β-lactamase

Sulopenem may be used to treat both simple and complex urinary tract infections as well as intra-abdominal infections, including those that are multidrug-resistant (MDR) and those caused by Gram-negative bacteria that produce extended-spectrum β-lactamase (ESBL) and are not susceptible to quinolones[1]. At a concentration of ≤1 μg/mL, sulopenem inhibits the growth of the majority of isolates of aerobic and anaerobic Gram-positive and Gram-negative bacteria, including methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (penicillin-susceptible and -resistant isolates), group A and B β-hemolytic streptococci, Listeria monocytogenes, Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis, but not P. aeruginosa and Stenotrophomonas maltophilia[1].

In experimental systemic infections in mice, Sulopenem has better protective effects than Imipenem/Cilastatin. Sulopenem has a lower ED50 in an experimental mixed infection of Escherichia coli and Bacteroides fragilis in mice. Sulopenem is more effective than CZON or Cefotiam in treating experimental lung infections caused by Klebsiella pneumoniae in guinea pigs[3].

Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the clinical use of sulopenem during lactation. Its secretion in breast milk is likely similar to that of imipenem and meropenem, with low concentrations expected to have no adverse effects on breastfed infants. Limited information suggests that even with daily administration of up to 2 grams of probenecid, low concentrations in breast milk are not expected to have any adverse effects on breastfed infants, especially those older than 2 months. There are reports that β-lactam antibiotics occasionally disrupt the infant's gut microbiota, leading to diarrhea or thrush, but these effects have not been adequately assessed. Sulopenem-probenecid can be used in breastfeeding women.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Safety Information
Prescription information includes warnings about hypersensitivity reactions, Clostridium difficile-associated diarrhea (CDAD), and the possibility of exacerbating gout in patients with a known history of gout. Orlynvah is contraindicated in patients with a history of hypersensitivity to Orlynvah components (sulpenem and probenecid) or other β-lactam antibiotics, patients with a known blood disorder, patients with a known uric acid kidney stone, and patients currently taking ketorolac tromethamine. The most common side effects of Orlynvah are diarrhea, nausea, vaginal yeast infection, headache, and vomiting.

[1].In Vitro Activity of Sulopenem, an Oral Penem, against Urinary Isolates of Escherichia coli. Antimicrob Agents Chemother. 2018;63(1):e01832-18.

[2].In vitro antibacterial activity and beta-lactamase stability of CP-70,429 a new penem antibiotic. Antimicrob Agents Chemother. 1993;37(7):1547-1551.

[3].In vitro and in vivo activities of sulopenem compared with those of imipenem and cephalosporins. Jpn J Antibiot. 1996;49(4):303-323.

Sulopenam is being studied in the clinical trial NCT03357614 (sulopenem followed by sulopenem-ezaloxazine/probenecid versus ertapenem followed by ciprofloxacin for the treatment of complicated urinary tract infections in adults). Sulopenam is an injectable thiopenem antibiotic with broad-spectrum antibacterial activity against most Gram-positive and Gram-negative bacteria. Sulopenam is ineffective against Pseudomonas aeruginosa. Furthermore, the drug is quite stable against the hydrolytic activity of various β-lactamases. Sulopenam is a penem antibiotic. It is marketed as a combination of the prodrug [sulopenem-ezaloxazine] and [probenecid]. Disease or condition: Uncomplicated urinary tract infection (UUTI) refers to a bacterial infection of the bladder in women without any structural abnormalities in the female urinary system. Approximately half of all women will experience at least one UUTI in their lifetime.
Efficacy
The efficacy of Orlynvah was evaluated in two phase 3 randomized, double-blind, controlled clinical trials (Trial 1 and Trial 2), both of which enrolled adult women with urinary tract infections (UTIs). Orlynvah is administered twice daily, one tablet each time, for 5 days.
Trial 1 (NCT05584657) was a non-inferiority trial in which 2214 adult women with UTIs were randomized to receive treatment. Orlynvah showed efficacy against amoxicillin/clavulanate-sensitive pathogens, with an overall response rate (combined microbiological and clinical remission) of 62%, compared to 55% in the amoxicillin/clavulanate group. Trial 2 (NCT03354598) was a non-inferiority trial in which 1660 adult women with urinary tract infections (uUTIs) were randomized to receive treatment. Orlynvah demonstrated efficacy in patients infected with ciprofloxacin-resistant pathogens, with an overall response rate of 48%, compared to 33% in the ciprofloxacin group. A total of 1932 patients were enrolled in the two trials to receive Orlynvah treatment. Clinical trials evaluating Orlynvah for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) did not confirm its efficacy. Safety Information: Prescribing information includes warnings regarding hypersensitivity reactions, Clostridium difficile-associated diarrhea (CDAD), and potential exacerbation of gout in patients with a known history of gout. Orlynvah is contraindicated in patients with a history of allergy to any component of Orlynvah (sulfapyridine ethamsylate and probenecid) or other β-lactam antibiotics, patients with a known blood disorder, patients with a known uric acid kidney stone, and patients currently taking ketorolac tromethamine. The most common side effects of Orlynvah include diarrhea, nausea, vaginal yeast infection, headache, and vomiting.

C12H14NNAO5S3

371.43

370.99318

C, 38.81; H, 3.80; N, 3.77; Na, 6.19; O, 21.54; S, 25.90

112294-81-2

120788-07-0

23701017

Typically exists as solid at room temperature

1

8

4

22

569

5

CC(C1C2N(C1=O)C(=C(S2)SC3CCS(=O)C3)C(=O)[O-])O.[Na+]

MRHMJKHFABHUKB-LQUSNCHHSA-M

InChI=1S/C12H15NO5S3.Na/c1-5(14)7-9(15)13-8(11(16)17)12(20-10(7)13)19-6-2-3-21(18)4-6;/h5-7,10,14H,2-4H2,1H3,(H,16,17);/q;+1/p-1/t5-,6+,7+,10-,21-;/m1./s1

sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(1R,3S)-1-oxothiolan-3-yl]sulfanyl-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Sulopenem sodium; CP-70429 sodium; W7SAA53IV0; Sulopenem (sodium); UNII-W7SAA53IV0;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Typically soluble in DMSO (e.g. 10 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)