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Pharmacology Research & Perspectives Dec 2022The most recent consensus guidelines for dosing and monitoring vancomycin recommended the use of area-under-the-curve with Bayesian estimation for therapeutic... (Review)
Review
The most recent consensus guidelines for dosing and monitoring vancomycin recommended the use of area-under-the-curve with Bayesian estimation for therapeutic monitoring. As this is a modern concept in the practice of clinical pharmacy, the main objective of this review is to introduce the fundamentals of Bayesian estimation and its mathematical application as it relates to vancomycin therapeutic drug monitoring. In addition, we aim to identify pharmacokinetic (PK) software programs that incorporate Bayesian estimation for vancomycin dosing and to describe the PK models utilized in those software programs for the adult population. Twelve software programs that utilize Bayesian estimation were identified, which included: Adult and Pediatric Kinetics, Best Dose, ClinCalc, DoseMeRx, ID-ODS, InsightRx, MwPharm++, NextDose, PrecisePK, TDMx, Tucuxi, and VancoCalc. The software programs varied in the population PK models used as the Bayesian a priori. With the presence of various vancomycin Bayesian software programs, it is important to choose those that utilize PK models reflective of the specific patient population.
Topics: Adult; Humans; Child; Vancomycin; Bayes Theorem; Anti-Bacterial Agents; Drug Monitoring; Pharmacy
PubMed: 36398492
DOI: 10.1002/prp2.1026 -
PloS One 2014To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia. (Observational Study)
Observational Study
BACKGROUND
To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia.
METHODS
Patients ≥18 years admitted on general wards were included. Routinely vancomycin trough and peak plasma concentrations were measured with a fluorescence polarization immunoassay. Pharmacokinetic parameters of individual patients were determined with maximum a posterior Bayesian estimation (MW Pharm 3.60). Neutropenia was defined as neutrophils <0.5×109 cells/L.
PRINCIPAL FINDINGS
A total of 171 patients were included. Patients with neutropenia (n = 56) had higher clearance of vancomycin (CLva), 67 (±26) mL/min, compared to patients without neutropenia (n = 115), CLva 50 (±22) mL/min (p<0.001). No significant difference was found in serum creatinine and vancomycin volume of distribution. Neutropenia was positively associated with CLva, independently of relevant co-variables (B: 12.122, 95%CI: 1.095 to 23.149, p = 0.031). On average patients with neutropenia needed 33% higher doses of vancomycin to attain adequate exposure, i.e. AUC24≥400 mg×h/L. Furthermore, 15 initially neutropenic patients in our study group received vancomycin for a second administration period. Ten patients received the second administration period during another neutropenic period and 5 patients during a non-neutropenic phase. All 5 patients with vancomycin during both neutropenic and non-neutropenic phase had higher CLva (91 (±26) mL/min) during the neutropenic period and lower CLva (45 (±10) mL/min) during the non-neutropenic phase (p = 0.009).
CONCLUSION
This study shows that most patients with neutropenia have augmented CLva. In a small group of patients that received vancomycin during two episodes, the augmented CLva seems to be reversible in the non-neutropenic period. Our data indicate that it is important to increase the daily dose with one third in patients with neutropenia (from 15 mg/kg twice daily to 13 mg/kg three times daily). Frequent performance of therapeutic drug monitoring in patients with neutropenia may prevent both therapy failure due to low AUCs and overcomes toxicity due to high vancomycin trough concentrations during recovery from neutropenia.
Topics: Aged; Anti-Bacterial Agents; Area Under Curve; Bayes Theorem; Drug Monitoring; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Multivariate Analysis; Neutropenia; Vancomycin
PubMed: 25390637
DOI: 10.1371/journal.pone.0112008 -
Therapeutic Drug Monitoring Feb 2022Neonatal infections are associated with high morbidity and mortality rates. Optimal treatment of these infections requires knowledge of neonatal pharmacology and...
BACKGROUND
Neonatal infections are associated with high morbidity and mortality rates. Optimal treatment of these infections requires knowledge of neonatal pharmacology and integration of neonatal developmental pharmacokinetics (PKs) of antimicrobial drugs in the design of dosing regimens for use with different gestational and postnatal ages. Population PK and pharmacodynamic models are used to personalize the use of these drugs in these fragile patients. The final step to further minimize variability in an individual patient is therapeutic drug monitoring (TDM), where the same population PK/pharmacodynamic models are used in concert with optimally drawn blood samples to further fine-tune therapy. The purpose of this article is to describe the present status and future role of model-based precision dosing and TDM of antimicrobial drugs in neonates.
METHODS
PubMed was searched for clinical trials or clinical studies of TDM in neonates.
RESULTS
A total of 447 articles were retrieved, of which 19 were concerned with antimicrobial drugs. Two articles (one aminoglycoside and one vancomycin) addressed the effects of TDM in neonates. We found that, in addition to aminoglycosides and vancomycin, TDM also plays a role in beta-lactam antibiotics and antifungal drugs.
CONCLUSIONS
There is a growing awareness that, in addition to aminoglycosides and vancomycin, the use of beta-lactam antibiotics, such as amoxicillin and meropenem, and other classes of antimicrobial drugs, such as antifungal drugs, may benefit from TDM. However, the added value must be shown. New analytical techniques and software development may greatly support these novel developments.
Topics: Aminoglycosides; Anti-Bacterial Agents; Antifungal Agents; Drug Monitoring; Humans; Infant, Newborn; Vancomycin
PubMed: 34369442
DOI: 10.1097/FTD.0000000000000919 -
PloS One 2015Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat... (Comparative Study)
Comparative Study Meta-Analysis Review
Efficacy and Safety of Metronidazole Monotherapy versus Vancomycin Monotherapy or Combination Therapy in Patients with Clostridium difficile Infection: A Systematic Review and Meta-Analysis.
BACKGROUND
Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients.
METHODS
A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported.
RESULTS
Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p < 0.0001).
CONCLUSIONS
Metronidazole and vancomycin are equally effective for the treatment of mild CDI, but vancomycin is superior for the treatment of severe CDI. Combination therapy is not superior to monotherapy because it appears to be associated with an increase in the rate of AEs.
Topics: Adult; Aged; Anti-Bacterial Agents; Child; Child, Preschool; Clostridioides difficile; Drug Therapy, Combination; Enterocolitis, Pseudomembranous; Female; Humans; Male; Metronidazole; Middle Aged; Treatment Outcome; Vancomycin
PubMed: 26444424
DOI: 10.1371/journal.pone.0137252 -
Cell Host & Microbe May 2023Clostridioides difficile infections (CDIs) remain a healthcare problem due to high rates of relapsing/recurrent CDIs (rCDIs). Breakdown of colonization resistance...
Clostridioides difficile infections (CDIs) remain a healthcare problem due to high rates of relapsing/recurrent CDIs (rCDIs). Breakdown of colonization resistance promoted by broad-spectrum antibiotics and the persistence of spores contribute to rCDI. Here, we demonstrate antimicrobial activity of the natural product class of chlorotonils against C. difficile. In contrast to vancomycin, chlorotonil A (ChA) efficiently inhibits disease and prevents rCDI in mice. Notably, ChA affects the murine and porcine microbiota to a lesser extent than vancomycin, largely preserving microbiota composition and minimally impacting the intestinal metabolome. Correspondingly, ChA treatment does not break colonization resistance against C. difficile and is linked to faster recovery of the microbiota after CDI. Additionally, ChA accumulates in the spore and inhibits outgrowth of C. difficile spores, thus potentially contributing to lower rates of rCDI. We conclude that chlorotonils have unique antimicrobial properties targeting critical steps in the infection cycle of C. difficile.
Topics: Animals; Mice; Swine; Vancomycin; Clostridioides difficile; Anti-Bacterial Agents; Clostridium Infections
PubMed: 37098342
DOI: 10.1016/j.chom.2023.04.003 -
ACS Infectious Diseases Jul 2023Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites of infection....
Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites of infection. Instead, screening in more physiologically relevant conditions may reveal novel activity for existing antibiotics. Here, we screened a panel of antibiotics reported to lack activity against the opportunistic Gram-negative bacterium, , under low-nutrient and low-iron conditions, and discovered that the glycopeptide vancomycin inhibited the growth of at low micromolar concentrations through its canonical mechanism of action, disruption of peptidoglycan crosslinking. Spontaneous vancomycin-resistant mutants underwent activating mutations in the sensor kinase of the two-component CpxSR system, which induced cross-resistance to almost all classes of β-lactams, including the siderophore antibiotic cefiderocol. Other mutations that conferred vancomycin resistance mapped to WapR, an α-1,3-rhamnosyltransferase involved in lipopolysaccharide core biosynthesis. A WapR P164T mutant had a modified LPS profile compared to wild type that was accompanied by increased susceptibility to select bacteriophages. We conclude that screening in nutrient-limited conditions can reveal novel activity for existing antibiotics and lead to discovery of new and impactful resistance mechanisms.
Topics: Vancomycin; Pseudomonas aeruginosa; Anti-Bacterial Agents; Glycopeptides; Nutrients
PubMed: 37279282
DOI: 10.1021/acsinfecdis.3c00167 -
Injury Aug 2022Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical...
Concentrations of co-administered vancomycin and meropenem in the internal dead space of a cannulated screw and in cancellous bone adjacent to the screw - Evaluated by microdialysis in a porcine model.
BACKGROUND
Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical Gram-positive and Gram-negative antibiotic coverage. To ensure full antibiotic protection of the cannulated screw and the bone tissue, it is generally accepted that target tissue antibiotic concentrations, as a minimum, reach and remain above relevant epidemiological cut-off minimal inhibitory concentrations (T>MIC) for a sufficient amount of time.
METHODS
8 female pigs were included. Microdialysis catheters were placed in the internal dead space of a cannulated screw placed in tibial cancellous bone, in tibial cancellous bone adjacent to the screw (mean distance to the screw: 3 mm), and in cancellous bone on the contralateral tibia. Following single-dose simultaneous intravenous administrations of vancomycin (1000 mg) and meropenem (1000 mg), microdialysates and plasma were dynamically sampled over 8 h. The applied MIC targets ranged from 1 to 4 µg/mL for vancomycin and 0.125-2 µg/mL for meropenem RESULTS: For both drugs, and for all MIC targets investigated (except for the high vancomycin target: 4 µg/mL), the internal dead space of the cannulated screw had the shortest T>MIC. At the low MIC targets T>MIC ranged between 88 and 449 min across sampling sites for vancomycin (1 µg/mL), and 148-406 min for meropenem (0.125 µg/mL). For the high MIC targets, T>MIC ranged between 3 and 446 min for vancomycin (4 μg/mL) and 17-181 min for meropenem (2 μg/mL). Vancomycin displayed longer T>MIC (2 and 4 μg/mL), higher area under the concentration time curve (AUC) and peak drug concentration in the proximal tibial cancellous bone without a screw nearby. For meropenem, only the cancellous bone AUC was significantly higher on the side with no screw.
CONCLUSION
We found short T>MIC, particularly for the high MIC targets for vancomycin and meropenem, both inside the cannulated screw and in cancellous bone adjacent to the screw. The presence of a cannulated screw impaired the penetration of especially vancomycin into cancellous bone adjacent to the screw. More aggressive or different vancomycin and meropenem approaches may be considered to encompass contaminating differences and to ensure a theoretically more sufficient antibiotic protection of cannulated screws when used in the management of open lower extremity fractures.
Topics: Animals; Anti-Bacterial Agents; Cancellous Bone; Female; Meropenem; Microdialysis; Swine; Vancomycin
PubMed: 35710595
DOI: 10.1016/j.injury.2022.06.008 -
Journal of Global Antimicrobial... Mar 2021To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC) could be optimised for...
OBJECTIVES
To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC) could be optimised for tuberculosis treatment. We also explored vancomycin synergy and antagonism with d-cycloserine and benzylpenicillin.
METHODS
We determined MICs of two Mycobacterium tuberculosis (Mtb) laboratory strains (H37Ra and H37Rv) and two drug-susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using Mtb H37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight doses administered twice daily over 28 days, mimicking a 6-h half-life. Using the HFS-TB, vancomycin was tested in combination with d-cycloserine and benzylpenicillin to determine synergy or antagonism between drugs targeting the same pathway.
RESULTS
Vancomycin MICs were 12 and 48 mg/L in drug-susceptible clinical isolates but >96 mg/L in all MDR isolates.In the HFS-TB, vancomycin killed 3.9 ± 0.6 log CFU/mL Mtb. The EC was calculated as AUC/MIC of 184.6 ± 106.5. Compared with day 0, 1.0 and 2.0 log CFU/mL kill was achieved by AUC/MIC of 168 and 685, respectively. Acquired vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but synergistic with d-cycloserine, which inhibits upstream d-Ala-d-Ala ligase and alanine racemase.
CONCLUSION
Our proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via inhalational drug delivery. Addition of drugs synergistic with vancomycin, e.g. d-cycloserine, may lower the vancomycin concentrations required to kill Mtb.
Topics: Antitubercular Agents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Vancomycin
PubMed: 33508482
DOI: 10.1016/j.jgar.2021.01.005 -
Emergence of Clinical Clostridioides difficile Isolates With Decreased Susceptibility to Vancomycin.Clinical Infectious Diseases : An... Jan 2022Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few...
BACKGROUND
Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few antibiotics recommended for both nonsevere and severe CDI cases. We sought to determine whether vancomycin nonsusceptible C. difficile strains are circulating in the patient population.
METHODS
Stool samples from patients with CDI were collected from 438 and 98 patients at a large university hospital in Houston, Texas, and Nairobi, Kenya, respectively. The stools were examined for the presence of vancomycin and metronidazole nonsusceptible C. difficile using broth dilution culture, Etest (BioMérieux, France), polymerase chain reaction (PCR), whole-genome sequencing, and in vivo testing in a CDI mouse model.
RESULTS
Of the Houston stool samples, 114/438 (26%) had vancomycin nonsusceptible C. difficile isolates and 128/438 (29%) were metronidazole nonsusceptible. Similarly, 66 out of 98 (67%) and 83/98 (85%) of the Nairobi patients harbored vancomycin and metronidazole nonsusceptible isolates, respectively. Vancomycin treatment of a CDI mouse model infected with a vancomycin nonsusceptible isolate failed to eradicate the infection. Whole-genome sequencing analyses did not identify vanA genes, suggesting a different mechanism of resistance.
CONCLUSIONS
C. difficile strains exhibiting reduced susceptibility to vancomycin are currently circulating in patient populations. The spread of strains resistance to vancomycin, a first-line antibiotic for CDI, poses a serious therapeutic challenge. Routine susceptibility testing may be necessary.
Topics: Animals; Anti-Bacterial Agents; Clostridioides; Clostridioides difficile; Clostridium Infections; Humans; Kenya; Mice; Vancomycin
PubMed: 35016207
DOI: 10.1093/cid/ciaa912 -
BMC Pediatrics May 2023Methicillin-resistant Staphylococcus aureus (MRSA) can cause invasive infections with significant mortality in neonates. This study aimed to analyze the clinical...
BACKGROUND
Methicillin-resistant Staphylococcus aureus (MRSA) can cause invasive infections with significant mortality in neonates. This study aimed to analyze the clinical characteristics and antibiotic resistance profiles of invasive MRSA infections and determine risk factors associated with invasive MRSA infections in newborn inpatients.
METHODS
This multicenter retrospective study of inpatients from eleven hospitals in the Infectious Diseases Surveillance of Pediatrics (ISPED) group of China was performed over a two-year period (2018-2019). Statistical significance was calculated by applying the χ2 test or by Fisher's exact test in the case of small sample sizes.
RESULTS
A total 220 patients were included. Among included cases, 67 (30.45%) were invasive MRSA infections, including two deaths (2.99%), while 153 (69.55%) were noninvasive infections. The invasive infections of MRSA occurred at a median age of 8 days on admission, which was significantly younger compared to 19 days in noninvasive cases. Sepsis (86.6%) was the most common invasive infection, followed by pneumonia (7.4%), bone and joint infections (3.0%), central nervous system infection (1.5%), and peritonitis (1.5%). Congenital heart disease, low birth weight infant (<2500 g), but not preterm neonates, and bronchopulmonary dysplasia, were more commonly found in invasive MRSA infections. All these isolates were susceptible to vancomycin and linezolid and were resistant to penicillin. Additionally, 69.37% were resistant to erythromycin, 57.66% to clindamycin, 7.04% to levofloxacin, 4.62% to sulfamethoxazole-trimethoprim, 4.29% to minocycline, 1.33% to gentamicin, and 3.13% were intermediate to rifampin.
CONCLUSION
Low age at admission (≤8 days), congenital heart disease, and low birth weight were associated with invasive MRSA infections in neonates, and no isolates resistant to vancomycin and linezolid were found. Determining these risks in suspected neonates may help identify patients with imminent invasive infections who may require intensive monitoring and therapy.
Topics: Infant; Infant, Newborn; Humans; Child; Methicillin-Resistant Staphylococcus aureus; Anti-Bacterial Agents; Vancomycin; Retrospective Studies; Linezolid; Staphylococcal Infections; Inpatients; Microbial Sensitivity Tests; Drug Resistance, Microbial
PubMed: 37231456
DOI: 10.1186/s12887-023-04084-0