Review
Infectious Diseases
Kashaf Khalid, Katharina Rox
Summary: In the face of increasing antimicrobial resistance and a decline in novel antibiotics, it is crucial to accelerate the development of new treatment options. Understanding PK/PD and PTA of drugs and utilizing in silico methods to predict these parameters have become essential. This review examines recent examples and highlights the importance of PK/PD models and in silico techniques in accelerating drug development.
Article
Microbiology
S. M. Bhavnani, M. Trang, D. C. Griffith, O. Lomovskaya, J. P. Hammel, J. S. Loutit, S. K. Cammarata, M. N. Dudley, P. G. Ambrose, C. M. Rubino
Summary: This study analyzed the pharmacokinetic-pharmacodynamic (PK-PD) target attainment of Meropenem-vaborbactam using population pharmacokinetic models, nonclinical PK-PD targets, in vitro surveillance data, and simulation. The results supported a specific dosing regimen and provided dosing adjustments for patients with renal impairment.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Pharmacology & Pharmacy
Richard C. Franzese, Lynn McFadyen, Kenny J. Watson, Todd Riccobene, Timothy J. Carrothers, Manoli Vourvahis, Phylinda L. S. Chan, Susan Raber, John S. Bradley, Mark Lovern
Summary: The increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria has led to a global health crisis, and the approval of ceftazidime-avibactam combination therapy for children has provided an updated dosage regimen based on population pharmacokinetic models, showing promise for pediatric treatment.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Microbiology
Milo Gatti, Matteo Rinaldi, Cecilia Bonazzetti, Paolo Gaibani, Maddalena Giannella, Pierluigi Viale, Federico Pea
Summary: This study aimed to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion ceftazidime-avibactam and the microbiological outcome of difficult-to-treat resistant Gram-negative infections. The study found that optimized joint PK/PD target attainment could be a way to eradicate these infections and render combination therapy unnecessary.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Article
Infectious Diseases
Xiao-Shan Zhang, Yu-Zhen Wang, Da-Wei Shi, Fang-Min Xu, Jun-Hui Yu, Jie Chen, Guan-Yang Lin, Chun-Hong Zhang, Xu-Ben Yu, Cong-Rong Tang
Summary: This article describes two cases of patients receiving renal replacement therapy who were treated with ceftazidime-avibactam. In the case of intermittent hemodialysis (IHD), 2.5 g of CZA was administered after each session of IHD, with an additional dose of 1.25 g given during the interdialytic interval. In the case of continuous venovenous hemodialysis (CVVHD), 2.5 g of CZA was given every 12 hours in 2-hour infusions. Both dosing regimens maintained effective drug concentrations and exerted antimicrobial effects during the treatment.
INFECTIOUS DISEASES AND THERAPY
(2022)
Article
Infectious Diseases
Valentin al Jalali, Peter Matzneller, Anh Duc Pham, Wisse van Os, Michael Woelfl-Duchek, Maria Sanz-Codina, Andreas Vychytil, Birgit Reiter, Thomas Stimp, Markus Zeitlinger
Summary: This study investigated the pharmacokinetics of CAZ/AVI in patients undergoing APD and found similar PK profiles of the drug in plasma and peritoneal dialysate, indicating the suitability of a fixed-dose combination. Monte Carlo simulations showed that even a low dose of CAZ/AVI achieved a high probability of target attainment for treating infections in APD patients.
CLINICAL MICROBIOLOGY AND INFECTION
(2023)
Article
Pharmacology & Pharmacy
Alzbeta Zavrelova, Martin Sima, Jana Malakova, Petra Rozsivalova, Pavla Paterova, Pavel Zak, Benjamin Visek, Danica Michalickova, Ondrej Slanar, Jakub Radocha
Summary: This study aims to evaluate the pharmacokinetics of off-label high-dose ceftazidime in cancer patients with extensively drug-resistant Pseudomonas aeruginosa infections. The study found that the high-dose regimen had a significantly higher probability of achieving the pharmacokinetic/pharmacodynamic target with a low occurrence of adverse effects.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Infectious Diseases
Marco Falcone, Francesco Menichetti, Dario Cattaneo, Giusy Tiseo, Sara Baldelli, Valentina Galfo, Alessandro Leonildi, Enrico Tagliaferri, Antonello Di Paolo, Manjunath P. Pai
Summary: This study investigated dosing strategies for aztreonam with avibactam in critically ill patients, finding that pragmatic and lower daily dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2021)
Article
Infectious Diseases
Paolo Gaibani, Milo Gatti, Matteo Rinaldi, Cristina Crovara Pesce, Tiziana Lazzarotto, Maddalena Giannella, Donatella Lombardo, Stefano Amadesi, Pierluigi Viale, Federico Pea, Simone Ambretti
Summary: The study described the dynamic evolution of a KPC-Kp infection in a critically ill patient treated with CAZ-AVI combination therapy. Results indicated high adaptability of KPC to CAZ-AVI, with resistance evolution during treatment, emphasizing the importance of identifying optimal PK/PD targets to prevent recurrence.
INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
(2021)
Article
Infectious Diseases
Inmaculada Lopez-Montesinos, Maria Milagro Montero, Sandra Domene-Ochoa, Carla Lopez-Causape, Daniel Echeverria, Luisa Sorli, Nuria Campillo, Sonia Luque, Eduardo Padilla, Nuria Prim, Santiago Grau, Antonio Oliver, Juan P. Horcajada
Summary: This study correlates the in vivo and in vitro findings of a patient with extensively drug-resistant P. aeruginosa infection, indicating a correlation between decreasing plasma levels of CAZ-AVI and the emergence of resistance. The study suggests that maintaining plasma CAZ-AVI levels at least 4 times the minimum inhibitory concentration (MIC) can prevent the development of resistance.
Article
Microbiology
Niklas Kroemer, Lisa F. Amann, Aneeq Farooq, Christoph Pfaffendorf, Miklas Martens, Jean-Winoc Decousser, Nicolas Gregoire, Patrice Nordmann, Sebastian G. Wicha
Summary: Rational combination therapy can increase efficacy and prevent the emergence of resistance. This study found that the combination of ceftazidime/avibactam and fosfomycin showed strong synergy in suppressing bacterial count and preventing resistance. Clinical evaluations are needed to explore dose reductions and the use of this combination for highly resistant strains.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Thanh Bach, Gregory A. Deye, Ellen E. Codd, John Horton, Patricia Winokur, Guohua An
Summary: Oxfendazole, a potent veterinary antiparasitic drug, is being developed for human use to treat various parasitic infections. Results from recent clinical trials showed that the pharmacokinetics of oxfendazole is nonlinear and affected by food, with mild effects on hemoglobin concentrations. Population pharmacokinetic-pharmacodynamic modeling was used to quantitatively characterize the relationship between oxfendazole dose, pharmacokinetics, and hemoglobin concentration, facilitating dose optimization for different patient populations with parasitic infections.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Roxane Rohani, Paul R. Yarnold, Marc H. Scheetz, Michael N. Neely, Mengjia Kang, Helen K. Donnelly, Kay Dedicatoria, Sophie H. Nozick, Rachel L. Medernach, Alan R. Hauser, Egon A. Ozer, Estefani Diaz, Alexander V. Misharin, Richard G. Wunderink, Nathaniel J. Rhodes
Summary: This study aimed to investigate the difference in target attainment of meropenem between plasma and epithelial lining fluid (ELF). The study found that some patients did not achieve the target attainment in both plasma and ELF, and those who achieved target attainment in plasma did not necessarily have the same effect in ELF. Patients with a higher creatinine clearance rate may have poorer target attainment in ELF. Additionally, the dosage and loading dose may also affect the target attainment.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Article
Microbiology
Oluwaseun Egbelowo, Jansy P. Sarathy, Kamunkhwala Gausi, Matthew D. Zimmerman, Han Wang, Gert-Jan Wijnant, Firat Kaya, Martin Gengenbacher, Nhi Van, Yonatan Degefu, Carol Nacy, Bree B. Aldridge, Claire L. Carter, Paolo Denti, Veronique Dartois
Summary: SQ109 is a novel well-tolerated drug candidate for the treatment of drug-resistant tuberculosis, with multiple targets and high accumulation in lung and cellular lesion areas. Studies have shown that its concentrations against replicating, nonreplicating, and intracellular M. tuberculosis are markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Microbiology
Jiao Xie, Qianting Yang, Xinyan Han, Yuzhu Dong, Tao Zhang, Youjia Li, Meixi Ji, Chenwei Liu, Yan Cai, Yan Wang
Summary: This study found that differences in pharmacokinetics/pharmacodynamics target attainment are often overlooked when antifungals are switched in critically ill patients. The results showed that triazoles at guideline-recommended doses could achieve target exposure for de-escalation treatment, while fluconazole and voriconazole performed poorly. Additionally, the achievement of target exposure for echinocandins decreased as body weight increased, with intermittent dosing strategy showing slightly higher CFR values in most simulations compared to conventional dosing strategy.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Review
Pharmacology & Pharmacy
Shampa Das, Diansong Zhou, Wright W. Nichols, Andy Townsend, Paul Newell, Jianguo Li
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
(2020)
Article
Microbiology
Shampa Das, Adam Johnson, Laura McEntee, Nicola Farrington, Adam Kirby, Jennifer Unsworth, Ana Jimenez-Valverde, Ruwanthi Kolamunnage-Dona, Justine Bousquet, Laethitia Alibaud, Carole Sable, Magdalena Zalacain, Martin Everett, William Hope
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Microbiology
Shampa Das, Richard Fitzgerald, Asad Ullah, Marcin Bula, Andrea M. Collins, Elena Mitsi, Jesus Reine, Helen Hill, Jamie Rylance, Daniela M. Ferreira, Karen Tripp, Andrea Bertasini, Samantha Franzoni, Mameli Massimiliano, Omar Lahlou, Paola Motta, Philip Barth, Patrick Velicitat, Philipp Knechtle, William Hope
Summary: The study revealed that cefepime and enmetazobactam had similar concentration-time profiles in plasma and epithelial lining fluid, with a partitioning of 60.59% and 53.03% between plasma and ELF, respectively. The findings suggest that the cefepime-enmetazobactam regimen may be a promising treatment option for nosocomial pneumonia caused by multidrug-resistant Enterobacteriaceae.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Letter
Microbiology
Shampa Das, Martin Everett, Magdalena Zalacain, William Hope
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Oncology
Johanna Berkhout, Maria J. Melchers, Anita C. Van Mil, Claudia M. Lagarde, Wright W. Nichols, Johan W. Mouton
Summary: The post-antibiotic effect (PAE) of ceftazidime-avibactam in vivo was evaluated in thigh- and lung-infection models with Pseudomonas aeruginosa in neutropenic mice. PAE was negative for most strains in thigh infection due to rapid bacterial growth after drug concentrations fell below target values, while positive and longer in lung infection.
JOURNAL OF CHEMOTHERAPY
(2021)
Article
Microbiology
Christopher A. Darlow, Fernando Docobo-Perez, Nicola Farrington, Adam Johnson, Laura McEntee, Jennifer Unsworth, Ana Jimenez-Valverde, Silke Gastine, Ruwanthi Kolamunnage-Dona, Renata M. A. de Costa, Sally Ellis, Francois Franceschi, Joseph F. Standing, Mike Sharland, Michael Neely, Laura Piddock, Shampa Das, William Hope
Summary: Antimicrobial resistance in neonatal sepsis is a global issue, with high mortality rates in low- and middle-income countries. A combination therapy of fosfomycin and amikacin shows enhanced bactericidal activity and synergy against resistant strains. Monte Carlo simulations support the efficacy of this combination regimen for the treatment of neonatal sepsis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Infectious Diseases
Andrew Cristinacce, James G. Wright, Merran Macpherson, Joseph Iaconis, Shampa Das
Summary: For recently licensed antibiotics such as ceftaroline fosamil, probability of target attainment (PTA) curves have been used to support dose recommendations, while limited information is available on PTA for older antibiotics. A retrospective analysis was conducted to construct PTA curves for 4 antibiotics against Staphylococcus aureus in patients with complicated skin and soft tissue infections (cSSTIs). Ceftaroline achieved PTAs >99.9% at MIC90, while comparators failed to achieve PTAs >90% even with increased doses.
DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE
(2021)
Review
Pediatrics
Christopher A. Darlow, Renata M. A. da Costa, Sally Ellis, Francois Franceschi, Mike Sharland, Laura Piddock, Shampa Das, William Hope
Summary: Neonatal sepsis is a major cause of up to 680,000 deaths annually worldwide, with many bacteria developing resistance to antibiotics. Research has identified five antibiotics that meet the criteria for use in neonatal sepsis, but there are still some knowledge gaps that need to be addressed through further studies.
Article
Infectious Diseases
Christopher A. Darlow, Nicola Farrington, Adam Johnson, Laura McEntee, Jennifer Unsworth, Ana Jimenez-Valverde, Ruwanthi Kolamunnage-Dona, Renata M. A. Da Costa, Sally Ellis, Francois Franceschi, Mike Sharland, Michael Neely, Laura J. Piddock, Shampa Das, William Hope
Summary: This study assessed the efficacy of flomoxef and fosfomycin as a potential alternative treatment for neonatal sepsis in low- and middle-income countries. The combination therapy showed synergy in terms of bacterial killing and prevention of fosfomycin resistance. The findings suggest that flomoxef/fosfomycin could be an effective regimen for neonatal sepsis in settings with antimicrobial resistance.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2022)
Article
Microbiology
Nicola Farrington, Laura McEntee, Adam Johnson, Jennifer Unsworth, Christopher Darlow, Ana Jimenez-Valverde, Christoph Hornik, Rachel Greenberg, Julie Schwartz, Shampa Das, William Hope
Summary: Neonatal sepsis is a burden on healthcare systems worldwide, and the increasing prevalence of antimicrobial drug resistance compromises the use of recommended first-line agents. However, the development of new antimicrobial agents for neonatal bacterial meningoencephalitis is still uncertain due to the challenges of studying this disease in clinical settings, particularly in premature infants. In this study, a new platform and approach were developed to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis, using Pseudomonas aeruginosa as the challenge organism. The pharmacodynamics of meropenem and tobramycin were defined in these models, and the results showed significant differences in their antibacterial activities. The developed experimental models can be used to estimate the pharmacodynamics and potential efficacy of currently licensed agents and those in development for neonatal bacterial meningoencephalitis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Editorial Material
Infectious Diseases
Soren Gatermann, Shampa Das, Luc Dubreuil, Christian G. Giske, Gunnar Kahlmeter, Gerard Lina, Christoffer Lindemann, Alasdair MacGowan, Joseph Meletiadis, Gian Maria Rossolini, John Turnidge, Rafael Canton
CLINICAL MICROBIOLOGY AND INFECTION
(2022)
Article
Infectious Diseases
Wright W. Nichols, Patricia A. Bradford, Sushmita D. Lahiri, Gregory G. Stone
Summary: This review analyzes the biochemistry, structural biology, and basic microbiology of ceftazidime/avibactam, showing that avibactam inhibits the majority of serine-dependent beta-lactamases in Enterobacterales and Pseudomonas aeruginosa, potentially enhancing the antibacterial activity of ceftazidime.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2022)
Article
Infectious Diseases
Wright W. Nichols, Patricia A. Bradford, Gregory G. Stone
Summary: This review discusses the preclinical pharmacokinetics/pharmacodynamics (PK/PD) research and clinical translation of ceftazidime/avibactam for the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. Animal models and Monte Carlo simulations show that avibactam protects ceftazidime and achieves the desired drug exposure levels.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2022)
Review
Infectious Diseases
Wright W. Nichols, Sushmita D. Lahiri, Patricia A. Bradford, Gregory G. Stone
Summary: This article reviews the resistance to ceftazidime/avibactam and its primary pharmacology, which is thematically linked with recent reviews of the basic in vitro and in vivo translational biology of the combination (J Antimicrob Chemother 2022; 77: 2321-40 and 2341-52). Single-step exposures to 8x MIC of ceftazidime/avibactam resulted in frequencies of resistance in Enterobacterales or Pseudomonas aeruginosa.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2023)
Review
Infectious Diseases
Wright W. Nichols, Patricia A. Bradford, Gregory G. Stone
Summary: This article is a review of the microbiological findings in drug-exposed patients using the beta-lactam/beta-lactamase inhibitor combination ceftazidime/avibactam. Clinical trials showed that the microbiological response rates ranged from 58.8% to 86.1% depending on the susceptibility of the pathogens and the type of infection. Case studies also demonstrated comparable microbiological outcomes between ceftazidime/avibactam and other antibacterial treatments.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2023)