Synthesis and antimicrobial spectrum of FCE 22101 and its orally available ester FCE 22891

Franceschi, Giovanni; Perrone, Ettore; Alpegiani, Marco; Bedeschi, Angelo; Battistini, Carlo; Zarini, Franco; Bruna, C. Della

doi:10.1093/jac/23.suppl_c.1

Cited by 15 publications

(9 citation statements)

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“…FCE 22101 is reported to differ from other penems in that it does not have any potency against pseudomonads [Barry et al, 1989;Franceschi et al, 1989;Neu et al, 1985]. Our results were consistent with earlier findings in this regard.…”

Section: Discussionsupporting

confidence: 92%

“…It is a sodium salt of (5R,6S) carbamoyloxymethyl-6-[(R) -1 -hydroxyethyl]penem -3 -carboxylic acid, which is currently being considered as a possible orally or parenterally admin istered agent [Franceschi et al, 1989], It is characterized by good stability to beta lac tamases and broad spectrum activity against both aerobic, facultative, and an aerobic bacteria [Barry et al, 1989;Dornbusch et al, 1989;Maskell et al, 1989;Wise and Ballard, 1989].…”

Section: Discussionmentioning

confidence: 99%

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Antibacterial Activity of FCE 22101 against Relatively Resistant Blood Culture Isolates

Qadri¹,

Ueno²,

Ellis³

1991

Chemotherapy

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In vitro antibacterial activity of the new penem FCE 22101 was tested against blood culture isolates from 1,374 consecutive patients in a major tertiary care referral center in Saudi Arabia. Many of the isolates were significantly more resistant to commonly used beta lactams. Of the 809 members of Enterobacteriaceae tested all but 14 isolates of Enterobacter were susceptible to FCE 22101 with an MIC range of 0.12–8.0 μg/ml. It inhibited all the 183 isolates of Staphylococcus aureus, both methicillin-sensitive and methicillin-resistant. Ninety percent of coagulase-negative staphylococci and enterococci were susceptible to this new penem. All isolates of Acinetobacter, CDC group VE-2 and Brucella melitensis from blood were inhibited by FCE 22101. However, it was ineffective against pseudomonads. Of the nine other beta lactam drugs tested for comparison, only imipenem was found to be more inhibitory, at lower MIC values, than FCE 22101.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Antibacterial Activity of FCE 22101 against Relatively Resistant Blood Culture Isolates

Qadri¹,

Ueno²,

Ellis³

1991

Chemotherapy

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“…SCH 29482 is orally absorbed to produce a peak concentration of about 13 jig/ml following a 500-mg dose (9, 13j, but the extent of absorption cannot be estimated in the absence of parenteral data. When given as the acetoxymethyl ester FCE 22891, the absorption of FCE 22101 is approximately 30% (5,16).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, a renal dipeptidase inhibitor is coadministered with imipenem, the first member of this group of antimicrobial agents to be used commercially (14). Some penems are orally absorbed either as the parent molecule (9, 13) or after incorporation into a prodrug (5,16). Given the potent antibacterial activity of penems and carbapenems, research continues in an effort to find new agents with potential clinical utility (10, 12).…”

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confidence: 99%

Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

Foulds

Knirsch

Lazar

et al. 1991

Antimicrob Agents Chemother

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CP-65,207 is a new broad-spectrum penem antimicrobial agent that is a 1:1 mixture of two stereoisomers. Five minutes after a 10-min intravenous infusion of 1 g of CP-65,207 to volunteers, mean concentrations in serum were 33 ,ug of the R isomer per ml and 29 tig of the S isomer per ml. Following rapid distribution, half-lives of the isomers were 53 and 55 min, respectively. Concentrations in urine exceeded 800 ,ug of each isomer per ml. Recovery of the S isomer in urine (46%) was much greater than recovery of the R isomer (26%). The serum kinetics of the S isomer (volume of distribution, 319 ml/kg; total clearance, 315 ml/min; elimination rate constant, 0.80 h-1) were similar when it was given alone and when it was contained in 207, demonstrating that the presence of the R isomer has little effect on the serum kinetics of the S isomer. However, when the S isomer was given alone, the urinary recovery of intact S isomer (36%) was substantially lower than that when it was given with the R isomer as 207 (57%). Administration of the S isomer alone did not produce the unpleasant sulfurous odor in urine that was observed following administration of 207. Oral doses of a prodrug, which contained 1 g of CP-65,207, produced peak concentrations in serum of 1.6 ,ug of the R isomer per ml and 1.8 ,ug of the S isomer per ml. Approximately 36% of the S-isomer component was absorbed, and 20% of this isomer was recovered in urine. A 1-g oral dose of the prodrug of the single S isomer provides concentrations in serum above 1.0 ,ig/ml (the MIC for 90% of over 1,000 hospital pathogens) for 3.5 h, suggesting that the drug given orally will prove to be efficacious against many infections.Carbapenem and penem antimicrobial agents are betalactams that usually demonstrate a broad spectrum of activity and a high potency in vitro. However, penems and carbapenems also are susceptible to hydrolysis by the renal dehydrodipeptidase found in the brush border cells of animal and human kidneys (9,11,14). Thus, a renal dipeptidase inhibitor is coadministered with imipenem, the first member of this group of antimicrobial agents to be used commercially (14). Some penems are orally absorbed either as the parent molecule (9, 13) or after incorporation into a prodrug (5,16). Given the potent antibacterial activity of penems and carbapenems, research continues in an effort to find new agents with potential clinical utility (10, 12).CP-65,207 (2) is a potent broad-spectrum antibacterial agent with activity comparable to that of imipenem, with the exception that it has significantly lower activity against Pseudomonas aeruginosa (8). The MIC for 90% of over 1,000 hospital pathogens was approximately 1.0 jig/ml (8).CP-65,207 is a mixture of a more polar R isomer (CP-65,207-R) and a less polar S isomer (CP-65,207-S; also called 429) in approximately a 1:1 ratio (Fig. 1). While the isomers have very similar antibacterial activities, in vitro studies and animal experiments indicate that the S isomer is more resistant to hydrolysis by the renal dipetidase e...

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“…1) is a prodrug of FCE 22101, a penem antibiotic with a broad spectrum of activity against gramppsitive and -negative bacteria, and is stable to most bacterial 13-lactamases (4,14). While FCE 22101 must be administered parenterally, FCE 22891 is absorbed from the gastrointestinal tract.…”

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confidence: 99%

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers

Efthymiopoulos¹,

Benedetti²,

Sassella³

et al. 1992

Antimicrob Agents Chemother

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respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0o (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.FCE 22891 (Fig.

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Synthesis and antimicrobial spectrum of FCE 22101 and its orally available ester FCE 22891

Cited by 15 publications

References 0 publications

Antibacterial Activity of FCE 22101 against Relatively Resistant Blood Culture Isolates

Antibacterial Activity of FCE 22101 against Relatively Resistant Blood Culture Isolates

Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers

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