A Phase 1, Randomized, Open-Label, Trial Evaluating the Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Intravenous Carbavance™ (RPX2014/RPX7009) in Healthy Adult Subjects

RPX7009(beta-lactamase inhibitor) is being studied in combination with a carbapenem (RPX2014) to treat bacterial infections, including those due to multi-drug resistant bacteria.

Start Date01 Feb 2014

Sponsor / Collaborator

Rempex Pharmaceuticals, Inc.

NCT02020434 / CompletedPhase 1

A Phase 1, Open-label, Single-dose Study to Determine the Safety and Pharmacokinetics of Carbavance™ (RPX2014/RPX7009) in Subjects With Renal Insufficiency

RPX7009(beta-lactamase inhibitor) is being studied in combination with carbapenem (RPX2014)to treat bacterial infections, including those due to multi-drug resistant bacteria.

Start Date01 Jan 2014

Sponsor / Collaborator

Rempex Pharmaceuticals, Inc.

NCT01897779 / CompletedPhase 1

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple Ascending-dose Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous RPX2014 and RPX7009 Alone and in Combination in Healthy Adult Subjects

RPX7009 (beta-lactamase inhibitor) is being studied in combination with a carbapenem (RPX2014) to treat bacterial infections, including those due to multi-drug resistant bacteria.

Start Date01 Jul 2013

Sponsor / Collaborator

Rempex Pharmaceuticals, Inc.

100 Clinical Results associated with Vaborbactam

100 Translational Medicine associated with Vaborbactam

100 Patents (Medical) associated with Vaborbactam

356

Literatures (Medical) associated with Vaborbactam

01 Jan 2025·INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS

Identification of blaKPC-90 in Klebsiella pneumoniae associated with ceftazidime-avibactam resistance and the translocation & truncation of resistant genes mediated by IS26

Article

Author: Yang, Weiwei ; Zhao, Yuanxun ; Ma, Xiaobo ; Hu, Fupin ; Chen, Wannan ; Xu, Heping

OBJECTIVES:

In this study, we discovered bla_KPC-90 in ceftazidime-avibactam resistant clinical isolates of K. pneumoniae from a patient with multiple comorbidities and investigated the resistance & transfer mechanism of bla_KPC-90.

METHODS:

K. pneumoniae strains carrying bla_KPC-2 and bla_KPC-90 were isolated from the patient. Antimicrobial susceptibility tests and whole genome sequencing were performed to investigate the phenotype & genotype of strains. Conjugation assays, cloning experiment, kinetic parameters measuring, outer membrane protein SDS-PAGE and qRT-PCR were performed to explore the spread and antimicrobial resistance mechanisms.

RESULTS:

KPC-90 isolates had an insertion of two amino acids (Thr180_Ser181 ins Tyr Thr) compared to the wildtype KPC-2. Antimicrobial susceptibility testing of isolates with KPC-90 vs. KPC-2 showed ceftazidime-avibactam MICs of >128 vs. 1-2 mg/L, meropenem-vaborbactam MICs of 4 vs. 1 mg/L, meropenem MICs of 4-8 vs. >128 mg/L and imipenem MICs of 0.5-1 vs. 64 mg/L. Analysis of kinetic parameters of KPC-90 compared to KPC-2 showed decreased hydrolysis of carbapenems and increased IC50 of avibactam. Genetic characterization of the plasmid revealed that IS26 could mediate the intramolecular inversion, translocation and truncation of the resistance determinant region.

CONCLUSION:

We have described the case of a patient infected with bla_KPC-90-carrying K. pneumoniae strains and investigated the mechanism of resistance to carbapenems and ceftazidime-avibactam associated with bla_KPC-2 and its variants. We have also focused on the functional diversity of IS26 in relation to antimicrobial resistance. In the future, it is crucial to pay more attention to the evolution and horizontal transmission of bla_KPC.

31 Dec 2024·Emerging Microbes & Infections

Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae

Article

Author: Shen, Siquan ; Ding, Li ; Shi, Qingyu ; Tang, Chengkang ; Yin, Dandan ; Hu, Fupin ; Yang, Yang ; Han, Renru ; Wu, Shi ; Guo, Yan

Ceftazidime-avibactam resistance attributable to the bla_KPC-2 gene mutation is increasingly documented in clinical settings. In this study, we characterized the mechanisms leading to the development of ceftazidime-avibactam resistance in ST11-K47 hypervirulent Klebsiella pneumoniae that harboured the bla_KPC-135 gene. This strain possessed fimbriae and biofilm, demonstrating pathogenicity. Compared with the wild-type KPC-2 carbapenemase, the novel KPC-135 enzyme exhibited a deletion of Glu168 and Leu169 and a 15-amino acid tandem repeat between Val262 and Ala276. The bla_KPC-135 gene was located within the Tn6296 transposon truncated by IS26 and carried on an IncFII/IncR-type plasmid. Compared to the bla_KPC-2-positive cloned strain, only the MIC of ceftazidime increased against bla_KPC-135-positive K. pneumoniae and wasn't inhibited by avibactam (MIC 32 μg/mL), while clavulanic acid and vaborbactam demonstrated some inhibition. Kinetic parameters revealed that KPC-135 exhibited a lower K_m and kcat/Km with ceftazidime and carbapenems, and a higher (∼26-fold) 50% inhibitory concentration with avibactam compared to KPC-2. The KPC-135 enzyme exerted a detrimental effect on fitness relative to the wild-type strain. Furthermore, this strain possessed hypervirulent determinants, which included the IncHI1B/FIB plasmid with rmpA2 and expression of type 1 and 3 fimbriae. In conclusion, we reported a novel KPC variant, KPC-135, in a clinical ST11-K47 hypervirulent K. pneumoniae strain, which conferred ceftazidime-avibactam resistance, possibly through increased ceftazidime affinity and decreased avibactam susceptibility. This strain simultaneously harboured resistance and virulence genes, posing an elevated challenge in clinical treatment.

01 Dec 2024·DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE

The volatile organic compounds detection in MDR Gram-negatives antimicrobial susceptibility testing: Results from a four-month laboratory experience

Article

Author: Maugeri, Gaetano ; Migliorisi, Giuseppe ; Scalia, Guido ; Stefani, Stefania ; Calvo, Maddalena

Systemic bacterial infections represent a significant clinical challenge due to the increasing resistance rate towards antimicrobials. An essential key to controlling antimicrobial resistance spread is to administer targeted therapy after a precise minimum inhibitory concentration reporting. Among the available fast technologies for antimicrobial susceptibility testing (AST), the VITEK^Ⓡ REVEAL™ (Biomerieux, Florence, Italy) proposes volatile organic compounds (VOC) colourimetric arrays to discriminate between susceptible and resistant Gram-negative isolates directly from positive blood cultures. We evaluated this methodology during a four-month laboratory experience on 40 positive blood culture samples, reporting a comparison to standard culture-based methods. The protocol revealed an essential agreement of 100 % between the conventional and the experimental procedures, while the categorical agreement resulted in 97.5 % due to one very major error (VME) for meropenem/vaborbactam in K. pneumoniae. Although further studies will be necessary to investigate its performance on rare microorganisms, the VITEK^Ⓡ REVEAL™ demonstrated an optimal sensitivity in defining MIC values for multi-drug resistant (MDR) microorganisms. These results encourage the application of the method in all high-risk epidemiological areas, confirming the effectiveness of VOC detection in monitoring bacterial susceptibility profiles.

News (Medical) associated with Vaborbactam

24 Mar 2023

·www.businesswire.com

Cidara Therapeutics and Melinta Therapeutics Announce FDA Approval of REZZAYO™ (rezafungin for injection) for the Treatment of Candidemia and Invasive Candidiasis

Cidara Therapeutics, Inc. (Nasdaq: CDTX) and Melinta Therapeutics, LLC today announced that the U.S. Food and Drug Administration (FDA) approved REZZAYO™ (rezafungin for injection) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. REZZAYO is the first new treatment option approved for patients with candidemia and invasive candidiasis in over a decade. 'The FDA approval of REZZAYO represents a significant milestone for Cidara, and for patients confronted with difficult-to-treat and often deadly candidemia and invasive candidiasis' “The FDA approval of REZZAYO represents a significant milestone for Cidara, and for patients confronted with difficult-to-treat and often deadly candidemia and invasive candidiasis,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “I am extremely proud of all of the Cidara employees who collectively advanced REZZAYO from preclinical development to NDA approval and am grateful to the many patients and healthcare teams who have participated in the clinical studies.” George Thompson, M.D., principal investigator in the ReSTORE trial and professor of clinical medicine at the University of California, Davis, School of Medicine, added, “The FDA approval of REZZAYO is tremendous news for those of us who have been hoping for a new option to treat our patients with these deadly fungal infections. Based on the totality of clinical data generated, REZZAYO has the potential to simplify the management of invasive candidiasis and enhance the continuity of echinocandin care.” The FDA approval of once-weekly REZZAYO was based on clinical data from Cidara’s global ReSTORE Phase 3 trial and supported by the STRIVE Phase 2 clinical trial and extensive non-clinical development program. In clinical studies, REZZAYO, dosed once-weekly, met the FDA and EMA primary endpoints, demonstrating statistical non-inferiority versus caspofungin, a current once-daily standard of care. In addition, overall rates of adverse events and serious adverse events were comparable in patients receiving REZZAYO and caspofungin, while rates of adverse events leading to study drug discontinuation were also similar for REZZAYO and caspofungin. Based on Qualified Infectious Disease Product (QIDP) designation, REZZAYO was approved under Priority Review. Christine Ann Miller, president and chief executive officer of Melinta Therapeutics, added, “We are thrilled that the FDA has approved REZZAYO, and are firmly committed to offering this innovative therapy to address unmet medical needs and simplify the treatment for patients suffering from invasive Candida infections. We intend to leverage our expansive commercial infrastructure and experience launching anti-infective drugs into acute care settings. We are working closely with Cidara and anticipate bringing REZZAYO, a differentiated once-weekly treatment to patients, this summer.” Last year, Melinta announced that it had acquired the exclusive rights to commercialize REZZAYO in the U.S. from Cidara. Cidara retains the rights to rezafungin in Japan and has licensed the commercial rights to Melinta Therapeutics in the U.S. and Mundipharma in all other geographies. The European Medicines Agency (EMA) accepted the marketing authorization application (MAA) for rezafungin in August 2022 and it is currently under review. About REZZAYO™ (rezafungin for injection) REZZAYO (rezafungin for injection) is a novel once-weekly echinocandin approved in the United States for the treatment of candidemia and invasive candidiasis in adults. REZZAYO is currently being studied for the prevention of invasive fungal diseases in adults undergoing allogeneic blood and marrow transplantation. The structure and properties of REZZAYO are specifically designed to improve upon a clinically validated mechanism. About Cidara Therapeutics Cidara is developing long-acting therapeutics designed to improve the standard of care for patients facing serious diseases. The Company’s portfolio is comprised of new approaches aimed at transforming existing treatment and prevention paradigms leveraging drug-Fc conjugates (DFCs) targeting viral and oncological diseases from Cidara’s proprietary Cloudbreak® platform. Cidara is headquartered in San Diego, California. For more information, please visit www.cidara.com. About Melinta Therapeutics Melinta Therapeutics, LLC provides innovative therapies to people impacted by acute and life-threatening illnesses. Our commercial portfolio currently includes the newly approved REZZAYO (rezafungin for injection), in addition to six commercial-stage products: Baxdela® (delafloxacin), Kimyrsa® (oritavancin), Minocin® (minocycline) for Injection, Orbactiv® (oritavancin), TOPROL-XL® (metoprolol succinate) and Vabomere® (meropenem and vaborbactam). With an unsurpassed commitment to providers and the patients they serve, we work to ensure that all people who need our therapies can receive them. We focus our expanding portfolio on serving patients with an unmet need because that’s how we make the most meaningful impact. At Melinta, we’re visionaries dedicated to innovation while staying grounded in what matters most: patients. For additional information, including product and respective important safety information, please visit our website.

Drug ApprovalClinical ResultPriority Review

26 Jan 2023

·pipelinereview.com

Cidara Therapeutics and Melinta Therapeutics Announce FDA Advisory Committee Recommends Approval of Rezafungin for the Treatment of Candidemia and Invasive Candidiasis

FDA decision expected by PDUFA target action date of March 22, 2023 If approved, rezafungin will be the first new drug for the treatment of candidemia and invasive candidiasis in over a decade SAN DIEGO, CA & PARSIPPANY, NJ, USA I January 25, 2023 I Cidara Therapeutics, Inc. (Nasdaq: CDTX) and Melinta Therapeutics, LLC today announced that the U.S. Food and Drug Administration (FDA) Antimicrobial Drugs Advisory Committee voted favorably 14 to 1 that Cidara, as part of its New Drug Application (NDA), provided sufficient evidence supporting a favorable benefit-risk assessment for a limited use indication for rezafungin for the treatment of candidemia and invasive candidiasis in adult patients with limited or no alternative treatment options. “We are extremely pleased that the FDA’s advisory committee has recommended that the FDA approve rezafungin for difficult-to-treat and often deadly candidemia and invasive candidiasis,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “This positive recommendation is a significant step towards our goal of providing a once-weekly treatment option for patients with invasive Candida infections, for which no new drugs have been approved in over a decade. We believe rezafungin, if approved, could provide an effective new alternative for patients battling these potentially deadly diseases. We want to thank the many patients and healthcare teams who have participated in the clinical studies of these deadly infections, and we look forward to working with the FDA as it completes its review of our application.” The Committee’s positive vote was based on clinical data from the Cidara’s global ReSTORE Phase 3 and supported by the STRIVE Phase 2 clinical trials and extensive non-clinical development program. Rezafungin dosed once-weekly demonstrated statistical non-inferiority versus caspofungin, the current standard of care, dosed once-daily, meeting the primary endpoints for both the FDA and the European Medicines Agency (EMA). “The Committee’s robust discussion was an important step in the FDA’s review of rezafungin. We are pleased that the committee recognized the unmet need that rezafungin will address in the treatment of candidemia and invasive candidiasis. We remain committed to working closely with our partner Cidara in securing FDA approval of rezafungin,” Christine Ann Miller, president and chief executive officer of Melinta Therapeutics, added. “We also look forward to leveraging our established commercial infrastructure and experience in marketing infectious disease products, especially within the hospital and acute care settings, to make rezafungin available to healthcare providers and their patients, if approved.” The FDA is not bound by the Advisory Committee’s recommendations, but generally takes the recommendation into consideration when making its decision. Cidara’s NDA for rezafungin was accepted for filing and granted Priority Review by the FDA on September 20, 2022. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of March 22, 2023, enabled by rezafungin’s designation as a Qualified Infectious Disease Product (QIDP). Last year, Melinta announced that it had acquired the exclusive rights to commercialize rezafungin in the U.S. from Cidara. Cidara retains the rights to rezafungin in Japan and has licensed the commercial rights to Melinta Therapeutics in the U.S. and Mundipharma in all other geographies. The European Medicines Agency (EMA) accepted the marketing authorization application (MAA) for rezafungin in August 2022 and it is currently under review. About Cidara Therapeutics Cidara is developing long-acting therapeutics designed to improve the standard of care for patients facing serious diseases. The Company’s portfolio is comprised of new approaches aimed at transforming existing treatment and prevention paradigms, first with its lead Phase 3 antifungal candidate, rezafungin, in addition to drug-Fc conjugates (DFCs) targeting viral and oncological diseases from Cidara’s proprietary Cloudbreak ® platform. Cidara is headquartered in San Diego, California. For more information, please visit www.cidara.com . About Melinta Therapeutics Melinta Therapeutics, LLC provides innovative therapies to people impacted by acute and life-threatening illnesses. Our portfolio currently includes six commercial-stage products: Baxdela ® (delafloxacin), Kimyrsa ® (oritavancin), Minocin ® (minocycline) for Injection, Orbactiv ® (oritavancin), TOPROL-XL ® (metoprolol succinate) and Vabomere ® (meropenem and vaborbactam). Melinta also has a licensing agreement in place with Cidara Therapeutics securing the rights to market and distribute the development candidate, rezafungin in the United States. With an unsurpassed commitment to providers and the patients they serve, we work to ensure that all people who need our therapies can receive them. We focus our expanding portfolio on serving patients with an unmet need because that’s how we make the most meaningful impact. At Melinta, we’re visionaries dedicated to innovation while staying grounded in what matters most: patients. For additional information, including product and respective important safety information, please visit our website . SOURCE: Cidara Therapeutics

License out/inNDAPriority Review

100 Deals associated with Vaborbactam

External Link

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D10998	Vaborbactam	J01DH52	DB12107

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Phase 1	AU	Rempex Pharmaceuticals, Inc.	01 Dec 2012

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