Penems: <i>In Vitro</i> and <i>In Vivo</i> Experiments

Zak, O.; Lang, Marc; Cozens, Robert; Kónopka, E. A.; Mett, Helmut; Schneider, Peter; Tosch, W.; Scartazzini, Riccardo

doi:10.1002/j.1552-4604.1988.tb05736.x

“…Penems are synthetic beta-lactams that, as a class, possess a number of interesting properties which include a broad antibacterial spectrum and low susceptibility to hydrolysis by ,B-lactamases but, at the same time, are inactivated by renal dipeptidases found in the brush border of the kidney (20). A number of novel penems have been evaluated in the past decade; SCH-29482 and SCH-34343 (2, 10, 11) have rivaled carbapenems like imipenem in antibacterial activity, yet in clinical trials they were found to have undesirable side effects.…”

mentioning

confidence: 99%

“…The broad antibacterial spectrum of penems, however, has encouraged continued research in order to find clinically useful compounds. Two of these penems, FCE-22101 and SUN-5555, are in clinical trials (20). 207 ( Fig.…”

mentioning

confidence: 99%

In vitro activity of CP-65,207, a new penem antimicrobial agent, in comparison with those of other agents

Gootz

¹

,

Retsema

²

,

Girard

³

et al. 1989

Antimicrob Agents Chemother

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CP-65,207 is a new parenteral penem antibiotic with a broad spectrum that includes gram-positive, gram-negative, and anaerobic microorganisms, with MICs for 90% (MIC90s) of the majority of 1,101 clinical pathogens tested being '1 ,ig/ml. The compound was from 10-to 100-fold more active than cefoxitin and broad-spectrum cephalosporins against gram-positive bacteria and anaerobes. CP-65,207 was less active than imipenem for staphylococci, group A streptococci, and Enterococcus faecalis. Against members of the family Enterobacteriaceae, CP-65,207 was in general 100-fold more active than cefoxitin, 5-to 10-fold more active than broad-spectrum cephalosporins, and 2-fold more active than imipenem. Fresh clinical isolates that were resistant to broad-spectrum cephalosporins were highly susceptible to 207 and imipenem (MIC90,1 ,ug/ml). Isolates of Enterococcusfaecalis, Serratia marcescens, and anaerobic Peptococcus spp. had MIC9,s of 8, 2, and 3.12 ,ug/mI, respectively. CP-65,207 was not very active against methicillin-resistant staphylococci or Pseudomonas aeruginosa. Killing kinetics showed that against some strains CP-65,207 is rapidly bactericidal at concentrations well below those required to achieve a similar degree of killing with cefotaxime, ceftazidime, and ceftriaxone. CP-65,207 was only slightly susceptible to hydrolysis by type I cephalosporinases and TEM-1, SHV-1, and PSE-2 plasmid-encoded enzymes. It had the highest affinity for penicillin-binding proteins 2, 1A, 1B, and 3 in cell-free preparations of Escherichia coli W-7.Penems are synthetic beta-lactams that, as a class, possess a number of interesting properties which include a broad antibacterial spectrum and low susceptibility to hydrolysis by ,B-lactamases but, at the same time, are inactivated by renal dipeptidases found in the brush border of the kidney (20). A number of novel penems have been evaluated in the past decade; SCH-29482 and SCH-34343 (2, 10, 11) have rivaled carbapenems like imipenem in antibacterial activity, yet in clinical trials they were found to have undesirable side effects. The broad antibacterial spectrum of penems, however, has encouraged continued research in order to find clinically useful compounds. Two of these penems, FCE-22101 and SUN-5555, are in clinical trials (20). 207 ( Fig. 1) is a new parenteral penem that demonstrates high activity against gram-positive, gram-negative, and anaerobic bacteria that in some itistances is significantly imtproved over cefoxitin and the broad-spectrum cephalosporins. The current study characterizes the in vitro activity of CP-65,207 compared with those of both cephalosporins and imipenem.( Susceptibility studies. Antibiotic susceptibility studies were performed in microdilution trays containing 0.2 ml of unsupplemented Mueller-Hinton broth (MHB) per well with twofold dilutions of antibiotic (3). Inocula were grown overnight in MHB and diluted in broth to give a final inoculum of approximately 7.5 x 105 CFU/ml. Inoculated plates were incubated at 37°C in air for 18 h.

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“…Penems are totally synthetic beta-lactams, while the carbapenems were derived from fermentation products, with thienamycin being the first member of the group identified (86,151,182). Unlike carbapenems, the penems discovered to date lack activity against P. aeruginosa.…”

Section: Discovery Of Penicillin Gmentioning

confidence: 99%

“…Several penem compounds have undergone clinical trials, but none has had the wide spectrum of imipenem. For reasons relating to unacceptable side effects, the remaining penems evaluated so far have not progressed to the marketplace (119,122,128,182). One of the drawbacks of carbapenems and penems is their unique susceptibility to degradation by eucaryotic renal dehydropeptidase I found in the brush borders of the kidney (86).…”

Section: Discovery Of Penicillin Gmentioning

confidence: 99%

“…SCH-29482, FCE-22891, and SUN-5555 have shown relatively good oral absorption in humans (74,168,182). This characteristic could result in a dual mode of dosing for these agents: an intravenous formulation for treating serious infections in the hospital and a less expensive oral formulation to be used as follow-up therapy once clinical improvement has occurred.…”

Section: Discovery Of Penicillin Gmentioning

confidence: 99%

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Discovery and development of new antimicrobial agents

Gootz

¹

1990

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The unprecedented growth in the number of new antibiotics over the past two decades has been the result of extensive research efforts that have exploited the growing body of knowledge describing the interactions of antibiotics with their targets in bacterial cells. Information gained from one class of antimicrobial agents has often been used to advance the development of other classes. In the case of beta-lactams, information on structure-activity relationships gleaned from penicillins and cephalosporins was rapidly applied to the cephamycins, monobactams, penems, and carbapenems in order to discover broad-spectrum agents with markedly improved potency. These efforts have led to the introduction of many new antibiotics that demonstrate outstanding clinical efficacy and improved pharmacokinetics in humans. The current review discusses those factors that have influenced the rapid proliferation of new antimicrobial agents, including the discovery of new lead structures from natural products and the impact of bacterial resistance development in the clinical setting. The development process for a new antibiotic is discussed in detail, from the stage of early safety testing in animals through phase I, II, and III clinical trials.

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Carbapenems and Penems

Southgate

¹

,

Osborne

²

2000

Kirk-Othmer Encyclopedia of Chemical Technology

2

0

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In the period up to 1970 most β‐lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono‐ and bicyclic β‐lactam structures have been described. The carbapenems originated from natural sources; the penem ring and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are: 7‐oxo‐( R )‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 7 H 7 NO 3 , and 7‐oxo‐( R )‐4‐thia‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 6 H 5 NO 3 S, respectively. Carbapenems include thienamycin (C 11 H 16 N 2 O 4 S), MM 4550 (C 13 H 16 N 2 O 9 S 2 ), MM 13902 (C 13 H 16 N 2 O 8 S 2 ), MM 17880 (C 13 H 18 N 2 O 2 S 2 ), PS‐5 (C 13 H 18 N 2 O 4 S), carpetimycin A (C 14 H 18 N 2 O 6 S), asparenomycin A (C 14 H 16 N 2 O 6 S), and pluracidomycin A (C 9 H 11 NO 10 S 2 ). Only S. cattleya and S. penemfaciens have been reported to give thienamycin. Thienamycin is isolated as a colorless, hygroscopic, zwitterionic solid. Carbapenems are extremely sensitive to many reaction conditions. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure–activity relationships. One consequence of the discovery of the carbapenem natural products has been the development of new synthetic methods. Only chemical synthesis could provide the quantities of N ‐formimidoyl thienamycin (MK 0787) necessary for clinical trials and commercial production. A synthetic approach that involves the [3,4] bond formation using a carbene insertion reaction has been highly successful. A second method makes use of the lactone from acetone dicarboxylate. Thienamycin, the olivanic acids, and the majority of carbapenems are highly active broad‐spectrum antibiotics. Of the natural products, thienamycin is the most potent. Unlike carbapenems, no penems have been found in nature. The penem acid was shown to possess antibacterial activity in spite of its rather limited stability. Penems include SCH 29482 (C 10 H 13 NO 4 S 2 ), SCH 34343 (C 11 H 14 N 2 O 6 S 2 ), FCE 221201 (C 10 H 12 N 2 O 6 S), and others. 6‐Unsubstituted penems exhibit good activity against both gram‐positive and gram‐negative bacteria. Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem–cilastatin combination has become a commercial product. Meropenem was expected to be the second carbapenem on the market.

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Penems: In Vitro and In Vivo Experiments

Cited by 13 publications

References 16 publications

In vitro activity of CP-65,207, a new penem antimicrobial agent, in comparison with those of other agents

In vitro activity of CP-65,207, a new penem antimicrobial agent, in comparison with those of other agents

Discovery and development of new antimicrobial agents

Carbapenems and Penems

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