 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C22H20N8O5S4 |
| Molecular Weight | 604.70 |
| Exact Mass | 604.044 |
| CAS # | 189345-04-8 |
| PubChem CID | 9938701 |
| Appearance | White to yellow solid powder |
| LogP | 0.67 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 14 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 39 |
| Complexity | 1040 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | CCO/N=C(/C1=NSC(=N1)N)\C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)SC4=NC(=CS4)C5=CC=[N+](C=C5)C)C(=O)[O-] |
| InChi Key | RGFBRLNVZCCMSV-BIRGHMBHSA-N |
| InChi Code | InChI=1S/C22H20N8O5S4/c1-3-35-27-13(16-26-21(23)39-28-16)17(31)25-14-18(32)30-15(20(33)34)12(9-36-19(14)30)38-22-24-11(8-37-22)10-4-6-29(2)7-5-10/h4-8,14,19H,3,9H2,1-2H3,(H3-,23,25,26,28,31,33,34)/b27-13-/t14-,19-/m1/s1 |
| Chemical Name | (6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl]amino]-3-[[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate |
| Synonyms | T-91825; PPI-0903M; T91825; PPI0903M; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | β-lactam; bacterial cell wall synthesis |
| ln Vitro | PPI-0903M works well against S. MRSA (MIC50=1 μg/mL) and other aureus infections (MIC50=0.25 μg/mL) [1]. When it comes to heteromycin intermediate S, PPI-0903M works well. MIC50s for aureus are 0.25–4 μg/mL[1]. |
| ln Vivo | AK-599 (20 mg/kg; sc three times daily for two days) decreased lung bacterial cell counts by more than 99.9% in a rat model of pneumonia caused by MRSA [2]. |
| Enzyme Assay | T-91825 was active against both gram-positive and gram-negative bacteria, unlike vancomycin and linezolid, which are inactive against gram-negative bacteria. The 90% minimum inhibitory concentration of T-91825 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) was 2 micro g/ml. This activity was comparable to those of vancomycin, linezolid, teicoplanin, and arbekacin. T-91825 was similarly active against vancomycin-intermediate S. aureus. In a time-kill study, T-91825 showed more rapid and distinct decrease of viable cells of two MRSA strains than did vancomycin and linezolid in vitro. [2] |
| Cell Assay |
The in vitro activities of PPI-0903M in comparison to those of selected antimicrobial agents against gram-positive pathogens are summarized in Table 1. Among all cephalosporins tested, PPI-0903M shows the greatest activity against gram-positive organisms, including resistant isolates. PPI-0903M was very active against S. aureus, including methicillin-resistant (MRSA) strains. PPI-0903M was 8- to >16-fold more potent than cefepime and 16- to >32-fold more active than ceftriaxone against MRSA strains. PPI-0903M was also active against hetero-vancomycin-intermediate S. aureus (100 strains), with MIC results ranging from 0.25 to 4 μg/ml (MIC at which 50% of strains were inhibited [MIC50], 1 μg/ml; MIC at which 90% of strains were inhibited [MIC90], 2 μg/ml). Furthermore, 91 and 93% of these isolates were resistant to cefepime and ceftriaxone, respectively. Against 11 quinupristin-dalfopristin-non-susceptible strains, PPI-0903M MIC results were similar in activity to that described for MRSA (MIC50 and MIC90, 1 μg/ml).
[1] PPI-0903M was slightly more potent against coagulase-negative staphylococci (CoNS) than against S. aureus. Against methicillin-resistant CoNS (80 strains), the PPI-0903M MIC50 and MIC90 results were 0.25 and 0.5 μg/ml, respectively. PPI-0903M (MICs, ≤0.016 to 2 μg/ml) was also active against CoNS (51 strains) having reduced susceptibility to vancomycin (hVIS; MIC, 4 μg/ml). Those hVIS strains were resistant to other β-lactam antibiotics, including imipenem. PPI-0903M was also active against 15 tested quinupristin-dalfopristin-nonsusceptible strains (MIC90, 1 μg/ml). Although all methicillin-resistant staphylococci should be considered resistant to all β-lactams by the CLSI/NCCLS interpretive criteria (3, 12), the activities of PPI-0903M against these staphylococci would imply potential clinical utility against MRSA depending upon the dosing and pharmacokinetics of the molecule. The susceptibility rates of these isolates to PPI-0903M awaits breakpoint determination by regulatory and consensus organizations. [1] As with other β-lactams, PPI-0903M in vitro activity against S. pneumoniae (178 strains; Table 1) varied according to penicillin susceptibility. Penicillin-resistant strains (50 strains; MIC90, 0.25 μg/ml) showed the most elevated PPI-0903M MICs (0.06 to 0.5 μg/ml), but they remained low, and PPI-0903M potency was generally eightfold greater than that of either ceftriaxone or cefepime. Resistance to levofloxacin did not affect PPI-0903M in vitro activity, and multidrug-resistant strains (resistant to six drugs; see Table 1) were all inhibited by PPI-0903M at ≤0.5 μg/ml. [1] PPI-0903M was also very potent against β-hemolytic streptococci, with the vast majority of strains inhibited at ≤0.016 μg/ml. The highest PPI-0903M MIC among the β-hemolytic streptococci was only 0.03 μg/ml (two group F strains). Levofloxacin-resistant β-hemolytic streptococci were also very susceptible to PPI-0903M (MIC90, ≤0.016 μg/ml). Viridans group streptococci susceptibility to PPI-0903M fluctuated according to the penicillin susceptibility, and resistance to levofloxacin did not adversely influence the PPI-0903M in vitro activity against this pathogen. When quinupristin-dalfopristin-nonsusceptible streptococcal strains were tested, PPI-0903M MIC results varied widely from ≤0.016 μg/ml (two S. bovis strains and one S. mitis strain) to 8 μg/ml (two S. mitis strains). [1] PPI-0903M showed limited activity against both vancomycin-susceptible and -resistant Enterococcus faecium. In addition, vancomycin-resistant E. faecalis isolates (MIC50, 4 μg/ml) had slightly higher PPI-0903M MICs than vancomycin-susceptible E. faecalis strains (MIC50, 2 μg/ml). [1] PPI-0903M activity was also evaluated against a combined collection of linezolid-resistant staphylococcal and streptococcal strains, which included seven S. aureus strains (PPI-0903M MICs, 1 to 4 μg/ml), two CoNS strains (PPI-0903M MICs, 0.5 μg/ml), and one Streptococcus oralis strain (PPI-0903M MIC, ≤0.016 μg/ml). These PPI-0903M MIC ranges were consistent with those of linezolid-susceptible staphylococci (data not shown). Despite the small number of isolates tested, it is concluded that PPI-0903M retained an activity against linezolid-resistant gram-positive organisms, excluding enterococci. [1] PPI-0903M was the most active cephalosporin tested against Bacillus spp. (Table 1), with MIC results ranging from 0.06 to 32 μg/ml (MIC50, 4 μg/ml, and MIC90, 8 μg/ml). Imipenem (MIC90, 4 μg/ml), levofloxacin (MIC90, 0.25 μg/ml), and vancomycin (MIC90, 1 μg/ml) also showed reasonable activity against this pathogen. [1] The spectrum of activity of PPI-0903M against gram-negative bacteria is similar to those of the expanded-spectrum cephalosporins. Among the Enterobacteriaceae (221 strains) (Table 2), the vast majority of Citrobacter freundii (MIC90, 2 μg/ml), non-extended-spectrum-β-lactamase (ESBL)-producing E. coli (MIC90, 0.12 μg/ml) or Klebsiella pneumoniae (MIC90, 0.5 μg/ml), Morganella morganii (MIC90, 0.12 μg/ml), Proteus mirabilis (MIC90, 0.12 μg/ml), and Serratia marcescens (MIC90, 2 μg/ml) were inhibited at ≤2 μg/ml of PPI-0903M. However, as with other expanded-spectrum cephalosporins, PPI-0903M MIC results were observed to be elevated for some Enterobacter cloacae (MIC90, 32 μg/ml), Proteus vulgaris/Providencia spp. (MIC90, >32 μg/ml), and ESBL-producing strains regardless of species. [1] PPI-0903M was highly active against H. influenzae, and its in vitro activity was not affected by β-lactamase production (MIC90 of ≤0.016 μg/ml) (Table 2). In comparison, β-lactamase ampicillin-resistant strains showed PPI-0903M MIC results that were only slightly elevated (MIC90, 0.03 μg/ml). Moraxella catarrhalis and Neisseria meningitidis strains also showed low MICs for PPI-0903M (MIC90 of 0.12 μg/ml and ≤0.016 μg/ml, respectively) and most of the comparison antimicrobial agents. [1] In general, PPI-0903M showed in vitro activity most similar to that of ceftriaxone and less than that of cefepime or ceftazidime against a diverse group of nonfermentative gram-negative bacilli (60 strains; Table 2). Against anaerobes, PPI-0903M had excellent activity against some gram-positive organisms and marginal activity against Clostridium difficile (MIC50, 2 μg/ml, and MIC90, 4 μg/ml). Bacteroides fragilis and Prevotella spp. showed higher PPI-0903M MIC results (MIC90, >32 μg/ml) (Table 3). |
| Animal Protocol | The effect of TAK-599 against systemic infection caused by clinical isolates of MRSA in mice was comparable or superior to that of vancomycin, linezolid, teicoplanin, and arbekacin. In addition, TAK-599 at a dose of 20 mg/kg significantly decreased bacterial counts in lungs of mice in an experimental pneumonia model caused by MRSA in which vancomycin and linezolid were totally ineffective at the same dose. These results suggest the usefulness of TAK-599 in the treatment of MRSA infections in humans.[2] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Although no information is available on the use of ceftaroline during breastfeeding, cephalosporins are generally not expected to cause adverse effects in breastfed infants. Occasionally disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush have been reported with cephalosporins, but these effects have not been adequately evaluated. Ceftaroline is acceptable in nursing mothers. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
| References |
[1]. Sader HS, et, al. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob Agents Chemother. 2005 Aug;49(8):3501-12. [2]. Iizawa Y, et, al. In vitro antimicrobial activity of T-91825, a novel anti-MRSA cephalosporin, and in vivo anti-MRSA activity of its prodrug, TAK-599. J Infect Chemother. 2004 Jun;10(3):146-56. |
| Additional Infomation |
Ceftaroline is a cephalosporin that is the active metabolite of the prodrug ceftaroline fosamil. Used for the treatment of adults with acute bacterial skin and skin structure infections. It has a role as an antibacterial drug, an antimicrobial agent and a drug metabolite. It is a member of 1,3-thiazoles, a cephalosporin, an iminium betaine, an oxime O-ether and a member of thiadiazoles. Ceftaroline is a Cephalosporin Antibacterial. A fifth-generation cephalosporin antibacterial agent that is used to treat skin infections caused by bacteria in adults and newborns. Ceftaroline has a 1,3-thiazolidine ring attached to the C-7 position of its cephalosporin core. See also: Ceftaroline Fosamil (active moiety of). PPI-0903M is a novel N-phosphono-type cephalosporin active against oxacillin-resistant staphylococci and many other gram-positive organisms. This study evaluated the in vitro activity and spectrum of PPI-0903M against 1,478 recent clinical isolates collected from 80 medical centers (22 countries). PPI-0903M demonstrated broader in vitro activity against gram-positive bacteria, particularly against multidrug-resistant staphylococci and streptococci of current clinical concern, than currently available extended-spectrum cephalosporins while maintaining similar activity against gram-negative pathogens.[1] Our study showed that PPI-0903M was very active against many clinically important bacterial pathogens, especially streptococci (β-hemolytic, viridans group, and pneumococci), staphylococci (S. aureus and CoNS), H. influenzae, and M. catarrhalis. In vitro activity of PPI-0903M against these pathogens was similar to or more potent than those of other described anti-MRSA cephalosporins. Moreover, PPI-0903M exhibited activity against several multidrug-resistant gram-positive pathogens that may cause both community-acquired and nosocomial infections, including MRSA and penicillin-resistant S. pneumoniae. While possessing enhanced activity against resistant gram-positive cocci, PPI-0903M retains in vitro activity against common gram-negative pathogens. This spectrum of activity distinguishes it from currently available β-lactams and suggests that PPI-0903 has potential for use in the treatment of bacterial infections in the hospital environment. The prodrug, PPI-0903, is current under the phase I clinical evaluation and has the potential to be a unique addition to the well-established, safe cephalosporin class.[1] |
Solubility Data
| Solubility (In Vitro) | DMSO : 100 mg/mL (165.37 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.13 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6537 mL | 8.2686 mL | 16.5371 mL | |
| 5 mM | 0.3307 mL | 1.6537 mL | 3.3074 mL | |
| 10 mM | 0.1654 mL | 0.8269 mL | 1.6537 mL |