PC-904, a Novel Broad-Spectrum Semisynthetic Penicillin with Marked Antipseudomonal Activity: Microbiological Evaluation

The in vitro activities of cefpiramide and apalcillin were compared with those of other third-generation cephalosporins and extended-spectrum penicillins against over 1,000 clinical bacterial isolates. The activity of cefpiramide against Pseudomonas aeruginosa was comparable to those of piperacillin and cefoperazone, inhibiting 90% of strains at concentrations sl6.0 ,ug/ml. This drug was also active against a broad range of gram-negative organisms but was generally less active than many of the other cephalosporins tested against members of the family Enterobacteriaceae. The activity of cefpiramide against gram-positive organisms was comparable to that of cefoperazone. Apalcillin, along with ceftazidime, was the most active agent tested against P. aeruginosa and Acinetobacter calcoaceticus subsp. anitratus, inhibiting 90% of these strains at concentrations <8 ,Lg/ml. Against other gram-negative and gram-positive organisms, its activity was similar to that of piperacillin. The activities of both cefpiramide and apalcillin were significantly reduced by the presence of several plasmid-mediated j-lactamases in a series of otherwise isogenic strains of P. aeruginosa in comparison with their activities against a parent strain which lacks these enzymes. Many strains of Enterobacter cloacae were synergistically inhibited by the combination of gentamicin with either cefpiramide (5 of 10 strains) or apalcillin (6 of 10 strains). Most strains of P. aeruginosa were synergistically inhibited by the combination of gentamicin with either cefpiramide (8 of 10 strains) or apalcillin (10 of 10 strains). However, cefoxitin antagonized the activity of both cefpiramide and apalcillin against most of these same strains.Cefpiramide (SM-1652, WY-44,635) is a new semisynthetic cephalosporin that is structurally related to cefoperazone. A number of recent studies have documented its broad spectrum of activity against both gram-negative and gram-positive organisms. Compared with other cephalosporins, it is particularly active against Pseudomonas aeruginosa (6,8,14). In addition, cefpiramide has a half-life of approximately 4.5 h in humans, which is significantly longer than those of other third-generation cephalosporins, such as ceftazidime and cefoperazone, but shorter than that of ceftriaxone (10).Apalcillin (PC-904) is a naphthyridine derivative of ampicillin. Its spectrum of activity is similar to that of piperacillin, although it exhibits greater activity against P. aeruginosa than does piperacillin (1,5,12,13). Apalcillin also differs from piperacillin in having a slightly longer half-life and in being largely eliminated by hepatobiliary mechanisms (9).In the present study, we examined the in vitro activity of both cefpiramide and apalcillin against more than 1,000 routine clinical isolates of gram-positive and gram-negative bacteria as well as organisms selected for resistance to multiple antibiotics. The activity of these two agents was also tested in combination with other P-lactams and gentamicin.

Section: Discussionsupporting

confidence: 82%

“…Its spectrum of activity is similar to that of piperacillin, although it exhibits greater activity against P. aeruginosa than does piperacillin (1,5,12,13). Apalcillin also differs from piperacillin in having a slightly longer half-life and in being largely eliminated by hepatobiliary mechanisms (9).…”

mentioning

confidence: 96%

Comparative in vitro activities of cefpiramide and apalcillin individually and in combination

Allan¹,

Eliopoulos²,

Ferraro³

et al. 1985

“…It has a broad spectrum of antibacterial activity, including activity against Pseudomonas aeruginosa (1,(4)(5)(6)(7)(8). The present report compares apalcillin with piperacillin and carbenicillin against all bacterial isolates that were selected for antimicrobial susceptibility testing in four separate institutions over a 45-to 60-day period.…”

mentioning

confidence: 99%

In vitro activity of apalcillin compared with those of piperacillin and carbenicillin against 6,797 bacterial isolates from four separate medical centers

Barry¹,

Jones²,

Ayers³

et al. 1984

Quantitative susceptibility tests were performed in four separate medical centers, in which apalcillin was compared with piperacillin and carbenicillin. Data from tests of 6,797 isolates confirmed that apalcillin and piperacillin had nearly identical spectra of activity but that apalcillin was significantly more active against Pseudomonas aeruginosa (MIC required to inhibit 90% of strains, 2.0 versus 64 micrograms/ml) and Acinetobacter calcoaceticus subsp. anitratus (MIC required to inhibit 90% of strains, 2.0 versus 16 micrograms/ml). Against 166 anaerobic bacterial isolates, apalcillin demonstrated in vitro activity.

“…PC-904, sodium 6-[D(-)-a-(hydroxy-1,5-naphthyridine -3 -carboxamido)phenylacetamido]-penicillanate, is a new antipseudomonal penicillin with a broad and potent antibacterial spectrum against gram-negative bacteria, including Pseudomonas species (8,9).…”

mentioning

confidence: 99%

New Antipseudomonal Penicillin, PC-904: Affinity to Penicillin-Binding Proteins and Inhibition of the Enzyme Cross-Linking Peptidoglycan

Noguchi¹,

Matsuhashi

Takaoka³

et al. 1978

The mechanism of action of a new antipseudomonal penicillin, PC-904, was studied with respect to its binding affinities to penicillin-binding proteins (PBPs) and its inhibitory activities on cross-linking enzymes of peptidoglycan synthesis in vitro. PC-904 showed especially high affinity (compared with that of penicillin G) to Escherichia coli PBP-3. It also had high affinities to PBP-2 and -1Bs and low affinities to PBP-1A, -4, -5, and -6. Similar results were obtained with Pseudomonas aeruginosa , in which this antibiotic showed very high affinity (compared with that of penicillin G) to PBP-3, -1A (presumably corresponding to E. coli PBP-1Bs), and -2; there was especially high affinity to PBP-3 and much less affinity to PBP-1B (presumably corresponding to E. coli PBP-1A). These results are compatible with morphological observations that at concentrations near its minimal inhibitory concentration or less, this antibiotic induced the formation of filamentous cells of E. coli and P. aeruginosa . At higher concentrations or after prolonged incubation, it induced lysis of the cells. The remarkably high affinity of PC-904 to pseudomonal PBP-3, -1A, and -2 may partly explain the potent antipseudomonal activity of this antibiotic. In E. coli , the concentration of PC-904 required to inhibit the cross-linking reaction in enzymatic peptidoglycan synthesis, presumably carried out by PBP-1Bs, was as low as the inhibitory concentrations of penicillin G, ampicillin, and carbenicillin.