Notably, we identified differentially expressed genes that were lineage-specific or common to the lineages tested, including genes that have not been previously reported to contribute to a VISA phenotype. Changes in gene expression were accompanied by reduced growth rate, increased cell wall thickness, and reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin. Our results provide support to the idea that changes in gene expression contribute to the development of VISA among three CCs that are a prominent cause of human infections.
PubMed: 38916317
DOI: 10.1128/spectrum.00486-24 -
Cureus May 2024This case emphasizes the significance of recognizing and managing species. Here, we present a unique case of species isolated from the cerebrospinal fluid of a...
This case emphasizes the significance of recognizing and managing species. Here, we present a unique case of species isolated from the cerebrospinal fluid of a 60-year-old female with recently diagnosed human immunodeficiency virus (HIV) and small cell carcinoma of the lung. Management involved a two-week course of intravenous vancomycin. species are infrequently encountered in clinical practice. Sharing this case report aims to enhance the limited understanding of species infections and encourages discussion among healthcare professionals regarding its diagnosis and management.
PubMed: 38915964
DOI: 10.7759/cureus.61072 -
Frontiers in Cellular and Infection... 2024is a major causative pathogen of osteomyelitis. Intracellular infections of resident bone cells including osteocytes can persist despite gold-standard clinical...
is a major causative pathogen of osteomyelitis. Intracellular infections of resident bone cells including osteocytes can persist despite gold-standard clinical intervention. The mechanisms by which intracellular evades antibiotic therapy are unknown. In this study, we utilised an infection model of human osteocytes to investigate whether antibiotic-mediated dysregulation of autophagy contributes to this phenomenon. Infected or non-infected osteocyte-like cells were exposed to combinations of rifampicin, vancomycin, and modulators of autophagy. Intracellular bacterial growth characteristics were assessed using colonyforming unit (CFU) analysis, viable bacterial DNA abundance, and the rate of escape into antibiotic-free medium, together with measures of autophagic flux. Rifampicin, alone or in combination with vancomycin, caused a rapid decrease in the culturability of intracellular bacteria, concomitant with stable or increased absolute bacterial DNA levels. Both antibiotics significantly inhibited autophagic flux. However, modulation of autophagic flux did not affect viable bacterial DNA levels. In summary, autophagy was shown to be a factor in the host-pathogen relationship in this model, as its modulation affected the growth state of intracellular with respect to both their culturability and propensity to escape the intracellular niche. While rifampicin and vancomycin treatments moderately suppressed autophagic flux acutely, this did not explain the paradoxical response of antibiotic treatment in decreasing culturability whilst failing to clear bacterial DNA and hence intracellular bacterial load. Thus, off-target effects of rifampicin and vancomycin on autophagic flux in osteocyte-like cells could not explain the persistent infection in these cells.
Topics: Autophagy; Staphylococcus aureus; Osteocytes; Anti-Bacterial Agents; Humans; Vancomycin; Rifampin; Staphylococcal Infections; Host-Pathogen Interactions; DNA, Bacterial
PubMed: 38915921
DOI: 10.3389/fcimb.2024.1403289 -
Utility of beta-lactam allergy assessment in patients receiving vancomycin for surgical prophylaxis.Surgery in Practice and Science Mar 2024Beta-lactam antibiotics are first-line agents for most patients receiving antimicrobial prophylaxis in surgical procedures. Despite evidence showing low cross-reactivity...
BACKGROUND
Beta-lactam antibiotics are first-line agents for most patients receiving antimicrobial prophylaxis in surgical procedures. Despite evidence showing low cross-reactivity between penicillins and cephalosporins, patients with beta-lactam allergies commonly receive vancomycin as an alternative to avoid allergic reaction.
METHODS
Adult patients receiving vancomycin for surgical prophylaxis with a reported beta-lactam allergy at our institution between August 2017 to July 2018 were retrospectively evaluated for potential eligibility for penicillin allergy testing and/or receipt of standard prophylaxis.
RESULTS
Among 830 patients who received vancomycin for surgical prophylaxis, 196 reported beta-lactam allergy and were included in the analysis. Approximately 40 % of surgeries were orthopedic. Of patients receiving vancomycin as first-line therapy, 189 (96.4 %) were potentially eligible for beta-lactam prophylaxis.
CONCLUSIONS
Patients with beta-lactam allergies often qualify for receipt of a first-line antibiotic. An opportunity exists for improved allergy assessment as an antimicrobial stewardship intervention in surgical prophylaxis.
PubMed: 38915860
DOI: 10.1016/j.sipas.2023.100232 -
Scientific Reports Jun 2024Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the...
Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.
Topics: Gastrointestinal Microbiome; N-Methyl-3,4-methylenedioxyamphetamine; Animals; Rats; Male; Hyperthermia; Bile Acids and Salts; Anti-Bacterial Agents; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Deoxycholic Acid
PubMed: 38914648
DOI: 10.1038/s41598-024-65433-2 -
Intensive Care Medicine Experimental Jun 2024The aim of this experimental study was to elucidate whether different distances between central venous catheter tips can affect drug clearance during continuous renal...
BACKGROUND
The aim of this experimental study was to elucidate whether different distances between central venous catheter tips can affect drug clearance during continuous renal replacement therapy (CRRT). Central venous catheters (CVCs) are widely used in intensive care patients for drug infusion. If a patient receives CRRT, a second central dialysis catheter (CDC) is required. Where to insert CVCs is directed by guidelines, but recommendations regarding how to place multiple catheters are scarce. There are indications that a drug infused in a CVC with the tip close to the tip of the CDC, could be directly aspirated into the dialysis machine, with a risk of increased clearance. However, studies on whether clearance is affected by different CVC and CDC tip positions, when the two catheters are in the same vessel, are few.
METHODS
In this model with 18 piglets, gentamicin (GM) and vancomycin (VM) were infused through a CVC during CRRT. The CVC tip was placed in different positions in relation to the CDC tip from caudal, i.e., proximal to the heart, to cranial, i.e., distal to the heart. Serum and dialysate concentrations were sampled after approximately 30 min of CRRT at four different positions: when the CVC tip was 2 cm caudally (+ 2), at the same level (0), and at 2 (- 2) and 4 (- 4) cm cranially of the tip of the CDC. Clearance was calculated. A mixed linear model was performed, and level of significance was set to p < 0.05.
RESULTS
Clearance of GM had median values at + 2 cm, 0 cm, - 2 cm and - 4 cm of 17.3 (5.2), 18.6 (7.4), 20.0 (16.2) and 26.2 (12.2) ml/min, respectively (p = 0.04). Clearance of VM had median values at + 2 cm, 0 cm, - 2 cm and - 4 cm of 16.2 (4.5), 14.7 (4.9), 19.0 (10.2) and 21.2 (11.4) ml/min, respectively (p = 0.02).
CONCLUSIONS
The distance between CVC and CDC tips can affect drug clearance during CRRT. A cranial versus a caudal tip position of the CVC in relation to the tip of the CDC led to the highest clearance.
PubMed: 38913212
DOI: 10.1186/s40635-024-00635-6 -
Infection and Drug Resistance 2024In this study we aimed to evaluate the postoperative safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the...
Postoperative Bloodstream Infections in Patients with Peritoneal Surface Malignancies Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Risk Factors and Pathogen Resistance.
OBJECTIVE
In this study we aimed to evaluate the postoperative safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal surface malignancies (PSM), and analyzed the risk factors and pathogen resistance associated with bloodstream infections.
METHODS
We retrospectively analyzed the incidence of postoperative bloodstream infections in 1500 patients undergoing CRS and HIPEC for PSM. We utilized univariate and multivariate analyses to screen for independent risk factors associated with postoperative bloodstream infections in CRS combined with HIPEC.
RESULTS
Among the 1500 cases of individuals undergoing CRS combined with HIPEC, 207 cases (13.8%) experienced bloodstream infections. A total of 233 strains of pathogens were isolated and cultured, consisting of 151 gram-positive cocci, 52 gram-negative bacilli, and 30 fungi. Coagulase-negative staphylococci (SCN) were the gram-positive cocci (54.94%), while (7.30%) and (5.58%) dominated the Gram-negative bacilli. was the predominant fungus. Staphylococci exhibited high sensitivity to tigecycline, linezolid, vancomycin, and quinupristin/dalfopristin. However, and were resistant to imipenem. Furthermore, five parameters were associated with the development of bloodstream infections: age ( = 0.040), surgical history ( = 0.033), prior tumor treatment ( < 0.001), tumor tissue type ( = 0.034), and completeness of cytoreduction (CC) score ( = 0.004). Among these, age ( = 0.013), prior tumor treatment ( = 0.001), tumor tissue type ( = 0.032), and CC score ( = 0.002) emerged as independent risk factors for postoperative bloodstream infections in patients undergoing CRS combined with HIPEC.
CONCLUSION
Postoperative bloodstream infections in patients with PSM undergoing CRS combined with HIPEC are predominantly attributed to SCN, , and . Notably, Enterobacteriaceae exhibited resistance to carbapenem. Independent risk factors for postoperative infections in PSM include age, prior tumor treatment, tumor tissue type, and completeness of cytoreduction score.
PubMed: 38912220
DOI: 10.2147/IDR.S462639