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pubs.acs.org/journal/aidcbc
Characterization of SPR994, an Orally Available Carbapenem, with Activity Comparable to Intravenously Administered Carbapenems Aileen Rubio,* Michael J. Pucci, and Akash Jain
ACS Infect. Dis. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 08/20/18. For personal use only.
Spero Therapeutics, 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United States ABSTRACT: Carbapenems are potent antibacterials with broad-spectrum activity. However, poor oral absorption generally confines this important drug class to in-hospital use by intravenous (IV) administration. The continued rise in drug resistant pathogens creates a need for alternative oral therapies with broad-spectrum activity. SPR994 is a novel formulation of the orally bioavailable pivoxil prodrug of SPR859 (tebipenem) and is being developed as the first oral carbapenem for treatment of complicated urinary tract infections (cUTIs) in adults. Herein, we describe characteristics beneficial to oral administration and compare the in vitro and in vivo activity of SPR859 or SPR994 with IV carbapenems. β-lactam antibiotics are arguably the most successful class of compounds in the history of antibiotic therapies, due mostly to their long-standing record of safety and efficacy.1 Of the several subclasses of β-lactams, the carbapenems possess the broadest spectrum of activity and exhibit better β-lactamase stability compared to other β-lactams.2 These envious properties have resulted in carbapenems often being used as antibiotics of last resort, particularly against multidrug resistant (MDR) Gramnegative pathogens.2 However, all the approved carbapenems available in the United States today are parenterally administered. The recent increase in extended spectrum βlactamase (ESBLs) producing Enterobacteriaceae,3 frequently found pathogens in complicated urinary tract infections (cUTIs), means patients with this infection, but that are otherwise healthy, would need to be admitted to the hospital in order to receive a parenterally administered carbapenem, like meropenem or ertapenem (or others as shown in Figure 1). An oral carbapenem may help avoid hospitalization in such cases. For hospitalized patients being treated with intravenous (IV) carbapenems for infections due to documented or suspected ESBL-producing or fluoroquinolone (FQ) resistant Enterobacteriaceae, an oral carbapenem may provide the ability for an earlier discharge from the hospital, thereby reducing costs and associated complications.4 SPR859 (tebipenem) is a broad-spectrum agent from the carbapenem subgroup of β-lactam antibiotics and is active against Gram-negative and Gram-positive pathogens that cause serious and life-threatening infections, including ESBL producers as well as strains resistant to levofloxacin and trimethoprim/sulfamethoxazole.5 Like many other β-lactams, high hydrophilicity limits oral absorption. However, prodrug strategies have increased bioavailability after oral administration.6 A pivoxil prodrug of SPR859, referred to as tebipenem-pivoxil, is administered orally due to the better absorption and improved bioavailability of this prodrug form. Tebipenem-pivoxil is currently marketed only in Japan (Meiji Seika Pharma Co., Ltd., “Meiji”) as a granule formulation (Orapenem Fine Granules 10%) for pediatric use in the treatment of otitis media, sinusitis, and pneumonia.7 Orapenem was approved in Japan in April 2009 for use in the pediatric population based on a comprehensive data package. © XXXX American Chemical Society
As such, tebipenem-pivoxil has an established track record of nonclinical and clinical PK, efficacy, and safety. Tebipenem, the microbiologically active moiety, has broad-spectrum in vitro activity as shown by Fujimoto et al.8 with minimum inhibitory concentration (MIC50/90) values of ≤0.06 mg/L against a broad range of pathogens including Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis (methicillin susceptible), Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Enterobacter aerogenes. Tebipenem-pivoxil displays efficacy in multiple animal models of infection caused by a broad range of pathogens.5 For example, dose dependent efficacy (defined as ≥2 log reduction relative to the control) was demonstrated in mouse lung infection models caused by strains of penicillin-resistant Streptococcus pneumoniae and βlactamase-negative ampicillin-resistant Haemophilus influenzae, using doses of tebipenem less than 20 mg/kg (dosed three times per day).8 In addition, the serum and urine samples collected from healthy human subjects after receiving oral tebipenem-pivoxil contain high inhibitory and bactericidal activity against an ESBL-producing E. coli.10 Tebipenempivoxil was found to have high oral availability of 35−70% across preclinical species, and between 40% and 70% of active tebipenem is excreted in the urine after oral dosing in human volunteers,11 resulting in high exposure in the urinary tract. The pharmacokinetics of tebipenem were found to be linear within the expected dosing range. Administration of antibiotics to treat bacterial infections can have unintended consequences that include alterations in the composition and function of the intestinal microbiota.12 In particular, broad-spectrum oral agents might be expected to have significant effects, especially if there is antibacterial activity against anaerobic organisms. However, despite its broad-spectrum antibacterial activity including both aerobes and anaerobes,5,9 the effects of tebipenem on gut organisms in rodents was found to be minimal after oral dosing twice daily over 5 days and any effects on bacterial cell numbers appeared Received: July 30, 2018
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DOI: 10.1021/acsinfecdis.8b00188 ACS Infect. Dis. XXXX, XXX, XXX−XXX
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Figure 1. Chemical structures of carbapenems.
ESBL-containing E. coli strain H4/5 (TEM-1 and CTX-M-15), SPR994 dosed orally (PO) (at 100 mg/kg/day) displayed CFU/g reductions that were comparable or better than those mice dosed with meropenem (MEM) intravenously (IV) (at 300 mg/kg/day)17 as shown in Figure 2. SPR994 displayed a
to be transitory with recovery observed soon after cessation of treatment.13 To follow up on these animal experiments, Meiji Seika ran a study where the impact of the drug on the intestinal microflora of adult male subjects was evaluated. It was found that, similar to the results observed in rodents, the effects on the intestinal organisms were limited with minimal overall changes in the total numbers of bacteria. It was also observed that there was little selection of antibiotic-resistant organisms during the study. In several additional human clinical studies, Meiji Seika tracked patient adverse events including gastrointestinal issues, and although there was some variability in incidence among the smaller studies, diarrhea events were generally not excessively numerous and did not cause many patients to withdraw from studies.14 Therefore, current available data suggest that oral administration of tebipenempivoxil poses a minimal risk to the intestinal microflora during short-term treatment of bacterial infections and the drug appears to be well tolerated. SPR994, a novel oral formulation of tebipenem-pivoxil, is currently under clinical development by Spero Therapeutics to optimize the pharmacokinetic/pharmacodynamic (PK/PD) profile for adult use in cUTI. SPR859 was recently shown to have activity against a contemporary set of Enterobacteriaceae from the 2016 SENTRY program, including FQ-resistant and ESBL-producing isolates, which caused UTIs.15 SPR859 MIC values were comparable or more potent than the other carbapenems tested. Specifically, SPR859, imipenem (IMP), and ertapenem (ETP) had MIC90 values of 0.03, 0.25, and 0.03 mg/L, respectively, against E. coli (n = 101); 0.06, 0.5, and 0.25 mg/L, respectively, against K. pneumoniae (n = 208); 0.12, 2, and ≤0.015 mg/L, respectively, against Proteus mirabilis (n = 103). SPR859 was also tested against a number of anaerobic bacteria, including Clostridium diff icile, and found to have MIC50/90 potency that was similar to that of meropenem against Bacteroides, Fusobacterium, Porphyromonas, Prevotella, and other anaerobic bacteria that are commonly found in the gut.16 As such, the effects of SPR994 as an oral carbapenem for use in adult patients will require continued monitoring on any changes in composition or numbers in the intestinal microbiome during clinical development. In addition, SPR994 has shown efficacy in multiple animal models of infection. Recently, Spero Therapeutics presented efficacy data using wild type and ESBL-producing strains of E. coli or K. pneumoniae in a neutropenic murine thigh infection model.17,18 In an
Figure 2. Efficacy of SPR994 compared to meropenem in a murine neutropenic thigh infection model. Scatter plot of bacterial burden (CFU/g) 25 h following infection with E. coli H4/5 and treatment with test articles. Dots represent burdens (CFU/g) from individual thighs. Horizontal bars indicate the geometric mean of each treatment group. The concentration of each dose and frequency of administration of each drug is displayed on the x-axis. LoD, limit of detection (32 CFU/g). Numbers above each group indicate the change in burden (log10 CFU/g) from pretreatment levels. Note that vehicle and SPR994 3 mg/kg groups were terminated at 20 to 21 h postinfection; SPR994 100 mg/kg group comprised 2 animals (4 data points).
dose dependent reduction in burden when 3−100 mg/kg/day was administered orally, with maximal log reductions of 1.4 log10 CFU/g achieved with SPR994 dosed at 100 mg/kg/day. Additional experiments to establish the PK/PD driver(s) of efficacy to select dosing regimens for patients are ongoing. In summary, SPR994 represents an orally available antibiotic with broad-spectrum activity, including ESBL-producing Enterobacteriaceae, which is comparable to IV administered carbapenems. SPR994 administered orally may provide a favorable alternative therapy for patients experiencing cUTI B
DOI: 10.1021/acsinfecdis.8b00188 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
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(12) Francino, M. P. (2016) Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front. Microbiol. 6, 1543 (eCollection 2015). (13) Liu, C. X., Kato, N., Watanabe, K., and Sakata, T. (2000) Impact of a new quinolone, DU-6859a, and two oral carbapenems, CS-834 and L-084, on the rat and mouse caecal microflora. J. Antimicrob. Chemother. 46, 823−826. (14) Nakashima, M., Morita, J., and Aizawa, A. (2009) Pharmacokinetics and safety of oral carbapenem antibiotic tebipenem pivoxil tablets in healthy male volunteers. Jpn. J. Chemother. 57 (S-1), 82−89. (15) Mendes, R., Rhomberg, P. R., Watters, A., Cotroneo, N., Rubio, A., and Flamm, R. K. (2018) Antimicrobial activity assessment of tebipenem (SPR859) against an isolate collection causing urinary tract infections. Presented at ASM Microbe, June 7−11, Atlanta, GA, USA, Sun-560. (16) Citron, D. M., Tyrrell, K. L., Rubio, A., and Goldstein, E. J. C. (2018) In vitro activity of tebipenem (SPR859), tebipenem-pivoxil (SPR994) and Meropenem against a broad spectrum of anaerobic bacteria. Presented at ASM Microbe, June 7−11, Atlanta, GA, USA, Sun-559. (17) Corbett, D., Teague, J., Vaddi, A., Sharp, A., Daws, G., Howard, F., Holden, K., Jain, A., Warn, P., and Rubio, A. (2018) Dose Ranging and Dose Fractionation of Tebipenem-Pivoxil (SPR994) in Neutropenic Murine Thigh Models of Gram-Negative Bacterial Infection. Presented at ASM Microbe, June 7−11, Atlanta, GA, USA, Sun-564. (18) Grosser, L., Heang, K., Teague, J., Jain, A., Warn, P., Corbett, D., and Rubio, A. (2018) In Vivo Efficacy of Tebipenem-Pivoxil (SPR994) in an Acute Murine Thigh Infection Caused by Escherichia coli and Klebsiella pneumonia. Presented at ASM Microbe, June 7−11, Atlanta, GA, USA, Sun-566.
caused by ESBL-producing, FQ-resistant pathogens. Considering the rising prevalence of ESBL-producing, FQ-resistant E. coli, this is an important unmet need. Oral alternative therapeutics such as SPR994 may be expected to decrease the need for hospitalization and the use of venous catheterization, thus reducing costs and associated complications.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Author Contributions
All authors contributed equally to the development of this Viewpoint. Notes
The authors declare the following competing financial interest(s): All of the authors are employees of Spero Therapeutics.
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ACKNOWLEDGMENTS We wish to thank the following collaborators whose data are partially included in the Viewpoint (presented at the 2018 ASM Microbe in Atlanta, GA): Rod Mendes, Diane Citron, David Corbett, Nicole Cotroneo, Lena Grosser, and Katie Heang. We thank Kate Sulham and Thomas Zabawa for help with critical reading, figures, and formatting. We also thank Meiji Seika Pharma Co., Ltd. for their critical review.
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REFERENCES
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DOI: 10.1021/acsinfecdis.8b00188 ACS Infect. Dis. XXXX, XXX, XXX−XXX
