The oral penems and carbapenems

SUMMARY

The penem and carbapenem antibiotics provide some of the broadest spectrum coverage available and generally should only be used when narrower options are unavailable. The majority of available carbapenems can only be administered parenterally, but two orally administered penems (faropenem and sulopenem) and one orally administered carbapenem (tebipenem) are in increased use due to approvals in new markets. These oral agents have a spectrum of activity similar to widely used parenteral carbapenems but are simpler to administer than intravenous agents and will likely experience rapid increases in their rates of use as they are approved in new markets. In this review, we discuss their spectra of activity, pharmacokinetics, pharmacodynamics, clinical efficacy, toxicity, antimicrobial stewardship considerations, and potential clinical applications.

INTRODUCTION

The penem and carbapenem antibiotics are two related types of β-lactam antibiotics that have broad antibacterial activity against Gram-positive and Gram-negative aerobes and anaerobes. Due to their activity against resistant organisms and organisms that can produce extended-spectrum beta-lactamases (ESBL), they are generally used when narrower spectrum agents cannot be used, usually in the setting of multidrug-resistant organisms (MDROs). The members of these classes that are commercially available for use, by and large, have been agents that can only be administered intravenously, which has helped limit their use. However, there are now two penem antibiotics and one carbapenem antibiotic that have been gaining approval in an increasing number of markets that can be administered orally due to their enteral stability. The oldest of these agents is faropenem, which was originally developed in 1985 and eventually released to the Japanese market in 1997, and then in India and China in 2005 and 2006 (1–4). The application for faropenem was rejected by the United States (US) Food and Drug Administration (FDA) in 2006. After decades of being the sole oral penem available, sulopenem was approved for use in the United States in 2024 (5). The only commercially available oral carbapenem, tebipenem, was developed in 1994 and then released to the Japanese market in 2009 (6). While the US FDA rejected the initial application for approval of tebipenem in the United States in 2022, efforts are ongoing for eventual approval and sale in North America as well (7). Anticipating the increased ease of access to these oral agents and their relative ease of use as compared to intravenously administered carbapenems, we reviewed the available literature to define appropriate and rational usage guidance for routine bacterial infections. This review does not include data or discussion of these oral agents’ activity against mycobacterial species.

CLASSIFICATION OF PENEMS AND CARBAPENEMS

Carbapenems and penems are structurally similar but distinct β-lactam antimicrobials. Carbapenems have a four-membered β-lactam ring fused to a five-membered pyrroline ring with a carbon atom at position 1. By contrast, penems have a four-membered β-lactam ring fused to an unsaturated five-membered thiazoline ring with a sulfur atom at position 1. A separate class, oxapenems, has an oxygen atom in that position. In penem antibiotics, the sulfur in the 1 position of the five-membered ring prevents degradation by renal dehydropeptidase-1 (DHP-1), negating the need to administer with a DHP-1 inhibitor. Penem subgroups have been developed by changing the side chain at position 2 of the five-membered ring (Fig. 1) (8, 9). Sulopenem can be further specified as a thiopenem due to the presence of the sulfur atom in its side chain (Fig. 1) (9).

Fig 1.

Chemical structures. Chemical structures of tebipenem, faropenem, and sulopenem. Adapted from references 10–12.

Faropenem has been synthesized in three forms: a free acid, a sodium salt, and an ester prodrug. The sodium salt is available in Japan, China, and India. The ester prodrug, faropenem medoxomil, is synthesized by attaching the medoxomil portion via an ester linkage to position C3 of the five-membered ring and improves the bioavailability of the compound (13). Faropenem medoxomil is also referred to as faropenem daloxate in the literature, though this is not in keeping with International Nonproprietary Names conventions (14).

Sulopenem etzadroxil is a prodrug created by adding an etzadroxil to the carboxylic acid located at the C3 position of the core ring structure, improving its stability. When hydrolyzed by intestinal esterases, its active form can be absorbed into the bloodstream (9).

Tebipenem, an oral carbapenem, is available as tebipenem pivoxil hydrobromide, which is an ester prodrug. The pivoxil ester improves intestinal absorption, and the hydrobromide salt enhances stability to improve bioavailability (15). The 1-β-methyl group prevents degradation by renal DHP-1; therefore, tebipenem does not have to be co-administered with a DHP-1 inhibitor.

SPECTRUM OF ACTIVITY AND IN VITRO SUSCEPTIBILITIES

All three drugs demonstrate broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic organisms (Table 1). The individual spectrum details are described below.

TABLE 1.

Spectrum of activity of oral penems (faropenem, sulopenem) and carbapenems (tebipenem)^d

Organism	Faropenem					Sulopenem					Tebipenem
	No. of isolates	MIC range	MIC50 range	MIC90 range	References	No. of isolates	MIC range	MIC50 range	MIC90 range	References	No. of isolates	MIC range	MIC50 range	MIC90 range	References
Gram-positive organisms
Enterococcus faecalisa	25	0.25–32	-	-	(16, 17)	158	1 to >8	4	8	(18)	71	1 to >8	0.25–2	2 to 32	(19–21)
Enterococcus faecium	7	512–1,024	1,024	-	(16)	-	-	-	-	-	61	4 to >128	>32	>32	(19–21)
Methicillin-susceptible Staphylococcus aureus (MSSA)	NAc	0.03–0.5	0.12	0.12	(13)b	29	0.03–0.25	0.06	0.25	(18)	120	-	0.015 to <0.125	0.03–0.125	(19, 20, 22)
Methicillin-resistant Staphylococcus aureus (MRSA)	18	0.125–32	0.5	4	(16)	-	-	-	-	-	79	-	2–8	16	(19–21)
Streptococcus pneumoniae	3,239	≤0.004 to 2	-	0.06–1	(23–26)	-	-	-	-	-	486	≤0.063 to ≤0.25	≤0.063 to ≤0.25	≤0.063 to ≤0.25	(25, 27)
S. pneumoniae         Penicillin intermediate	1,135	≤0.004 to 0.5	0.06–0.25	0.25–0.5	(23–25, 28)	88	0.03–0.25	0.06	0.25	(29)	241	-	≤0.03 to ≤0.06	≤0.06	(25, 30)
S. pneumoniae         Penicillin resistant	692	-	0.25–1	0.5–2	(23–25, 28)	129	0.125–1.0	0.25	0.5	(29)	238	-	≤0.063 to 0.12	≤0.063 to 0.25	(20, 22, 25, 30)
Streptococcus pyogenes         (Group A)	30	0.008–0.015	0.015	0.015	(24)	-	-	-	-	-	92	-	<0.004 to 0.125	<0.004 to 0.125	(19–22)
Streptococcus agalactiae         (Group B)	NA	0.03–0.12	0.06	0.06	(13)b	-	-	-	-	-	61	<0.004 to 0.015	<0.004	0.015	(20, 22)
Gram-negative organisms
Acinetobacter baumannii	18	32–128	-	128	(16)	-	-	-	-	-	20	-	16	64	(19)
Burkholderia mallei	-	-	-	-	-	-	-	-	-	-	30	0.25–1	0.5	1	(31)
Burkholderia pseudomallei	-	-	-	-	-	-	-	-	-	-	29	1– 4	2	2	(31)
Francisella tularensis	-	-	-	-	-	-	-	-	-	-	29	0.5 to >64	16	>64	(31)
Hemophilus influenzae	2,365	≤0.02 to 32	0.5–4	0.25–16	(23, 24, 32)	-	-	-	-	-	41	≤0.06 to 1	≤0.06 to 0.125	0.125–0.5	(20, 33)
H. influenzae         BLPAR	61	0.125–32	0.5–1	2–8	(32)	-	-	-	-	-	37	-	≤0.06	0.125–0.5	(34)
Moraxella catarrhalis	532	0.008–1	0.25	0.5	(23, 24)	-	-	-	-	-	44	≤0.03 to 0.06	≤0.03	0.06	(20)
Neisseria gonorrhoeae	NA	≤0.008 to 0.5	0.06	0.25	(13)b	-	-	-	-	-	35	0.0156–0.5	0.25	0.25	(20)
Pseudomonas aeruginosa	25	512–1,024	1,024	NR	(16)	75	8 to >8	>8	>8	(18)	75	1–128	8	64	(19, 20)
Stenotrophomonas maltophilia	NA	>32	>32	>32	(13)b	-	-	-	-	-	15	-	32	64	(19)
Enterobacterales	-	-	-	-	-	1,647	0.008 to >32	0.03	0.25	(35)	4,194	-	0.015	0.06–0.125	(36, 37)
Citrobacter spp	-	-	-	-	-	-	-	-	-	-	15	≤0.004 to 0.06	0.015	0.06	(22)
Citrobacter freundii	NA	0.25–32	1	8	(13)b	29	0.015–0.5	0.06	0.12	(35)	25	-	≤0.125	0.25	(19)
Citrobacter koseri	-	-	-	-	-	9	0.015–0.3	0.03	NR	(35)	-	-	-	-	-
Escherichia coli	119	0.12–2	0.5	1	(1)	2770	≤0.008 to 4	0.03	0.03–0.06	(18, 35, 38)	2,937	-	≤0.015 to ≤0.125	0.015–1	(19, 20, 36, 37, 39)
Enterobacter spp	126	1–16	4	-	(40)	-	-	-	-	-	-	-	-	-	-
Enterobacter cloacae	NA	0.5–32	4	8	(2)	157	0.015–4	0.12	0.5	(18, 35)	128	-	≤0.03 to ≤0.125	0.125–1	(19, 20, 22)
Klebsiella spp.	NA	0.06–8	0.5	2	(13)b	347	0.015 to >32	0.03	0.12	(35)	-	-	-	-	-
Klebsiella aerogenes	NA	0.25 to >32	4	16	(13)b	33	0.03–1	0.12	0.25	(35)	101	≤0.03 to 0.125	≤0.03 to ≤0.12	0.06 to ≤0.12	(19, 20, 22)
Klebsiella oxytoca	NA	0.25–8	0.5	2	(13)b	76	0.03–0.25	0.06	0.06	(18, 35)	30	≤0.004 to 0.125	0.015	0.03	(22)
Klebsiella pneumoniae	NA	0.25–>32	0.5	2	(13)b	473	≤0.015 to >32	0.03–0.06	0.06–0.12	(18, 35)	938	≤0.015 to >8	≤0.03 to ≤ 0.125	≤0.03 to ≤0.5	(19, 20, 36, 37, 39)
Morganella morganii	NA	1 to 16	4	8	(13)b	20	0.12–1	1	1	(35)	-	-	-	-	-
Proteus spp.	-	-	-	-	-	-	-	-	-	-	91	0.12–1	0.25	0.25	(21)
Proteus mirabilis	NA	0.25–16	4	4	(13)b	179	0.015–1	0.25	0.25–0.5	(18, 35)	436	-	0.06–0.125	≤0.125 to 0.5	(19, 22, 36, 37, 39)
Providencia spp.	-	-	-	-	-	14	0.12–1	0.12	0.5	(35)	-	-	-	-	-
Serratia spp	16	1–16	8		(40)
Serratia marcescens	NA	1 to >128	8	32	(13)b	36	0.06–2	0.5	2	(35)	40	-	0.06–0.125	0.25–16	(19, 22)
Salmonella typhi/paratyphi	192	≤0.03 to 0.5	-	0.25	(41)	-	-	-	-	-	100	0.12–0.62	-	-	(42)
Yersinia pestis	-	-	-	-	-	-	-	-	-	-	29	≤0.0005 to 0.03	0.03	0.03	(31)
ESBL and AmpC producing Enterobacterales
Enterobacterales ESBL+	40	0.25–2	1	2	(43)	-	-	-	-	-	603	-	0.015–0.03	0.06–0.25	(36, 37)
E. coli ESBL+	174	-	1	2	(44)	352	0.008–1	0.03	0.06	(29, 35, 38)	2,035	≤0.004 to 0.25	0.015	0.015	(45)
E. coli ESBL + CTX-M+	291	0.5–8	-	-	(40)	-	-	-	-	-	269	0.008–0.25	0.015	0.03	(45)
E. coli ESBL + CTX-M-	88	0.25–8	-	-	(40)	-	-	-	-	-	-	-	-	-	-
K. pneumoniae ESBL+	37	-	1	2	(44)	69	0.015 to >32	0.06	0.12–1	(29, 35)	126	0.008 to >32	0.03	0.125 to >32	(21, 22)
Klebsiella spp. ESBL + CTX-M+	199	0.12–16	-	-	(40)	-	-	-	-	-	-	-	-	-	-
Klebsiella spp. ESBL + CTX-M-	27	0.12–16	-	-	(40)	-	-	-	-	-	-	-	-	-	-
Proteus spp. ESBL+	-	-	-	-	-	-	-	-	-	-	18	0.12–4	0.5	2	(21)
E. coli AmpC+	41	0.5–16	-	-	(40)	23	0.015–4	0.06	0.25	(18, 38)	39	0.008–0.5	0.015	0.03	(21, 37)
Proteus spp. AmpC+	-	-	-	-	-	-	-	-	-	-	13	0.12–2	0.5	1	(21)
All anaerobes	579	0.12–64	0.25	2	(46)b	990	≤0.015 to >16	0.125–0.25	1	(35, 47)	-	-	-	-	-
Bacteroides fragilis	68	0.12–64	0.25	1	(46)b	49	0.03–2	0.125	0.5	(47)	45	0.06–32	0.25	2	(20)

^a Since contemporary MIC data were available, MIC data prior to 2005 were not included in table, see reference (13). Isolate numbers were not provided.

^b Since contemporary MIC data were unavailable, MIC data published prior to 2005 were included in table, reference (13, 46).

^c NA indicates not applicable.

^d - indicates data not available.

Faropenem

Among Gram-positive organisms, faropenem exhibits good activity against S. pneumoniae (MIC90 range: 0.06–1 mg/L) (23–26), S. pyogenes (MIC50: 0.015 mg/L) (24), Group B Streptococcus (MIC50: 0.06 mg/L) (13), and methicillin-susceptible Staphylococcus aureus (MSSA) (MIC50: 0.12 mg/L) (13). Faropenem also demonstrates good activity against penicillin-resistant S. pneumoniae (MIC90 range: 0.5–2 mg/L) (23–25, 28). However, faropenem demonstrates no activity against E. faecium (MIC50: >1,024 mg/L) (16). For E. faecalis and MRSA, faropenem MIC values range from 0.25 to 32 mg/L and 0.125 to 32 mg/L, respectively, demonstrating variable activity due to acquired resistance described below (16, 17). Among Gram-negative organisms, faropenem shows good activity against H. influenzae, including those producing β-lactamase (MIC50 range: 0.5–4 mg/L) (23, 24, 32, 40, 48), Moraxella catarrhalis (MIC50: 0.25 mg/L) (23, 24), and N. gonorrhoeae, including against cefixime-resistant strains (MIC50: 0.06 mg/L) (13). Among Enterobacterales, good activity was noted for E. coli (MIC50: 0.5 mg/L) (1), K. pneumoniae (MIC50: 0.5 mg/L) (13), and Salmonella Typhi and Paratyphi (MIC90: 0.25 mg/L) (41). However, elevated MIC values were observed for Enterobacter species (MIC50: 4 mg/L), Citrobacter freundii (MIC range: 0.25–32 mg/L), Serratia marcescens (MIC50: 8 mg/L), Morganella morganii (MIC50: 4 mg/L), and Proteus mirabilis (MIC50: 4 mg/L) (13).

Studies examining faropenem activity against ESBL-producing Enterobacterales are limited and summarized as follows. One study reported that the MIC50 value of faropenem against ESBL-producing Enterobacterales was 1 mg/L (43). Another study found that the MIC50 value against ESBL-producing E. coli and K. pneumoniae was 1 mg/L (44). The MIC range for faropenem against CTX-M-positive and CTX-M-negative ESBL-producing E. coli was 0.5–8 mg/L and 0.25–8 mg/L, respectively (40), and the MIC range for faropenem against CTX-M-positive and CTX-M-negative ESBL-producing Klebsiella species was 0.12–16 mg/L (40). For AmpC-producing E. coli, the MIC range was found to be 0.5–16 mg/L (40).

Faropenem demonstrated no activity against Acinetobacter baumannii (MIC range: 32–128 mg/L) (16), Pseudomonas aeruginosa (MIC50: >1024 mg/L) (16), and Stenotrophomonas maltophilia (MIC50: >32 mg/L) (13).

Faropenem demonstrated good activity against anaerobic bacteria (MIC50: 0.25 mg/L) (46), including Bacteroides fragilis (MIC50: 0.25 mg/L) (46).

Sulopenem

Among Gram-positive organisms, sulopenem exhibits good activity against S. pneumoniae, including penicillin-resistant strains (MIC50 range: 0.008–0.25 mg/L) (29) and MSSA (MIC50: 0.06 mg/L) (18). However, sulopenem has higher MIC values against E. faecalis (MIC50: 4 mg/L) (18).

Among Gram-negative organisms, sulopenem has excellent activity against Enterobacterales (MIC50: 0.03 mg/L) (35), including E. coli (MIC50: 0.03 mg/L) (18, 35, 38), K. pneumoniae (MIC50: 0.03–0.06 mg/L) (18, 35), P. mirabilis (MIC50: 0.25 mg/L) (18, 35), K. aerogenes (MIC50: 0.12 mg/L) (35), E. cloacae (MIC50: 0.12 mg/L) (18, 35), C. freundii (MIC50: 0.06 mg/L) (35), S. marcescens (MIC50: 0.5 mg/L) (35), M. morganii (MIC50: 1 mg/L) (35), and Providencia species (MIC50: 0.12 mg/L) (35). Sulopenem demonstrates good activity against ESBL-producing E. coli (MIC50: 0.03 mg/L) (18, 35, 38) and ESBL-producing K. pneumoniae (MIC50: 0.06 mg/L) (18, 35). One study examined the activity of sulopenem against AmpC-producing E. coli and reported a MIC range of 0.06 mg/L (18). Sulopenem has no activity against P. aeruginosa (MIC50: >8 mg/L) (18). Sulopenem has good activity against anaerobic bacteria (MIC50: 0.125–0.25mg/L) (35, 47), including Bacteroides fragilis (MIC50: 0.125 mg/L) (47).

Tebipenem

Among Gram-positive organisms, tebipenem exhibits good activity against S. pneumoniae, including penicillin-resistant strains (MIC90 range: 0.06–0.25 mg/L) (25, 27), S. pyogenes (MIC50: <0.125 mg/L) (19–22), Group B Streptococcus (MIC50: <0.004 mg/L) (20, 22), and MSSA (MIC50: <0.125 mg/L) (19, 20, 22). However, tebipenem demonstrates no activity against E. faecium (MIC50: >32 mg/L) (19–21). For E. faecalis and MRSA, the MIC50 values range from 0.25 to 2 mg/L and 2 to 8 mg/L, respectively, demonstrating variable activity (19, 21). In addition, tebipenem exhibits good activity against Bacillus species (MIC50: 0.008 mg/L) (22), including B. anthracis (MIC50: 0.004 mg/L) (31) and Corynebacterium species (MIC50: 0.06 mg/L) (22). Among Gram-negative organisms, tebipenem demonstrates good activity against H. influenzae, including those producing β-lactamase (MIC50: <0.06 to 0.5 mg/L) (20, 33, 34, 49), M. catarrhalis (MIC50: <0.03 mg/L) (20), and N. gonorrhoeae, including against cefixime-resistant strains (MIC50: 0.25 mg/L) (20). Tebipenem has excellent activity against Enterobacterales (MIC50: 0.015 mg/L) (36, 37), including E. coli (MIC50: <0.125 mg/L) (19, 20, 36, 37, 39), K. pneumoniae (MIC50: <0.125 mg/L) (19, 20, 36, 37, 39), P. mirabilis (MIC50 range: 0.06–0.125 mg/L) (19, 20, 36, 37, 39), K. aerogenes (MIC50: <0.125 mg/L) (19, 20, 22), E. cloacae (MIC50: <0.125 mg/L) (19, 20, 22), C. freundii (MIC50: <0.125 mg/L) (19), S. marcescens (MIC50 range: 0.06–0.125 mg/L) (19, 22), Yersinia pestis (MIC50: 0.03 mg/L) (31), and S. Typhi/Paratyphi (MIC range: 0.12–0.62 mg/L) (42).

Tebipenem demonstrates good activity against ESBL-producing Enterobacterales (MIC50: ≤0.03 mg/L) (36, 37), including ESBL-producing E. coli (MIC50: ≤0.03 mg/L) (21, 22, 45), ESBL-producing K. pneumoniae (MIC50: 0.03 mg/L) (21, 22), and ESBL-producing Proteus species (MIC50: 0.5 mg/L) (21). Tebipenem also demonstrates good activity against third-generation cephalosporin-resistant E. coli (MIC50: 0.03 mg/L) (50) and K. pneumoniae (MIC50: 0.03 mg/L) (50), AmpC-producing E. coli (MIC50: 0.015 MG/L) (45) and AmpC-producing Proteus species (MIC50: 0.5 mg/L) (21). In addition, tebipenem has low MIC values against Burkholderia mallei (MIC50: 0.5 mg/L) (31) and B. pseudomallei (MIC50: 2 mg/L) (31). Tebipenem demonstrates no activity against A. baumannii (MIC50: 16 mg/L) (19), P. aeruginosa (MIC50: 8 mg/L) (19, 20), S. maltophilia (MIC50: 32 mg/L) (19) and Francisella tularensis (MIC50: 16 mg/L) (31).

Limited data are available examining tebipenem activity against anaerobic bacteria (20, 21). However, one study showed that it has good activity against B. fragilis (MIC50- 0.25 mg/L) (20).

Summary

All three drugs have broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic organisms. Regarding activity against Gram-positive organisms, all three drugs strongly inhibit Streptococcus species and MSSA, but variable activity was observed for E. faecalis. Faropenem and tebipenem additionally have unreliable activity against MRSA, and they are not active against E. faecium. Sulopenem activity data on MRSA and E. faecium are lacking.

For the Gram-negatives: All three drugs are active against H. influenzae, including those producing β-lactamase and M. catarrhalis. Faropenem and tebipenem demonstrate good activity against N. gonorrhoeae, including cefixime-resistant strains, but published studies examining sulopenem activity against N. gonorrhoeae are lacking.

Sulopenem and tebipenem strongly inhibit Enterobacterales. Although faropenem demonstrates activity against Enterobacterales, MIC50 values for E. coli and K. pneumoniae were at least threefold higher than those of sulopenem and tebipenem. While sulopenem and tebipenem strongly inhibit Enterobacter species, C. freundii, S. marcescens, M. morganii, and P. mirabilis, faropenem has MIC50 values that indicate unreliable activity against these organisms. Sulopenem and tebipenem strongly inhibit ESBL-producing, AmpC-producing Enterobacterales, but there are limited data with faropenem showing a wide MIC range, indicating its unreliable activity. The elevated MIC values of faropenem against Enterobacter species, C. freundii, and S. marcescens could be due to the lack of inhibition of AmpC enzymes as these three organisms are known to produce AmpC intrinsically. More data on faropenem activity against ESBL-producing and AmpC-producing Enterobacterales are needed. Given the potential role of these drugs in the treatment of ESBL- and AmpC-producing Enterobacterales (especially due to E. coli, Klebsiella species, and Proteus species) infections, the distribution of the MICs for these organisms is summarized in Fig. 2.

Fig 2.

Distribution of minimum inhibitory concentrations of faropenem, sulopenem, and tebipenem. Distribution of minimum inhibitory concentrations of oral penems (faropenem and sulopenem) and carbapenems (tebipenem) against multidrug-resistant Enterobacterales. ESBL = extended-spectrum beta-lactamases, carbapenemases. MIC50 = gray bars, MIC90 = black bars. N of isolates are included beside each organism-antibiotic combination. The only currently available interpretive data are included for sulopenem S ≤ 0.25, I = 0.5, R ≥ 1 μg/mL. Data are adapted from references (18, 35–37, 39, 40, 43, 45).

High MIC values were observed against P. aeruginosa, A. baumannii, and S. maltophilia, demonstrating a lack of activity of all three drugs against these organisms. Finally, all three drugs demonstrated good activity against anaerobic bacteria, especially B. fragilis.

MECHANISM OF ACTION AND RESISTANCE MECHANISMS

Faropenem

Faropenem derives its bactericidal activity from binding penicillin-binding proteins (PBPs) and is resistant to the effects of serine β-lactamases and cephalosporinases (40, 51–53). Faropenem exhibits high affinity for PBP1 in S. aureus and S. pneumoniae, while with Escherichia coli, it exhibits high affinity for PBP2 (51). Faropenem additionally demonstrates high binding affinity for PBP4 in Serratia marcescens, Proteus vulgaris, and E. faecalis. Faropenem is stable against penicillinase derived from S. aureus and E. coli, cephalosporinase derived from E. coli and P. vulgaris, and extended-spectrum β-lactamases (TEM/SHV/CTX-M) derived from E. coli, and other β-lactamases produced by anaerobic bacteria (40, 52, 53). However, faropenem is hydrolyzed by carbapenemases as would be expected (54).

High MIC values against faropenem in E. faecalis isolates were observed to be secondary to point mutations in PBP4 (17). The high MIC values for MRSA are due to the low affinity of faropenem to modified PBP2a. The lack of activity against P. aeruginosa is due to a combination of decreased permeability, active efflux, and AmpC β-lactamase production (55, 56). However, faropenem does not induce AmpC or upregulate the MexAB-OprM efflux pump (56).

Clinical studies examining acquired faropenem resistance or cross-resistance to parenteral carbapenems after exposure are lacking. However, a few in vitro studies have examined the effect of faropenem exposure on the selection of resistance mutations and cross-resistance to parenteral carbapenems (57–59). Among isolates of S. pneumoniae and H. influenzae, no resistance to faropenem was observed after 50 days of consecutive subcultures in sub-inhibitory concentrations (57). By contrast, serial passage of four E. coli isolates (3 ESBL-producing CTX-M and one pan-susceptible) resulted in a faropenem MIC of 64 µg/mL among all four isolates within 10 days (58). Elevated faropenem MICs persisted for all four isolates despite passage through antibiotic-free media for 10 days. Whole-genome sequencing of the mutant isolates showed mutations in ompC, the gene encoding outer membrane protein C, in all three ESBL-producing E. coli isolates. More concerningly, all three ESBL-producing E. coli mutant strains demonstrated elevated MICs to varying degrees for multiple carbapenems (doripenem, ertapenem, imipenem, and meropenem), indicating cross-resistance. The pan-susceptible E. coli mutant isolate had no change in carbapenem MICs. In another in vitro study involving K. pneumoniae clinical isolates, mutation frequencies were higher with faropenem when compared to meropenem (59). More interestingly, when the faropenem-exposed mutant strains were exposed to meropenem, higher mutation frequencies and conjugation efficiencies were observed relative to the parental strain. This suggests a higher likelihood of developing high-level resistance to meropenem following exposure to faropenem.

Sulopenem

Sulopenem inhibits PBPs and is stable against β-lactamase enzymes (60, 61). It exhibits a high affinity for PBP1 and PBP3 in S. aureus and PBP2 in E. coli (61). Sulopenem demonstrates stability against cephalosporinases (CMY/AmpC/ACT) and ESBLs (TEM/SHV/CTX-M/VEB). However, in isogenic strains of E. coli, it is hydrolyzed by class A, B, and D carbapenemases as expected (60). Sulopenem demonstrates activity against S. pneumoniae despite mutations in PBP1 and PBP2 rendering resistance to other β-lactam agents (57). As with faropenem, sulopenem lacks activity against MRSA due to its poor affinity to PBP2a (61). It additionally lacks activity against P. aeruginosa due to a combination of decreased permeability, active efflux, and AmpC β-lactamase production (56). There are no published clinical studies examining acquired resistance or elevated MICs to sulopenem and cross-resistance to parenteral carbapenems after exposure.

Tebipenem

Like the penems, tebipenem antibacterial activity is facilitated by inhibition of PBPs and resistance to β-lactamase enzymes (60, 62, 63). In E. coli and K. pneumoniae, tebipenem’s main target is PBP2, while in P. aeruginosa, it has high affinity for PBP2 and PBP3 (63). In H. influenzae, tebipenem binds to PBP1B, PBP2, PBP3A, and PBP3B with high affinity (64). In MSSA, tebipenem binds to PBP1, PBP2, PBP3, and PBP4 with very high affinity to PBP4 and PBP1 and lower affinity to PBP2 and PBP3. In MRSA, binding affinity to PBP2a is low (63). In S. pneumoniae, tebipenem exhibits high affinity to PBP1A, PBP1B, PBP2A, PBP2X, PBP2B, and PBP3 (64). Similar to sulopenem, tebipenem also demonstrates stability against ESBLs (TEM/SHV/CTX-M/VEB) and cephalosporinases (CMY/AmpC/ACT); however, it is hydrolyzed by class A, B, and D carbapenemases as expected (60, 62).

Tebipenem’s lack of activity against MRSA is attributable to its inability to bind to PBP2A. Tebipenem additionally does not have activity against P. aeruginosa, but the mechanism of resistance is mediated by efflux pumps, porins, AmpC β-lactamases, or a combination of multiple processes that are not known (56, 65). There are no studies examining acquired resistance or elevated MICs to tebipenem and cross-resistance to parenteral carbapenems after exposure.

PHARMACOKINETICS

Faropenem

Faropenem is available as a sodium salt and as an ester prodrug. The sodium salt of faropenem, which is available in Japan and India as 150 mg and 200 mg tablets, has a low bioavailability of 20%–30% (8), but further published studies on the pharmacokinetics of faropenem sodium are lacking.

Faropenem medoxomil, the ester prodrug, has improved bioavailability (70%–80%) compared to faropenem sodium (8). Peak concentrations (C_max) of faropenem medoxomil following a 300 mg dose in healthy adults reached approximately 13–14 mg/L after 1–2 hours, with about 88%–95% bound to serum proteins (66). Following absorption, faropenem medoxomil is rapidly hydrolyzed to active faropenem by serum esterases. Faropenem is more stable to renal DHP-1 compared to imipenem; however, some hydrolysis to inactive metabolites occurs (8). Elimination is primarily renal, with 8%–26% of unchanged faropenem recovered in urine (13). A summary of the faropenem medoxomil pharmacokinetic parameters is listed in Table 2.

TABLE 2.

Summary of pharmacokinetic data of oral penems (faropenem, sulopenem) and carbapenems (tebipenem)^a

	Bioavailability	Cmax	Tmax	Protein binding	T½	Urinary elimination	References
Faropenem medoxomil	70%–80%	300 mg dose = 13 mg/L	1–2 h	88-95%	0.9–1.3 h	14%–20%	(8, 13, 66)
Sulopenem etzadroxil +probenecid	40%–64%	500 mg dose = 1.69 mg/L	1–2 h	10%	1.18–1.28 h	40%	(67–69)
Tebipenem pivoxil	50%–60%	600 mg dose = 6.2–6.5 mg/L	1–2 h	42%	0.8–1.1 h	38%–64%	(70, 71)

^a C_max, maximum plasma concentration; T_max, time to maximum plasma concentration; T_½, half-life.

Sulopenem

There is limited published pharmacokinetic data on sulopenem, so data were obtained from conference abstracts, posters, and the briefing documents from the September 2024 FDA Antimicrobial Advisory Committee meeting.

Sulopenem etzadroxil is the oral prodrug that is rapidly hydrolyzed by intestinal esterases to active sulopenem. Sulopenem pharmacokinetics were evaluated in healthy volunteers with and without co-administration with probenecid in a fed and fasted state (67). Probenecid is a uricosuric agent and organic ion transport inhibitor known to increase plasma concentrations of weak organic acids like β-lactams by competitively inhibiting the renal tubular secretion. Under fasting conditions, sulopenem etzadroxil 500 mg had a mean C_max of 1.77 mg/L and area under the curve (AUC) of 3.68 mg*h/L compared to C_max of 1.86 mg/L and AUC of 4.54 mg*h/L in a fed state. When co-administered with 500 mg of probenecid in the fasting state, the C_max was similar (1.77 mg/L), and AUC slightly increased to 3.95 mg*h/L. In the fed state, coadministration with probenecid resulted in a C_max of 1.69 mg/L and an increased AUC (6.3 mg*h/L). Therefore, sulopenem etzadroxil is being investigated as a co-formulated bilayer tablet with 500 mg sulopenem etzadroxil and 500 mg probenecid to be administered with food to improve bioavailability, plasma exposure, and tolerability (Table 2). Like faropenem and tebipenem, sulopenem has a relatively short half-life of approximately 1 hour. The renal clearance of sulopenem was 18.98 ± 3.04 L/h and was reduced to 9.91 ± 2.53 when co-administered with probenecid, but the cumulative urinary recovery of sulopenem was similar regardless of probenecid administration (68). Urinary excretion after a single oral dose of sulopenem etzadroxil 2,000 mg was 40.8% (3.1% unchanged). Sulopenem is not recommended in patients with severe renal insufficiency (creatinine clearance <15 mL/min) or those receiving hemodialysis, given the lack of pharmacokinetic data in these populations (69).

Tebipenem

Tebipenem pivoxil hydrobromide is currently available in Japan as an oral granule. It is also being developed as 300 mg tablets. The ester prodrug is rapidly converted to the active moiety via carboxylesterases of the gastrointestinal tract. Bioavailability of oral tebipenem pivoxil hydrobromide has been reported as 50%–60% and appears to be unaffected by food (70) (Table 2). Tebipenem was found to maintain bioequivalence when crushed and administered with and without enteral nutrition via a nasogastric feeding tube in healthy subjects (72). Peak concentrations after a single 600 mg dose in healthy subjects (C_max 6.2 mg/L) are achieved within 1-2 hours (70).

One study evaluated tebipenem distribution into soft tissues was evaluated utilizing a microdialysis probe in healthy subjects and patients with diabetic foot infections (73). Tissue penetration was found to be 107% for healthy subjects with the free plasma AUC from 0 to 8 hours (AUC_0-8) being 5.61 mg-h/L, while the tissue AUC_0-8 was 5.99 mg-h/L. In patients with diabetic foot infections, tissue penetration was 90% with free plasma AUC_0-8 measured at 10.01 mg-h/L with a tissue AUC_0-8 of 8.60 mg-h/L (73).

Intrapulmonary concentrations of tebipenem have also been evaluated in healthy subjects with an overall penetration into epithelial lining fluid (ELF) of 19.1%. The ratio of tebipenem AUC_0-8 for ELF to unbound plasma was 0.191, and for alveolar macrophage (AM) to unbound plasma was 0.047 (74), this is similar to the ELF:plasma ratio achieved by meropenem, which is 0.20–0.29 (75). Peak tebipenem concentrations at 1 hour were 0.824 ± 0.315 mg/L in ELF and 0.151 ± 0.105 mg/L in AMs.

Tebipenem is eliminated by both renal and fecal routes. In healthy subjects, the elimination half-life of tebipenem was 0.8–1.1 hour (70). The fraction of unchanged tebipenem recovery in the urine ranged from 39% to 60% in healthy subjects (70, 71). In patients with renal impairment, tebipenem urinary excretion decreased and plasma AUC increased, indicating that dose adjustments will be necessary in patients with renal dysfunction. In subjects who received a 4 hour hemodialysis session, tebipenem exposure was decreased by approximately 41% (76).

PHARMACODYNAMICS

Faropenem

Like other β-lactams, faropenem exhibits time-dependent bactericidal activity. A pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed for faropenem against Bacillus anthracis in a murine postexposure prophylaxis inhalation model (77). In this analysis, free faropenem time above the MIC (ƒT > MIC) was the PK-PD index with the strongest correlation with survival (r² = 0.97). The ƒT > MIC value required for maximum survival against B. anthracis was 16.4%. This target is similar to the target ƒT > MIC for stasis of 13.9% reported for S. pneumoniae isolates in a neutropenic murine thigh model of infection, although the data are available in abstract findings only (78). Another PK-PD target attainment analysis was done for faropenem for E. coli and K. pneumoniae based on a 1,000 subject Monte Carlo simulation (79). Faropenem of 200–300 mg for every 8 hours was the doses modeled. The PK-PD target selected for faropenem was ƒT > MIC ≥ 20 based on data for carbapenems. Probability of target attainment (PTA) > 90% for faropenem was achieved only for isolates with MICs ≤ 0.06 mcg/mL. In this sample of 281 clinical isolates from Japan, none of the isolates were modeled to achieve a PTA > 90% with faropenem at a dose of 300 mg orally every 8 hours.

Sulopenem

Similar to the pharmacokinetic data for sulopenem, much of the pharmacodynamic data is from conference posters and the FDA Antimicrobial Advisory Committee briefing documents. In dose-fractionization studies in an in vitro infection model with E. coli and K. pneumoniae, the PK-PD index most associated with efficacy for sulopenem was ƒT > MIC (r² = 0.902) followed closely by free peak concentration to MIC ratio (ƒC_max: MIC) (r² = 0.885). In an in vitro infection model, the target % ƒT > MIC associated with net bacterial stasis, 1- and 2-log₁₀ colony-forming unit (CFU) reduction for Enterobacterales was 40.9%, 50.2%, and 62.6%, respectively (80). These targets are higher than those identified in a neutropenic murine thigh infection model with S. pneumoniae and K. pneumoniae. In the murine model, the ƒT > MIC target for stasis was 16.4%, for 1-log₁₀ CFU reduction was 17.0%, and for 2-log₁₀ CFU reduction was 20.1% (68). The differences in target values between the two models could be due to limitations of the in vitro model not being able to account for bladder tissue architecture or urodynamics.

The FDA review team prioritized the more conservative targets for the Antimicrobial Advisory Committee review. A hollow-fiber in vitro infection model was completed to evaluate sulopenem pharmacodynamics in the emergence of resistance for four different E. coli isolates (81). Simulated urinary concentrations from an oral 500 mg dose every 12 hours reduced the bacterial burden to below 1-log₁₀ CFU/mL for all four strains and prevented amplification of drug-resistant subpopulations over a 5-day study period. Population pharmacokinetic data were used to simulate PTA for sulopenem 500 mg with probenecid 500 mg administered orally every 12 hours using the stasis, 1-log₁₀, and 2-log₁₀ targets from the E. coli and K. pneumoniae in vitro models. Plasma concentrations simulated in the fed state resulted in a probability of greater than 90% achievement of bacterial stasis targets when ƒT > MIC = 40% for MICs up to 0.25 mg/L. The probability of achieving >90% target attainment in the urine was also evaluated. Urine concentrations with sulopenem 500 mg and probenecid 500 mg administered every 12 hours in a fed state were simulated with 1 and 2 hour bladder voiding patterns and demonstrated achievement of bacterial stasis targets when the ƒT > MIC = 40% for MICs up to eight mcg/mL (68).

Tebipenem

Like the oral penems, tebipenem also exhibits time-dependent bactericidal activity, but dosing is optimized using a non-traditional metric. Dose fractionation studies in murine models were performed to evaluate the PK-PD index most associated with efficacy, but none of the traditional PK-PD indexes described the data well (82). In particular, a regression line could not be generated using ƒT > MIC due to clumping of data at 100%, the r² correlation coefficient for ƒC_max: MIC was only 0.33, and the ƒAUC:MIC r² was 0.73. Because time-dependent pharmacodynamics were seen, two additional metrics were explored, and the AUC/MIC per length of dosing interval (ƒAUC/MIC*1/tau) had the strongest correlation with efficacy (r² = 0.96), followed by the minimum concentration in plasma (C_min) to MIC ratio (r² = 0.90).

In the pharmacodynamic murine thigh model with E. coli and K. pneumoniae, the median ƒAUC/MIC*1/tau value that induced stasis was 23 with an 8-hour dosing interval. A hollow-fiber infection model was used to study the pharmacodynamics of the emergence of resistance to tebipenem in ESBL-E. coli. More fractionated regimens (every 8 hours) resulted in progressively more suppression of resistant subpopulations (82). The ƒAUC/MIC*1/tau values of 34.58 to 51.87 resulted in logarithmic killing, and a value of 69.15 suppressed resistance.

Tebipenem PK-PD was further evaluated in a 7-day hollow-fiber infection model with ESBL-producing E. coli as monotherapy and as an oral step-down option after intravenous ertapenem (83). Tebipenem 600 mg every 8 hours monotherapy reduced bacterial growth by at least a 2-log₁₀ CFU reduction in four of the five isolates. Ertapenem 1,000 mg every 24 hours monotherapy resulted in a greater reduction of bacterial burden in all five isolates compared to tebipenem. When ertapenem was given for 1–3 days, followed by tebipenem for 4–6 days, growth was suppressed for all five isolates for 7 days, and no resistant subpopulations were noted.

INTERACTIONS

Faropenem, tebipenem, and sulopenem do not appear to be significant substrates for cytochrome P450 isoenzymes or P-glycoprotein, suggesting low potential risk for clinically relevant drug-drug interactions via these mechanisms (68). Similar to sulopenem, coadministration of probenecid with either faropenem or tebipenem increased plasma exposure and reduced renal clearance (13, 84). No significant drug-drug interactions were reported for faropenem with furosemide, digoxin, theophylline, warfarin, cholestyramine, ranitidine, aluminum-magnesium hydroxide, or hormonal contraceptives (13).

There is a well-described interaction between valproic acid derivatives and carbapenems that decreases serum concentrations of valproic acid; however, there is only a single published case report of a 6-year-old previously stable on home sodium valproate who presented with convulsive seizures the day after receiving tebipenem pivoxil (85). Serum valproic acid concentrations at the time of seizure presentation were low at 30 μg/mL. The mechanisms of the interaction between valproic acid derivatives and carbapenems have not been fully elucidated, and it is unknown whether this interaction occurs with penems. There is no published literature describing an interaction with valproic acid and faropenem, but intravenous sulopenem co-administered with valproic acid reduced the valproic acid C_max and AUC concentrations by 28% and 33%, respectively. Oral sulopenem etzadroxil without probenecid reduced valproic acid AUC by 25% and C_max by 19%. Oral sulopenem etzadroxil with probenecid had no effect on valproic acid concentrations according to the briefing document from the drug manufacturer for the FDA Advisory Committee meeting, but the specific data were not included. The mechanism is not fully understood, but it may be due to the probenecid. It should be noted that patients who required concomitant administration of valproic acid were listed as an exclusion criterion in the randomized clinical trials with sulopenem (68).

CLINICAL APPLICATIONS

The broad spectrum of faropenem, sulopenem, and tebipenem makes them attractive options for use in patients with bacterial infections whose resistance patterns would otherwise require definitive therapy with intravenous antibiotics. This would be especially useful in patients requiring extended durations of therapy, allowing them to forego outpatient parenteral antimicrobial therapy. Here, we summarize the clinical trials evaluating the efficacy of these drugs (Table 3). Several randomized controlled trials (RCTs) were conducted using faropenem for respiratory tract infections (RTIs), skin and soft tissue infections, and urinary tract infections (UTIs) before 2005. These studies were presented as abstracts in international conferences and have been summarized in a previous review (13). As these studies were not published in peer-reviewed journals and the data do not reflect the current antimicrobial resistance landscape, as they were conducted before 2005, we did not include them in this review.

TABLE 3.

Summary of randomized controlled trials involving oral penems (faropenem, sulopenem) and carbapenems (tebipenem)^a,b

	Trial	Criteria	Study population	Primary outcomes	Trial/comparator	Composite cure rate	Clinical cure rate	Composite cure rate for participants with ESBL infection	Cure rate for participants with bacteremia
Faropenem
Acute bacterial rhinosinusitis	Upchurch, 2006	Inclusion criteria: Adults with a clinical diagnosis of acute sinusitis with a duration of signs and symptoms 7–28 days and with radiographic evidence of infection	1,106 enrolled with valid per-protocol population being 871	Clinical response at the test-of-cure visit (7–21 days after the completion of treatment)	Faropenem medoxomil, 300 mg twice daily for 7 days	N/A	PP: 237/295 (80.3) ITT: 262/366 (71.6)	N/A	N/A
		Exclusion criteria: - symptoms suggesting allergic rhinitis - concomitant systemic antimicrobials - history of sinus surgery - history of chronic sinusitis - bacteremia, meningitis, or infection infiltrating the tissues neighboring the sinuses - use of topical or systemic corticosteroids			Faropenem medoxomil, 300 mg twice daily for 10 days	N/A	PP: 229/280 (81.8) ITT: 255/363 (70.2)	N/A	N/A
					cefuroxime axetil 250 mg twice daily for 10 days	N/A	PP: 213/286 (74.5) ITT: 222/370 (60.0)	N/A	N/A
Acute bacterial rhinosinusitis	Sigert, 2003	Inclusion criteria: male and female outpatients aged 18 years or older with acute sinusitis	558 patients randomized; 452 clinically evaluable for primary endpoint; 136 microbiologically evaluable	Clinical response 7–16 days post-therapy	faropenem daloxate (300 mg, twice daily for 7 days)	65/71 (91.5)	203/228 (89.0)	N/A	N/A
		Exclusion Criteria: - suspected bacteremia or meningitis, including infiltrated neighboring tissue of the sinus - history of sinus surgery - history of chronic sinusitis			cefuroxime axetil (250 mg, twice daily for 7 days)	59/65 (90.8)	198/224 (88.4)	N/A	N/A
Sulopenem
Uncomplicated lower urinary tract infection	Dunne, 2023	Inclusion criteria: Adult women with uncomplicated UTI	785 included in mMITT analysis for ciprofloxacin-sensitive population	Overall combined clinical and microbiologic response on day 12 for ciprofloxacin-susceptible organisms	Sulopenem etzadroxil 500 mg/probenecid 500 mg bilayer tablet twice daily for 5 days	247/370 (66.8)	300/370 (81.1)	NR	N/A
					Ciprofloxacin 250 mg twice daily for 3 days	326/415 (78.6)	349/415 (84.1)	NR	N/A
		Exclusion criteria: Symptoms suggestive of upper tract UTI	286 included in mMITT analysis for ciprofloxacin-resistant population	Overall combined clinical and microbiologic response on day 12 for ciprofloxacin-resistant organisms	Sulopenem etzadroxil 500 mg/probenecid 500 mg bilayer tablet twice daily for 5 days	92/147 (62.6)	122/147 (83.0)	NR	N/A
					Ciprofloxacin 250 mg twice daily for 3 days	50/139 (36.0)	87/139 (62.6)	NR	N/A
Uncomplicated Lower Urinary Tract Infection	FDA Application Document (trial 310)	Inclusion criteria: Adult women with uncomplicated UTI	922 in mMITT analysis for amoxicillin/clavulanate-sensitive population	Overall combined clinical and microbiologic response on day 12 for amoxicillin/clavulanate susceptible organisms	Oral sulopenem etzadroxil/probenecid 500 mg/500 mg twice daily for 5 days	296/480 (61.7)	NR	22/37 (59.5)	N/A
					Oral amoxicillin/clavulanate 875 mg/125 mg twice daily for 5 days.	243/442 (55.0)	NR	20/45 (44.4)	N/A
		Exclusion criteria: Symptoms suggestive of upper tract UTI	67 in mMITT analysis for amoxicillin/clavulanate-resistant population	Overall combined clinical and microbiologic response on day 12 for amoxicillin/clavulanate-resistant organisms	Oral sulopenem etzadroxil/probenecid 500 mg/500 mg twice daily for 5 days	26/42 (61.9)	NR	NR	N/A
					Oral amoxicillin/clavulanate 875 mg/125 mg twice daily for 5 days.	20/25 (80.0)	NR	NR	N/A
Upper urinary tract infection	Dunne, 2023	Inclusion criteria: Adults with symptoms suggestive of upper urinary tract infection (fever, nausea and vomiting, costovertebral angle tenderness, etc.) or with symptoms suggestive of complicated urinary tract infection (presence of indwelling catheters, neurogenic bladder, renal stones, abnormal urinary tract anatomy, etc.)	1,395 adults randomized 884 included in mMITT analysis	Clinical cure and microbiologic eradication, in the microbiologic modified intent-to-treat (mMITT) population at the test-of-cure (TOC) visit (day 21).	IV sulopenem 1,000 mg once daily followed by sulopenem etzadroxil 500 mg/probenecid 500 mg twice daily with planned 7–10 treatment duration	301/444 (67.8)	615/697 (88.2)	79/110 (71.8)	25/44 (56.8)
		Exclusion criteria: - chronic indwelling urinary catheters - abscess or emphysematous pyelonephritis - expected requirement of surgical intervention to achieve a cure - ileal loops - renal transplant			IV ertapenem 1,000 mg once daily followed by oral ciprofloxacin 500 mg or amoxicillin–clavulanate 875 mg twice daily with planned 7–10 day treatment duration	325/440 (73.9)	603/698 (86.4)	85/125 (68.0)	28/43 (65.1)
Intra-abdominal Infection	Dunne, 2024	Inclusion criteria: Adults with a diagnosis of complicated intra-abdominal infection with signs of systemic inflammation	674 enrolled 515 in micro-modified intent-to-treat population (analyzed for primary endpoint)	Clinical response at the day 28 visit in the micro-modified intent-to-treat population	IV sulopenem 1,000 mg once daily followed by one bilayer tablet of sulopenem etzadroxil 500 mg/probenecid 500 mg (from here forward referred to as oral sulopenem) twice a day. Total treatment duration up to 14 days	213/249 (85.5)	265/283 (93.6)	30/36 (83.3)	NR
		Exclusion criteria: - bowel perforation undergoing surgery within 12 hours - gastroduodenal ulcer perforation undergoing surgery within 24 hours - abdominal wall abscess - cholecystitis without rupture - simple appendicitis - anticipation for staged abdominal repair - APACHE II score greater than 30 - anticipated high risk for mortality within 28 days			IV ertapenem 1,000 mg once daily followed by either oral ciprofloxacin 500 mg twice a day plus oral metronidazole 500 mg four times a day or oral amoxicillin-clavulanate 875 mg twice a day, based on susceptibility of baseline pathogens. Total treatment duration up to 14 days	240/266 (90.2)	265/277 (95.5)	39/42 (92.9)	NR
Tebipenem
Upper urinary tract infection	Eckburg, 2022	Inclusion criteria: Adults over the age of 18 with study-defined diagnosis of pyelonephritis or complicated UTI	1,372 adults enrolled 868 included in mMITT analysis	Composite of clinical cure and microbiologic response at the test-of-cure visit (day 19 ± 2 days)	tebipenem pivoxil hydrobromide 600 mg PO every 8 hours plus a dummy infusion every 24 hours	264/449 (58.8)	336/449 (74.8)	92/105 (87.6)	34/47 (72.3)
		Exclusion criteria: - Carbapenem-resistant pathogen - CrCl <30 more than 1 dose of a short-acting antibiotic 72 hours prior to randomization - Severe hepatic impairment - Septic shock - Immune compromise - Hypersensitivity to any beta-lactam antibiotic			Ertapenem 1 g IV every 24 hours plus dummy tablets PO every 8 hours	258/419 (61.6)	321/419 (76.6)	81/85 (95.2)	35/53 (66.0)

^a PP: Per protocol; ITT: Intention to treat; mMITT: microbiologically evaluable modified intention to treat; N/A: not applicable; NR: not reported.

^b References: (68, 86–91).

Urinary tract infections

Common features of all published RCTs evaluating the treatment of UTIs using the oral penems and tebipenem were the exclusion of even moderately immunocompromised patients, the exclusion of severe manifestations of infection such as emphysematous pyelonephritis in cases of complicated UTIs, and a small representation of patients who had causative organisms with ESBL phenotypes.

It should be additionally noted that all of the trials described in this section have several common features that affect the interpretation of their results. In particular, due to requirements by the FDA, all trials have a primary endpoint that requires both clinical resolution of symptoms and microbiologic eradication as demonstrated by a negative urine culture. However, this definition does not fully reflect the contemporary management of urinary tract infections, which typically does not require a negative urine culture as a test of cure. In clinical practice, the patients who have achieved resolution of symptoms would be considered cured regardless of any growth on urine culture, as asymptomatic bacteriuria is not managed with antibiotics in the vast majority of cases (92). Furthermore, in trials examining complicated urinary tract infections, acute pyelonephritis, and complicated urinary tract infections are conflated and treated similarly despite an evolving contemporary understanding of what a “complicated” urinary tract infection is and how it should be treated (93). What is termed “complicated” cystitis affects a different patient population and has a different microbiologic profile (older patients, more resistant organisms) than acute pyelonephritis (younger patients, more susceptible organisms), so the proportion of each syndrome represented in these studies can then potentially have effects on their outcomes with respect to meeting non-inferiority targets (94).

Faropenem

There is only one published RCT investigating faropenem sodium for uncomplicated UTI. This trial was an open-label trial that examined duration rather than the efficacy of the drug as compared to comparator standards of care (1). In all, 200 adult women with acute uncomplicated cystitis were randomized. Women with renal transplants, pregnant women, and women with organisms resistant to faropenem were excluded. 97 women received faropenem 200 mg dosed three times per day for 3 days, and 103 women received faropenem at the same dose and frequency for 7 days. The primary endpoint was microbiologic cure at 5–9 days post-treatment, and the secondary endpoint was clinical cure at 5–9 post-treatment and at 4–6 weeks after treatment. After removing patients who were lost to follow-up and patients who did not have positive cultures at their initial evaluations, 73 women were analyzed in the 3-day group and 81 patients were analyzed in the 7-day group. Of those randomized to receive 3 days of therapy, 43/73 (58.9%) women included in the final analysis achieved the primary endpoint, and 56/73 (76.7%) achieved the secondary endpoint of clinical cure at 5–9 days. In the 7-day arm, 54/81 (66.7%) achieved microbiologic cure at 5–9 days, and 65/81 (80.2%) achieved clinical cure at the same time point. None of the differences were statistically significant. While these results support an increasingly voluminous body of literature illustrating that shorter courses of antibiotics are sufficient for uncomplicated infections, they do not provide much insight into the comparative efficacy of faropenem to narrower-spectrum drugs. That said, the cure rates achieved in all arms are lower than the cure rates demonstrated in the trials for tebipenem and sulopenem in both arms.

Sulopenem

There are two published RCTs evaluating the use of sulopenem for UTIs. An additional study for UTI using sulopenem has been completed but has not been published. However, this did undergo review by the FDA, so we included a discussion of this study as well and used the FDA antimicrobial advisory committee meeting draft to discuss this unpublished study (68).

The first trial involving sulopenem focused on a patient population of women greater than 18 years of age with uncomplicated UTI and comparing a 5-day course of oral sulopenem etzadroxil 500 mg/probenecid 500 mg bilayer tablet twice daily to a 3-day course of oral ciprofloxacin dosed at 250 mg twice daily. The primary composite endpoint was defined at day 12 (± 1 day) with the requirements that the patient be alive, their symptoms had resolved, they did not receive any additional antibiotics, and their urine culture was negative. The primary outcome of a composite clinical and microbiologic cure was analyzed separately for patients growing ciprofloxacin-susceptible organisms and ciprofloxacin-resistant organisms (88). In the final analysis, the microbiologically evaluable modified intent-to-treat (mMITT) group was analyzed for both ciprofloxacin-susceptible (mMITT-S) and ciprofloxacin-resistant (mMITT-R) isolates. The mMITT group was the group of randomized patients who received one or more doses of study medication and had urine cultures positive for either an Enterobacterales organism or Staphylococcus saprophyticus, and two or fewer organisms growing from the urine culture. The combined mMITT population amounted to 517 of the 835 participants who were randomized to receive sulopenem and 554 of the 836 participants randomized to receive ciprofloxacin.

For ciprofloxacin-susceptible organisms, sulopenem was not noninferior. In the mMITT-S analysis, the composite cure rate was 66.8% (247/370) for sulopenem and 78.6% (326/415) for ciprofloxacin, which did not meet the noninferiority margin of 10%. When comparing clinical cure rates alone, in the ciprofloxacin-susceptible arm, outcomes were similar with 81.1% (300/370) clinical cure with sulopenem compared to 84.1% (349/415) with ciprofloxacin. Microbiologic failure in the sulopenem group was driven primarily by asymptomatic bacteriuria at the test-of-cure visit.

For ciprofloxacin-resistant organisms, sulopenem achieved a 62.6% (92/147) composite cure rate and an 83% (122/147) clinical cure rate. Interestingly, even with ciprofloxacin-resistant organisms treated with ciprofloxacin, a clinical cure rate of 62.6% (87/139) was achieved despite a much lower composite clinical and microbiologic cure rate of 36% (50/139) (88). Finally, the overall composite cure rate for all 1,071 patients included in the mMITT analyses was 65.6% (339/517) in the sulopenem arm and 67.8% (376/554) in the ciprofloxacin arm.

In the combined mMITT group, 145 (13.5%) patients had ESBL isolates, 338 (31.6%) participants had isolates that were trimethoprim-sulfamethoxazole (TMP-SMX) resistant, and 293 (27.4%) had ciprofloxacin-resistant isolates. In patients with ESBL organisms, 41 out of 73 (56.2%) who received sulopenem met the primary outcome compared to 34/72 (47.2%) who received ciprofloxacin.

A second trial that was reported in the FDA new drug application compared 5 days of sulopenem etzadroxil/probenecid 500 mg/500 mg twice daily for 5 days with 5 days of oral amoxicillin/clavulanate 875 mg/125 mg for the treatment of uncomplicated UTI in women greater than 18 years of age. A total of 2,222 patients were randomized. Outcomes were again analyzed on an mMITT group defined similarly as in the preceding trial that included 522 patients who were randomized to receive sulopenem and 467 patients who were randomized to receive amoxicillin/clavulanate. Outcomes were analyzed separately as well for patients with amoxicillin/clavulanate-resistant organisms (the mMITT-R group) and -susceptible organisms (the mMITT-S group). The mMITT-R group, however, only had 67 patients across both arms.

In the combined mMITT analysis, overall composite cure rates were 61.7% (322/522) for the sulopenem group and 56.3% (263/467) for the amoxicillin/clavulanate group. These results indicate non-inferiority using a margin of 10% and superiority of sulopenem compared to amoxicillin/clavulanate. In the mMITT-S analysis, the microbiologic failure at the time of test of cure visit was lower in the sulopenem group compared to amoxicillin/clavulanate (14.6% [70/480] in the sulopenem versus 20.6% [91/442] in the amoxicillin/clavulanate). In the combined mMITT group, there were 98 patients with ESBL organisms, 261 patients with quinolone-resistant organisms, and 300 patients with TMP-SMX-resistant organisms (68). Outcomes for these subgroups were only partially reported in the mMITT-S group: 22/37 (59.5%) patients with ESBL isolates receiving sulopenem met the primary endpoint compared to 20/45 (44.4%) patients receiving amoxicillin/clavulanate. For patients with quinolone-resistant isolates, 62/120 (51.7%) receiving sulopenem met the primary endpoint compared to 63/128 (49.2%) receiving amoxicillin/clavulanate. The predominant organisms causing UTI in both trials were E. coli, K. pneumoniae, and P. mirabilis.

A limitation of both trials for uncomplicated lower urinary tract infection is their exclusion of essentially all patients who traditionally would be considered to have risk factors for resistant infection—that is, patients with abnormal urinary anatomy or instrumentation. Only a small minority of patients had organisms with ESBL phenotypes in both trials, and on subgroup analyses, there is no numeric or statistically significant difference in outcomes, though interpretation is limited by small numbers.

Based on these two studies, the FDA approved sulopenem for the treatment of uncomplicated UTIs in women due to E. coli, K. pneumoniae, and P. mirabilis when alternate antibiotics cannot be offered due to resistance. While there is dramatic regional variation in the overall incidence of UTIs caused by MDROs, rates of ESBL-producing Enterobacterales causing clinically significant infection are increasing globally (95). An uncomplicated UTI is not a particularly morbid infection, but highly resistant isolates may necessitate inpatient treatment as it is typically an outpatient disease (96). While resurrecting older practices such as using single-dose aminoglycosides may help mitigate the problem, administering one-time doses of intravenous antibiotics still may pose logistical challenges, and aminoglycosides still have unfavorable toxicity profiles as compared to beta-lactams. The availability of oral penems as alternative agents in these cases may be valuable in avoiding inpatient admissions for patients with highly resistant organisms, resulting in clinically significant UTI.

Sulopenem was additionally studied for complicated UTI and pyelonephritis in one published RCT. In this trial, patients with complicated UTI or pyelonephritis were randomized to receive either intravenous sulopenem 1,000 mg daily followed by oral sulopenem etzadroxil 500 mg/probenecid 500 mg twice daily or intravenous ertapenem 1,000 mg once daily followed by either oral ciprofloxacin 500 mg twice daily or amoxicillin/clavulanate 875 mg twice daily. There was a minimum requirement of 5 days of IV antibiotic therapy. In the ertapenem arm, if ciprofloxacin or amoxicillin/clavulanate was not appropriate oral step-downs, then IV therapy was continued. The total planned duration was 7–10 days with an allowance to continue to 14 days for bacteremic patients (87).

Similar to the trials for uncomplicated UTI, patients with shock and immune compromise were again excluded. The primary outcome was composite microbiologic cure with negative urine culture and clinical cure with resolution of symptoms at 21 days. The final analysis was performed on the mMITT group, which was defined as the group of patients who received at least one dose of study drug and had Enterobacterales growing in their initial urine culture. With this definition, despite randomizing a total of 1,385 patients, only 444 were analyzed in the sulopenem arm and 440 were analyzed in the ertapenem arm. Using the primary outcome, sulopenem was not able to demonstrate noninferiority to the comparator arm. The sulopenem arm achieved a 67.8% (301/444) cure rate compared to 73.9% (325/440) in the ertapenem arm. The difference was driven by microbiologic failure and a higher proportion of asymptomatic bacteriuria at the test-of-cure visit. As such, sulopenem does not have an FDA-approved indication for complicated UTI (87).

While the prevalence of resistance was fairly high overall, individual resistance patterns (ESBL, fluoroquinolone non-susceptibility, TMP-SMX resistance) still represented a minority of infections. There were 235/884 (26.5%) with ESBL organisms, 341/884 (38.6%) with quinolone-resistant isolates, and 315/884 (35.6%) with TMP-SMX-resistant isolates. There were no statistically significant differences in outcomes in these subgroups: Patients with ESBL-positive isolates met the primary endpoint in 79/110 (71.8%) of cases when they received sulopenem and in 85/125 (68.0%) of cases when they received ertapenem; patients with quinolone-resistant isolates met the endpoint in 112/162 (69.1%) of cases if they received sulopenem and in 116/179 (64.8%) of cases if they received ertapenem; and patients with TMP-SMX-resistant isolates achieved the primary endpoint in 106/154 (68.8%) cases in the sulopenem arm and 111/161 (68.9%) cases in the ertapenem arm.

In this study, a larger proportion of those in the sulopenem arm was able to step down to oral therapy to complete their course (603/695 or 86.8% compared to 463/697 or 66.4%), though this may have been an artifact of the study design, which only allowed for two possible stepdown regimens in the comparator arm. There was a statistically significant difference in the duration of IV therapy with those receiving IV sulopenem, remaining on IV therapy for 5 days compared to 6 days for those randomized to receive ertapenem followed by an oral stepdown.

Tebipenem

One trial has been published evaluating the use of tebipenem for complicated urinary tract infections (86). Adult patients with complicated UTI or pyelonephritis without severe manifestations (specifically, shock and immune-compromising conditions) were randomized to receive oral tebipenem pivoxil hydrobromide 600 mg every 8 hours with a daily IV placebo or IV ertapenem 1,000 mg daily with an oral placebo given every 8 hours for 7–10 days. The duration could be extended to 14 days for bacteremia. The primary endpoint at 19 days was a composite of negative urine culture and clinical resolution. The mMITT group was defined as patients with complicated UTI or pyelonephritis who received at least one dose of study drug and had a baseline culture positive for one or two uropathogens, excluding organisms that would not be expected to respond to either drug. However, notably, patients with cultures positive for Enterococcus were still included. Overall, 1,372 patients were randomized, and 868 patients were included in the mMITT analysis. Of these patients, 427 (49.2%) were classified as having pyelonephritis and 441 (50.8%) were classified as having complicated UTI. 58.8% (264/449) achieved composite cure in the tebipenem arm, and 61.6% (258/419) achieved the composite cure in the ertapenem arm (86). Tebipenem met the noninferiority margin of 12.5% when compared to ertapenem for overall response at the test of cure visit. E. coli (64.2%) was the predominant organism followed by K. pneumoniae (14.3%) and P. mirabilis (6.7%).

In the mMITT group, there were 782 patients with Enterobacterales growing from urine cultures. Of those, 190 (24.3%) patients had ESBL isolates, 305 (39.0%) patients had quinolone non-susceptible isolates, and 336 (43.0%) patients had TMP-SMX-resistant isolates. Outcomes for these subgroups at least numerically favored ertapenem. Patients with ESBL organisms had clinical response in 92/105 (87.6%) cases and microbiologic response in 58/106 (54.7%) cases in the tebipenem arm. In the ertapenem arm, 81/85 (95.3%) had clinical response and 53/86 (61.6%) cases had microbiologic response. Patients with quinolone non-susceptible isolates had clinical response in 143/159 (89.9%) cases and microbiologic response in 89/165 (53.9%) cases in the tebipenem arm. In the ertapenem arm, 137/146 (93.8%) had clinical response and 91/149 (61.1%) had microbiologic response. Patients with TMP-SMX-resistant isolates had clinical response in 155/168 (92.3%) cases and microbiologic response in 99/172 (57.6%) cases when they received tebipenem. If they received ertapenem, they had clinical response in 160/168 (95.2%) cases and microbiologic response in 109/170 (64.1%) cases.

Also included in the mMITT group were 100 (11.5%) patients that were bacteremic. A subgroup analysis of this bacteremic cohort revealed numerically similar cure rates for patients who received only oral therapy with tebipenem and those who received the comparator regimen that included an initial course of IV ertapenem (34/47 for tebipenem versus 35/53 for ertapenem) (Table 3), which may be evidence of favorable PK characteristics (86).

Overall, the results of this trial were deemed to be insufficient to support the approval of tebipenem by the FDA and requested additional trials (97). Specifically, this trial included patients who had clinical infection attributed to Enterococcus species, which would not be covered by ertapenem. Performing an analysis with these patients excluded from the mMITT group changes the primary outcome such that tebipenem no longer is able to meet the prespecified non-inferiority margin of 12.5% (98). An additional trial evaluating tebipenem in comparison to imipenem-cilastatin for complicated UTI is underway (99).

Upper and lower RTIs

All three agents discussed have demonstrated high degrees of potency against respiratory aerobes and anaerobes, especially S. pneumoniae, M. catarrhalis, and H. influenzae. As such, they would be expected to be effective for both upper and lower RTIs, though PK data remain incomplete.

Faropenem

While there have been a number of clinical trials whose results have been shared at conference proceedings, there are only two that have been published examining the use of faropenem in acute bacterial rhinosinusitis (ABRS) (89, 90). The details of the published trials are summarized in Table 3. The two studies demonstrated that faropenem was comparable to cefuroxime in clinical efficacy for the treatment of ABRS. Only one of the two studies provided microbiological data about the infections causing ABRS in 136 of 452 randomized participants (90). The culprit pathogens were S. pneumoniae, H. influenzae, S. aureus, and M. catarrhalis—all of which can be covered by narrower oral β-lactams (89). While a possible justification for the use of an oral penem could be made due to the rising rates of resistance of S. pneumoniae to oral cephalosporins, susceptible isolates still account for around 80% or more of surveyed isolates and amoxicillin/clavulanate maintains activity in excess of 90% (23, 24, 28). H. influenzae resistance, on the other hand, could be a stronger justification in areas in which there are high rates of β-lactamase negative, ampicillin-resistant strains that would potentially render most oral β-lactams ineffective (100). However, this would be a highly regional consideration and for most patients, older, narrower agents would be expected to work with a high degree of success.

Tebipenem

For the treatment of pneumonia, PK data for tebipenem suggest behavior similar to that of other oral β-lactams commonly used to treat pneumonia such as amoxicillin/clavulanate and cephalosporins (74). While there are no RCTs evaluating tebipenem for this indication, one published uncontrolled prospective study evaluating the efficacy of a 3-day course of tebipenem in pediatric pneumonia cases showed a success in 32 of 36 cases evaluated for cure (27). Three cases were lost to follow-up, and one patient developed acute otitis media.

Skin, soft tissue, and bone infections

No published clinical trial data exist describing the use of the oral penems or tebipenem for their use in skin, soft tissue, and bone infections (13).

Tebipenem has been shown to be able to achieve high concentrations in soft tissue, including in patients with diabetic foot infection, which suggests that like other oral β-lactams, they may have a role in step-down therapy in polymicrobial Gram-negative and anaerobic wound infections (73).

There is insufficient clinical and pharmacokinetic data to draw any conclusions about sulopenem’s possible utility in the treatment of skin and soft tissue infection.

Intra-abdominal infections

The spectrum of activity of the oral penems and tebipenem includes broad Gram-negative and anaerobic coverage, which would be expected to be useful for intra-abdominal infections. Only sulopenem has published trial data investigating this potential application.

Sulopenem

One published trial exists that attempts to evaluate the efficacy of IV sulopenem 1,000 mg daily with a transition to oral sulopenem etzadroxil 500 mg/probenecid 500 mg as compared to IV ertapenem 1,000 mg daily with an oral transition to either ciprofloxacin 500 mg twice daily with metronidazole 500 mg twice daily or amoxicillin/clavulanate 875 mg twice daily in adult patients (91). Five days of IV therapy were required before any transitions. Patients were included if they had signs or symptoms of complicated intra-abdominal infections and evidence of systemic inflammation. Patients were excluded if they had traumatic bowel perforation planned for surgery in 12 hours, duodenal perforation planned for surgery within 24 hours, simple or gangrenous cholecystitis without rupture, simple appendicitis, abdominal wall abscess, or bowel ischemia without perforation. In addition, patients who were critically ill or terminally ill were excluded. The mMITT group was defined as patients who had one or more Gram-negative study pathogens recovered within 48 hours before to 24 hours after the first dose of the study drug. The primary endpoint was clinical efficacy at day 28 in the mMITT population, meaning patients had to be alive with symptom resolution at day 28. Clinical cure was achieved in 85.5% (213/249) patients receiving sulopenem and 90.2% (240/266) in the ertapenem arm. Only 78 of the microbiologically evaluable patients had isolates with ESBL phenotypes. Of these cases, 30/36 (83.3%) demonstrated clinical response in the sulopenem arm and 39/42 (92.9%) demonstrated clinical response in the ertapenem arm. The median treatment duration was 9 days in both arms with more patients in the sulopenem arm being able to transition to oral therapy (276/335 (82.4%) vs 225/333 (67.6%)). Overall, the lower limit of the confidence interval did not meet the pre-specified non-inferiority margin (91).

TOXICITY AND GUT MICROFLORA IMPACT

Faropenem, sulopenem, and tebipenem all demonstrate favorable toxicity profiles as summarized in Table 4. In general, diarrhea was the most common adverse effect for all three agents. In none of the trials did patients in the oral penem or carbapenem arms develop Clostridioides difficile infection, though in all trials the follow-up window was a month or less. Post-marketing surveillance of tebipenem revealed a 9.4% incidence of diarrhea with therapy, accounting for nearly all of the documented adverse drug events. None of the drugs has been observed to be QT-prolonging agents, nor have they been shown to increase the risk of seizure outside of the known interaction between carbapenems and valproic acid, in which the former reduces the levels of the latter.

TABLE 4.

Summary of adverse events of oral penems (faropenem, sulopenem) and carbapenems (tebipenem)^a

Trial	Drug-related adverse event rate		Adverse events leading to discontinuation of drug		Most common adverse events
	Trial	Comparator	Trial	Comparator
Faropenem
Upchurch, 2006	154/729 (21.1)b	69/370 (18.6)	22/731 (3.0)b	16/371 (4.3)	Diarrhea
					Nausea
					Vaginal moniliasis
Sigert, 2003	26/274 (9.5)	28/273 (10.3)	7/274 (2.6)	2/273 (0.7)	Diarrhea
					Nausea or vomiting
					Skin rash
Sulopenem
Dunne, 2023	207/833 (24.8)	115/827 (13.9)	13/833 (1.6)	8/827 (1.0)	Diarrhea
					Nausea
					Headache
Dunne, 2023	42/695 (6.0)	64/697 (9.2)	3/695 (0.4)	4/697 (0.6)	Headache
					Diarrhea
Dunne, 2024	25/335 (7.5)	19/332 (5.7)	5/335 (1.5)	7/332 (2.1)	Diarrhea
					Nausea
					Post-operative wound infection
Tebipenem
Eckburg, 2022	64/685 (9.3)	42/687 (6.1)	1/685 (0.1)	8/687 (1.2)	Diarrhea
					Headache
					Nausea

^a References (86–91).

^b Combined rate from both faropenem arms.

There are no peer-reviewed published studies reporting the impact of faropenem and sulopenem on the gut microbiome; however, one conference abstract details a study in which healthy volunteers were exposed to various doses of faropenem (300, 600, and 1,200 mg) twice daily for 8 days to evaluate its effect on the intestinal microbiome. In comparison to the baseline prior to faropenem exposure, there was an increase in the abundance of Enterococcus species, especially E. faecium, but no relevant changes in Candida and Enterobacterales species in the gut flora after faropenem exposure (66).

A recent study examined the impact of tebipenem on gut microbiome among 30 healthy adults and compared it to amoxicillin/clavulanic acid (101). In this study, tebipenem was administered 600 mg every 8 hours for 10 days. Changes in colony count, diversity, and abundance of taxa were measured by collecting stool samples at nine different times including baseline, during treatment, and after treatment with the last sample collected after 180 days. Compared to baseline, following tebipenem treatment, there was a significant decrease in the counts of Enterobacterales, Enterococcus species, Candida species, and Bacteroides species, while in the amoxicillin/clavulanic acid group, Enterobacterales significantly increased, while no changes were observed in the abundance of Enterococcus species, Candida species, and Bacteroides species. Although the counts and diversity recovered to baseline during the follow-up period, it was slower in the tebipenem group. There was no selection of vancomycin-resistant Enterococcus species, but C. difficile was detected in one patient in the tebipenem group. The emergence of third-generation cephalosporin resistance among E. coli and K. pneumoniae was low (7%) in the tebipenem group, and there was no selection of carbapenem resistance. However, it is important to recognize that the study was performed in Sweden, where the ESBL- (and likely carbapenemase) producing Enterobacterales intestinal colonization prevalence among healthy adults is among the lowest in the world (102). Interestingly, in a recent animal study where mice were challenged with carbapenem-resistant K. pneumoniae carrying bla_NDM-1, tebipenem exposure did not promote the overgrowth of carbapenem-resistant K. pneumoniae (103).

ANTIMICROBIAL STEWARDSHIP CONSIDERATIONS

While oral penems and tebipenem could have a role in the management of uncomplicated and complicated UTIs and intra-abdominal infections due to their activity against MDROs, especially ESBL-producing Enterobacterales, clinical data so far have been only moderately supportive of these use cases. Published clinical trial data for faropenem is very limited and outdated, with no apparent interest from industry in getting FDA approval for these indications. Faropenem is widely used in India for various indications and in Japan for respiratory tract infections despite the lack of modern RCTs reflective of contemporary resistance patterns. The only peer-reviewed trial examining faropenem for the treatment of UTI shows clinical cure rates that are lower than other agents. Sulopenem has demonstrated non-inferiority against comparators (ciprofloxacin and amoxicillin-clavulanate) in two uncomplicated UTI RCTs among adult women, but did not demonstrate non-inferiority for the complicated UTI and intra-abdominal infections. Although tebipenem demonstrated non-inferiority to ertapenem for complicated UTI in one RCT, because of the inclusion of patients with infections due to Enterococcus when the control arm consisted of a regimen that would not be expected to be covered, the FDA requested additional RCTs to further support its clinical efficacy. There are no RCTs evaluating the role of tebipenem for intra-abdominal infections.

With respect to their role in empiric therapy for UTI, while antimicrobial resistance is increasing, the rates of resistance in many areas of the world do not justify first-line empiric coverage for most non-severe infections, especially for uncomplicated urinary tract infections, in which older, non-beta-lactam options are frequently available. While the trials do demonstrate the safety of the drugs, they do not directly address their most useful potential use cases due to the relative underrepresentation of patients with infections caused by resistant bacteria among trial participants. Still, the available trial data as well as the PK/PD data above allow for some preliminary direction in how best to utilize these agents. Despite the observed efficacy for respiratory tract infections, the broad Gram-negative spectrum of these agents is unnecessary for most cases of these infections.

One potentially impactful use case would be as therapy in patients with bacteremia secondary to quinolone non-susceptible, TMP-SMX-resistant, ESBL Enterobacterales. These patients currently have only IV options, which prolong hospital stay or necessitate the use of home IV therapy, which has its own set of risks. However, currently, there is not enough information in published clinical trials to support this use. The tebipenem trial examining complicated UTI did include a cohort of bacteremic patients, who did have numerically similar outcomes to the ertapenem arm, suggesting that this is an avenue that could be pursued further. The sulopenem trials investigating complicated UTI and intra-abdominal infections also did include a small number of bacteremic patients, but unfortunately, these trials required the use of IV sulopenem up front, which provides less useful information about this potential use case, though at the very least they suggest that sulopenem could be used as step-down therapy after an IV induction phase.

It has been well described that carbapenems increase the risk of multidrug-resistant, including carbapenem-resistant bacterial infection or colonization, following exposure much more significantly than narrower agents. A large systematic review investigating this correlation showed an odds ratio (OR) of 2.29 (CI 2.14–2.46) for developing multidrug-resistant bacterial colonization or infection following carbapenem exposure as compared to an OR of 1.32 (CI 1.13–1.54) for β-lactam/β-lactamase inhibitor combinations (104). There is no reason to expect that this risk would be any lower with the oral penems or tebipenem. Moreover, the concern is the possibility of cross-resistance among Gram-negative organisms to parenteral carbapenems after exposure to these oral agents, which could have serious consequences and limit the utility of parenteral carbapenems even without their exposure. In vitro studies involving faropenem have demonstrated cross-resistance to parenteral carbapenems among ESBL-producing Enterobacterales after exposure to faropenem; however, such studies are lacking for sulopenem and tebipenem (57, 58). The published RCTs involving oral sulopenem and tebipenem have not demonstrated this possibility yet; however, there were a limited number of patients with ESBL-producing Enterobacterales infections enrolled in these studies. Although one study evaluating the impact of tebipenem on gut microbiome among healthy adults did not show significant selection for ESBL- or carbapenemase-producing Enterobacterales, this study was conducted in a European region where the prevalence of these organisms is the lowest in the world and the utility of these oral agents for clinical infections is thus low (101, 102). The impact of these oral agents on the selection of ESBL- or carbapenemase-producing Enterobacterales needs to be studied in high-prevalence countries where the clinical utility of these agents is more valuable. For institutions that routinely test and prescribe oral penems, publication on the antibiogram could aid in tracking the emergence of resistance over time.

In its briefing approving sulopenem, the FDA included language warning against the use without proper stewardship controls, though no recommendations for specific action were included (68). The effect of a lack of proper stewardship controls can be seen in India where faropenem use outpaced that of meropenem as soon as it was introduced, with a continuing upward trajectory of use (3).

Given these risks and the existence of narrower, alternative agents appropriate for most indications and geographic regions, the broad spectrum of activity penems and tebipenem should preclude their use as first-line or empiric agents in most patients. Under optimal circumstances, the use of these agents should be as culture-directed definitive therapy only. When devising use policies, healthcare systems should advise reserving these agents for use in patients with uncomplicated UTI who are known to have resistant infection with no other options. Once more clinical data exist, a potential future indication would be as step-down therapy. They could be considered in patients who need consolidation therapy for complicated UTI or intra-abdominal infection who have already met clinical stability criteria, including symptomatic improvement, resolution of fever, and resolution of bacteremia. The currently available trial data, however, do not support this indication, and studies would need to be designed specifically examining these agents as step-down regimens without dictating the initial regimens, as was the case in the sulopenem trial examining intra-abdominal infection.

Data that would be necessary to further delineate the typical use case would be trials that enrolled only patients with resistant infections, as well as trials that specifically examined patients with bacteremias. In addition, while the toxicity profile of these agents seems to be comparable to intravenous carbapenems, further post-marketing data are needed to better describe the side effect and risk profiles of these agents.

ANTICIPATED FUTURE DEVELOPMENTS

While faropenem, sulopenem, and tebipenem should not be considered first-line options for most infections, there are a number of potential niche uses to which their broad spectrum of activity may lend them. Given that tebipenem does reach concentrations in ELF comparable to other oral β-lactams and that faropenem is already used in upper respiratory infections, the question arises as to whether these agents would be of use in the treatment of patients with resistant Gram-negative pulmonary infections and indeed, it has been suggested that tebipenem may be a potential therapy to consider in the treatment of Burkholderia mallei, B. pseudomallei, and Yersinia pestis given low MICs and high survival rates in murine models of pneumonic Y. pestis treated with tebipenem as compared to ciprofloxacin (31). However, tebipenem does appear to be hydrolyzed by β-lactamases produced by B. cepacia complex and B. gladioli in vitro, suggesting its use may be limited in patient subpopulations predisposed to resistant Gram-negative pulmonary infections such as patients with advanced structural lung disease due to cystic fibrosis or bronchiectasis (105). In addition, the apparent intrinsic resistance of P. aeruginosa to faropenem, sulopenem, and tebipenem further limits the potential application in these patient populations.

It has been suggested that tebipenem could be considered for the treatment of multidrug-resistant shigellosis given favorable MICs (106), but this application would be a highly specific one, as the recommended treatment for shigellosis does not hinge on antibiotics, but rather supportive therapy. In addition, when antibacterial therapy is pursued in severe cases, the use of an oral drug in a patient with severe diarrhea and possibly compromised absorption may be suboptimal. As a step-down agent, its use is somewhat obviated by the fact that the endpoint of therapy is frequently the improvement of diarrhea.

There are three uncontrolled studies examining the use of faropenem in the salvage therapy for H. pylori infections with varying degrees of eradication from 9.5% to 91% though in each case, faropenem was used as one agent in variable multidrug regimens. Still, in tandem with resistance testing, this suggests one more possible niche use of this class of drugs (107–109).

While no clinical data exist, XDR Salmonella typhi and Salmonella paratyphi isolates tested against tebipenem seem to have low enough MICs as to suggest clinical utility, with maximum MICs being 0.62 mg/L. In addition, synergy was demonstrated in vitro when combined with azithromycin. While this is early data, the treatment of XDR enteric fever may be a compelling use case for the oral carbapenems and penems, given their relative ease of use as compared to intravenous options (106).

Similarly, while there is no clinical experience currently, faropenem and tebipenem do have known activity against Neisseria gonorrhea. As the prevalence of MDR gonorrhea increases, these drugs may have a niche role in the treatment of these cases. However, there is currently insufficient clinical data and PK data regarding urethral and vaginal concentrations to come to any conclusions.

CONCLUSION

Faropenem, sulopenem, and tebipenem are three orally administered penem and carbapenem antibiotics with broad-spectrum activity and a favorable toxicity profile. The available PK/PD and clinical trial data indicate potential use of these drugs in the management of UTIs due to MDROs, especially ESBL-producing Enterobacterales. There is no convincing data for faropenem in the management of UTIs despite being used in some Asian countries. Although faropenem demonstrated clinical efficacy in some respiratory tract infections, due to its broad-spectrum activity and the possibility for selection of carbapenem-resistant Enterobacterales, its use should be discouraged. Sulopenem was approved in 2024 by the FDA for the management of uncomplicated UTI in adult women; however, it did not demonstrate non-inferiority to ertapenem for complicated UTIs and intrabdominal infections. Sulopenem is a welcome addition to the arsenal of available antibiotics, but its use should be restricted to culture-directed therapy when alternate antibiotics cannot be offered for the treatment of uncomplicated UTIs due to third-generation cephalosporin-resistant or ESBL-producing E. coli, K. pneumoniae, and P. mirabilis. Unfortunately, ESBL Enterobacterales infections are more common among patients with abnormal urinary anatomy or instrumentation, which are not considered as uncomplicated UTI. There will be a tendency by healthcare providers to use sulopenem in these situations. In addition, there are no data on the emergence of sulopenem resistance after exposure and the selection of cross-resistance to parenteral carbapenems. Therefore, the use of sulopenem should be strictly monitored in healthcare settings, and it is vital to study the potential generation of resistance due to sulopenem use. Tebipenem demonstrated non-inferiority against ertapenem for complicated UTI in one RCT, and a second trial is ongoing in which imipenem is the comparator. Approval of tebipenem in the future for complicated UTI could have a significant impact on patient care, especially those requiring intravenous carbapenem therapy. However, it is of the utmost importance to study the potential risk of cross-resistance to parenteral carbapenems after exposure to tebipenem.

Biographies

Dr. Sena Sayood is an Assistant Professor of Medicine in the Division of Infectious Diseases at Washington University School of Medicine in St. Louis, Missouri. He has been on the Barnes-Jewish Hospital antimicrobial stewardship program committee since 2021 and has served as its medical director since 2024. He completed medical school at the University of Nebraska, internal medicine residency at the University of Utah, and infectious diseases fellowship at Washington University in St. Louis. His clinical interests and research work are focused on antimicrobial stewardship interventions and clinical decision support to aid in antimicrobial stewardship.

Elizabeth Neuner received her Doctor of Pharmacy from St. Louis College of Pharmacy in 2006. She completed a pharmacy residency in 2007 and an infectious diseases pharmacy residency in 2008 at Barnes-Jewish Hospital. She previously practiced as an infectious diseases clinical coordinator for the Department of Pharmacy at the Cleveland Clinic for 11 years. Since 2019, she has practiced as an infectious diseases/antimicrobial stewardship clinical pharmacy specialist at Barnes-Jewish Hospital in St. Louis, Missouri.

Dr. Rebekah Dumm is an Assistant Professor in Pathology and Immunology at Washington University School of Medicine in St. Louis. She is a board-certified medical microbiologist and serves as a Medical Director for the Clinical Microbiology Laboratory and Molecular Infectious Disease Laboratories at Barnes-Jewish Hospital and St. Louis Children's Hospital. She specializes in bacteriology, antimicrobial susceptibility testing, and molecular syndromic infectious disease diagnostics, and her research focuses on rapid identification of multidrug-resistant organisms and appropriate utilization of advanced molecular diagnostics for the diagnosis of infectious diseases.

Dr. Sumanth Gandra is an infectious disease physician and currently an Associate Professor of Medicine in the Division of Infectious Diseases at Washington University School of Medicine, St. Louis, Missouri. His research work is focused on three major antimicrobial resistance mitigation areas: optimizing antibiotic use in low-income countries, infection prevention, and low-cost point of care diagnostics development. His clinical interests include the management of multidrug-resistant Gram-negative infections and orthopedic infections. His research work has been funded by the National institutes of Health, the Centers for Disease Control and Prevention, and the World Health Organization (WHO). He serves as a member of the Technical Advisory Group on AWaRe, an advisory group to the WHO on antimicrobial use and stewardship, and a panel member of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) multidrug-resistant Gram-negative infections treatment guidelines.