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Jeffrey Lipman - One of the best experts on this subject based on the ideXlab platform.

  • Cerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular Drain.
    Antimicrobial agents and chemotherapy, 2020
    Co-Authors: Fekade B Sime, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman, Melissa Lassig-smith, Jason A. Roberts
    Abstract:

    The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and Cerebrospinal Fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19 to 128) h·mg/liter and 323 (183 to 414) h·mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h·mg/liter and 52 (36 to 80) h·mg/liter, respectively. Mean ± standard deviation (SD) CSF Penetration ratios were 0.2 ± 0.2 and 0.2 ± 0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ≥0.9 for 40% fT>MIC in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1 mg/liter was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/liter).

  • Cerebrospinal Fluid Penetration of ceftolozane tazobactam in critically ill patients with an indwelling external ventricular drain
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Fekade B Sime, Melissa Lassigsmith, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman
    Abstract:

    The aim of this study was to describe the pharmacokinetics of ceftolozane/tazobactam in plasma and Cerebrospinal Fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥ 18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0g ceftolozane/tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modelled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (Inter quartile range, IQR) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19-128) h*mg/L, and 323 (183-414) h*mg/L respectively. For tazobactam, these values were 5.6 (2-24) h*mg/L and 52 (36-80) h*mg/L, respectively. Mean ± standard deviation (SD) CSF Penetration ratios were 0.2 ± 0.2 and 0.2±0.26 for ceftolozane and tazobactam respectively. With the 3.0 g 8-houly regimen, ≥ 0.9 probability of target attainment (PTA) for 40% fT>MIC in the CSF was possible only when MICs were ≤ 0.25 mg/L. The CSF cumulative fractional response for P. aeruginosa susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1mg/L was 12%. The current maximal dose of ceftolozane/tazobactam (3.0 g 8-hourly) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/L).

  • Antibiotic Distribution into Cerebrospinal Fluid: Can Dosing Safely Account for Drug and Disease Factors in the Treatment of Ventriculostomy-Associated Infections?
    Clinical Pharmacokinetics, 2018
    Co-Authors: Nilesh Kumta, Jeffrey Lipman, Jason A. Roberts, Menino Osbert Cotta
    Abstract:

    Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the Cerebrospinal Fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis. This paper aims to review the disease burden, infection rates, and common pathogens associated with ventriculostomy-associated infections. This review also seeks to describe the disease- and drug-related factors that influence antibiotic distribution into Cerebrospinal Fluid and provide a critical appraisal of current dosing of antibiotics commonly used to treat these types of infections. A Medline search of relevant articles was conducted and used to support a review of Cerebrospinal Fluid Penetration of vancomycin, including critical appraisal of the recent paper by Beach et al. recently published in this journal. We found that in the intensive care unit, ventriculostomy-associated infections are the most common and serious complication of external ventricular drain insertion and often result in prolonged patient stay and increased healthcare costs. Reported infection rates are extremely variable (between 0 and 45%), hindered by the inherent diagnostic difficulty. Both Gram-positive and Gram-negative organisms are associated with such infections and the rise of multi-drug-resistant pathogens means that effective treatment is an ongoing challenge. Disease factors that may need to be considered are reduced meningeal inflammation and the presence of critical illness; drug factors include physiochemical properties, degree of plasma–protein binding, and affinity to active transporter proteins present in the blood–Cerebrospinal Fluid barrier. The relationship between Cerebrospinal Fluid antibiotic exposures in the setting of ventriculostomy-associated infection and clinical response has not been fully elucidated for many of the antibiotics commonly used in its treatment. More thorough and clinically relevant investigations are needed to better define blood pharmacokinetic/pharmacodynamics targets and optimal therapeutic exposures for treatment of ventriculostomy-associated infections. It is hoped that this future research will be able to provide clearer recommendations for clinicians frequently faced with dosing-related dilemmas when treating patients with these challenging infections.

  • Cerebrospinal Fluid Penetration of high doses of intravenous ciprofloxacin in meningitis
    Clinical Infectious Diseases, 2000
    Co-Authors: Jeffrey Lipman, Anthony Allworth, Steven C Wallis
    Abstract:

    Nosocomial meningitis due to gram-negative organisms is a difficult clinical problem to manage because of both antibiotic resistance and poor Penetration of many antimicrobials across the blood-brain barrier. Ciprofloxacin has potential in treating this condition when used in high doses. We investigated the plasma and Cerebrospinal Fluid (CSF) levels of ciprofloxacin in a patient with Pseudomonas aeruginosa meningitis who was treated with 400 mg of intravenous ciprofloxacin every 8 hours. Ciprofloxacin levels in plasma peaked at 10.29 mg/L without resulting in accumulation (8-hour trough levels, <1 mg/L), whereas the CSF level increased to 0.9 mg/L. This CSF level was confirmed to be similar 1 week later. After 1 week of therapy, during which there were no side effects attributable to ciprofloxacin, the organism was eradicated, and there was some clinical improvement. We recommend that 400 mg of intravenous ciprofloxacin every 8 hours be considered for treatment of difficult-to-treat gram-negative bacillary meningitis.

  • Cerebrospinal Fluid Penetration of High Doses of Intravenous Ciprofloxacin in Meningitis
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2000
    Co-Authors: Jeffrey Lipman, Anthony Allworth, Steven C Wallis
    Abstract:

    Nosocomial meningitis due to gram-negative organisms is a difficult clinical problem to manage because of both antibiotic resistance and poor Penetration of many antimicrobials across the blood-brain barrier. Ciprofloxacin has potential in treating this condition when used in high doses. We investigated the plasma and Cerebrospinal Fluid (CSF) levels of ciprofloxacin in a patient with Pseudomonas aeruginosa meningitis who was treated with 400 mg of intravenous ciprofloxacin every 8 hours. Ciprofloxacin levels in plasma peaked at 10.29 mg/L without resulting in accumulation (8-hour trough levels,

Jerónimo Pachón - One of the best experts on this subject based on the ideXlab platform.

Jason A. Roberts - One of the best experts on this subject based on the ideXlab platform.

  • Cerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular Drain.
    Antimicrobial agents and chemotherapy, 2020
    Co-Authors: Fekade B Sime, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman, Melissa Lassig-smith, Jason A. Roberts
    Abstract:

    The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and Cerebrospinal Fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19 to 128) h·mg/liter and 323 (183 to 414) h·mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h·mg/liter and 52 (36 to 80) h·mg/liter, respectively. Mean ± standard deviation (SD) CSF Penetration ratios were 0.2 ± 0.2 and 0.2 ± 0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ≥0.9 for 40% fT>MIC in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1 mg/liter was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/liter).

  • Cerebrospinal Fluid Penetration of very high-dose meropenem: a case report.
    Annals of clinical microbiology and antimicrobials, 2018
    Co-Authors: Thomas Kerz, Friederike D. Von Loewenich, Jason A. Roberts, Axel Neulen, Florian Ringel
    Abstract:

    Standard dosing of meropenem (2 g t.i.d.) produces CSF concentrations of only 1–2 mg/L which is inferior to the clinical breakpoint for most Gram-negative bacteria. There is therefore concern that dosing must be increased in order to achieve therapeutic CSF concentrations for bacteria with susceptibility close to clinical breakpoints. Yet, the effects of high-dose meropenem on CSF concentrations are not well described in literature. We therefore determined meropenem CSF-levels in a patient who was treated with 15 g/day of meropenem. Our patient suffered from a brain trauma and an external ventricular drainage was implanted. Later, a carbapenemase-producing Acinetobacter baumannii (OXA-23, NDM-1) was isolated from blood cultures and CSF. The MIC for meropenem was > 32 mg/L (R), and we opted for a combination therapy of meropenem, colistin and fosfomycin. Meropenem was given at an unusual high-dose (15 g/day) with the aim of achieving high CSF concentrations. CSF concentrations peaked at 64 mg/L. Yet, the patient succumbed to an intracranial bleed into a preexisting cerebral contusion. High-dose meropenem can achieve CSF levels largely superior to those achieved with commonly recommended dosing regimens. Though our patient succumbed to an intracranial bleed which could be regarded as a severe adverse event, we suggest that meropenem dosing can be increased when pathogens with increased MICs are found in the CSF. More in vivo data are however needed to determine the safety of high-dose meropenem.

  • Antibiotic Distribution into Cerebrospinal Fluid: Can Dosing Safely Account for Drug and Disease Factors in the Treatment of Ventriculostomy-Associated Infections?
    Clinical Pharmacokinetics, 2018
    Co-Authors: Nilesh Kumta, Jeffrey Lipman, Jason A. Roberts, Menino Osbert Cotta
    Abstract:

    Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the Cerebrospinal Fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis. This paper aims to review the disease burden, infection rates, and common pathogens associated with ventriculostomy-associated infections. This review also seeks to describe the disease- and drug-related factors that influence antibiotic distribution into Cerebrospinal Fluid and provide a critical appraisal of current dosing of antibiotics commonly used to treat these types of infections. A Medline search of relevant articles was conducted and used to support a review of Cerebrospinal Fluid Penetration of vancomycin, including critical appraisal of the recent paper by Beach et al. recently published in this journal. We found that in the intensive care unit, ventriculostomy-associated infections are the most common and serious complication of external ventricular drain insertion and often result in prolonged patient stay and increased healthcare costs. Reported infection rates are extremely variable (between 0 and 45%), hindered by the inherent diagnostic difficulty. Both Gram-positive and Gram-negative organisms are associated with such infections and the rise of multi-drug-resistant pathogens means that effective treatment is an ongoing challenge. Disease factors that may need to be considered are reduced meningeal inflammation and the presence of critical illness; drug factors include physiochemical properties, degree of plasma–protein binding, and affinity to active transporter proteins present in the blood–Cerebrospinal Fluid barrier. The relationship between Cerebrospinal Fluid antibiotic exposures in the setting of ventriculostomy-associated infection and clinical response has not been fully elucidated for many of the antibiotics commonly used in its treatment. More thorough and clinically relevant investigations are needed to better define blood pharmacokinetic/pharmacodynamics targets and optimal therapeutic exposures for treatment of ventriculostomy-associated infections. It is hoped that this future research will be able to provide clearer recommendations for clinicians frequently faced with dosing-related dilemmas when treating patients with these challenging infections.

Donna Brown - One of the best experts on this subject based on the ideXlab platform.

  • the disposition and Cerebrospinal Fluid Penetration of morphine and its two major glucuronidated metabolites in adults undergoing lumbar myelogram
    Pharmacotherapy, 1993
    Co-Authors: Steven Laizure, Joseph H. Miller, Robert C. Stevens, David J. Donahue, Robert E. Laster, Donna Brown
    Abstract:

    Study Objective. To determine the pharmacokinetic disposition of morphine and its two major glucuronidated metabolites, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), in serum and their Penetration into Cerebrospinal Fluid (CSF). Design. A single-dose, open-label pharmacokinetic study. Setting. The Memphis Neurosciences Center at Methodist Hospital. Patients. Twenty patients undergoing a diagnostic lumbar myelogram. Interventions. All patients received morphine sulfate 10 mg intramuscularly approximately 1.5 hours before the procedure. Measurements and Main Results. Three blood samples were drawn after the dose and a CSF sample was drawn immediately after lumbar puncture. The mean ± standard deviation for the half-life of morphine was 2.8 ± 1.4 hours. The apparent half-lives of M6G and M3G were 5.7 ± 3.1 and 6.3 ± 2.2 hours, respectively, and were inversely related to the estimated creatinine clearance (r=-0.61, p<0.007 and r=-0.69, p<0.002, respectively). The mean concentrations of morphine, M6G, and M3G in the CSF (collection time 1.5 ± 0.32 hrs, n=19) were 3.1 ± 3.7, 12.5 ±17.6, and 19.6 ±16.1 nmol/L, respectively. Conclusions. Elderly patients and patients with renal dysfunction receiving morphine may experience prolonged analgesic and adverse effects secondary to a decrease in the clearance of M6G.

  • The Disposition and Cerebrospinal Fluid Penetration of Morphine and Its Two Major Glucuronidated Metabolites in Adults Undergoing Lumbar Myelogram
    Pharmacotherapy, 1993
    Co-Authors: Steven Laizure, Joseph H. Miller, Robert C. Stevens, David J. Donahue, Robert E. Laster, Donna Brown
    Abstract:

    Study Objective. To determine the pharmacokinetic disposition of morphine and its two major glucuronidated metabolites, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), in serum and their Penetration into Cerebrospinal Fluid (CSF). Design. A single-dose, open-label pharmacokinetic study. Setting. The Memphis Neurosciences Center at Methodist Hospital. Patients. Twenty patients undergoing a diagnostic lumbar myelogram. Interventions. All patients received morphine sulfate 10 mg intramuscularly approximately 1.5 hours before the procedure. Measurements and Main Results. Three blood samples were drawn after the dose and a CSF sample was drawn immediately after lumbar puncture. The mean ± standard deviation for the half-life of morphine was 2.8 ± 1.4 hours. The apparent half-lives of M6G and M3G were 5.7 ± 3.1 and 6.3 ± 2.2 hours, respectively, and were inversely related to the estimated creatinine clearance (r=-0.61, p

Takashi Seto - One of the best experts on this subject based on the ideXlab platform.

  • Erlotinib for Non‐Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101)
    The oncologist, 2020
    Co-Authors: Kaname Nosaki, Takeharu Yamanaka, Akinobu Hamada, Yoshimasa Shiraishi, Taishi Harada, Daisuke Himeji, Takeshi Kitazaki, Noriyuki Ebi, Takayuki Shimose, Takashi Seto
    Abstract:

    LESSONS LEARNED This phase II trial evaluated the efficacy of erlotinib for patients with non-small cell lung cancer with leptomeningeal metastasis. The 17 Cerebrospinal Fluid specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance-conferring T790M mutation. The cytological objective clearance rate was 30.0% (95% confidence interval: 11.9%-54.3%). The median time to progression was 2.2 months. The rate of Cerebrospinal Fluid Penetration among these patients was equivalent to those in previous reports regarding leptomeningeal metastasis. BACKGROUND Leptomeningeal metastases (LM) occur in approximately 5% of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. However, no prospective study has identified an active chemotherapeutic drug in this setting. METHODS Patients were considered eligible to receive erlotinib if they had NSCLC with cytologically confirmed LM. The objective cytological clearance rate, time to LM progression (TTP), overall survival (OS), quality of life outcomes, and pharmacokinetics were analyzed. This study was closed because of slow accrual at 21 of the intended 32 patients (66%). RESULTS Between December 2011 and May 2015, 21 patients (17 with activating epidermal growth factor receptor [EGFR] mutations) were enrolled. The 17 Cerebrospinal Fluid specimens available were all negative for the T790M mutation, which confers erlotinib resistance. The clearance rate was 30.0% (95% confidence interval [CI]: 11.9%-54.3%), the median TTP was 2.2 months, and the median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (p = .0113 and p < .0054, respectively). The mean Cerebrospinal Fluid Penetration rate was 3.31% ± 0.77%. There was a good correlation between plasma and Cerebrospinal Fluid (CSF) concentrations, although there was no clear correlation between pharmacokinetic parameters and clinical outcome. CONCLUSION Erlotinib was active for LM and may be a treatment option for patients with EGFR-mutated NSCLC and LM.