Beta-Lactamase Stability of HR 756, a Novel Cephalosporin, Compared to That of Cefuroxime and Cefoxitin

Fu, Kwung P.; Neu, Harold C.

doi:10.1128/aac.14.3.322

Cited by 122 publications

(58 citation statements)

References 14 publications

(11 reference statements)

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“…(2-4). The activity is partially related to 8i-lactamase stability because, as we have already shown, the compound is not destroyed by gram-negative fl-lactamases (5).…”

Section: Materlals and Methodsmentioning

confidence: 96%

“…These latter organisms often have been resistant both to older cephalosporins and even to the new ones. Recently a cephalosporin, HR 756, 7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoximino)acetamido] cephalosporanic acid, has been reported to be active against Pseudomonas (5,6). We have shown that this agent is resistant to ,8-lactamases (5) and so have undertaken an extensive evaluation of this agent to compare its activity to other fi-lactam compounds, both penicillins and cephalosporins.…”

mentioning

confidence: 99%

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HR 756, a New Cephalosporin Active Against Gram-Positive and Gram-Negative Aerobic and Anaerobic Bacteria

Neu

Aswapokee

et al. 1979

Antimicrob Agents Chemother

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152

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The in vitro activity of HR 756, 7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoximino)acetamido] cephalosporanic acid, was investigated against 659 isolates. HR 756 inhibited Neisseria and Haemophilus species at concentrations similar to those needed with ampicillin. It inhibited β-lactamase-producing N. gonorrhoeae and H. influenzae . HR 756 was the most active compound tested against members of the Enterobacteriaceae , inhibiting most isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, Enterobacter , and Shigella at concentrations of less than 0.1 μg/ml. It was twice as active as carbenicillin against Pseudomonas aeruginosa and inhibited Bacteroides fragilis as well as cefoxitin. HR 756 killed E. coli, Staphylococcus aureus , and P. aeruginosa at rates similar to other β-lactam antibiotics.

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“…(2-4). The activity is partially related to 8i-lactamase stability because, as we have already shown, the compound is not destroyed by gram-negative fl-lactamases (5).…”

Section: Materlals and Methodsmentioning

confidence: 96%

mentioning

confidence: 99%

HR 756, a New Cephalosporin Active Against Gram-Positive and Gram-Negative Aerobic and Anaerobic Bacteria

Neu

Aswapokee

et al. 1979

Antimicrob Agents Chemother

Self Cite

152

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“…HR 756 is one of this group of newer cephalosporin antibiotics resistant to some beta-lactamases produced by gram-negative bacilli (7,8). Although beta-lactamases are not the only factors involved in resistance to cephalosporin antibiotics (12), one would ordinarily expect that beta-lactamase-resistant drugs would exhibit more antibacterial activity than antibiotics which were sensitive to these enzymes.…”

Section: Resultsmentioning

confidence: 99%

“…The 28 strains of Enterobacter included representatives of the following species: E. cloacae, 9; E. aerogenes, 7; E. hafniae, 4; E. agglomerans, 3; and unidentified as to species, 5. The 25 indole-positive Proteus isolates included 8 strains of P. morganii, 7 strains of P. rettgeri, and 10 Susceptibility testing. Agar dilution and broth dilution minimum inhibitory concentrations (MICs) were determined using Mueller-Hinton agar and broth (MHA, MHB; Difco Laboratories, Detroit, Mich.) and nutrient agar (NA) and broth (Difco) according to previously described methods (3,13).…”

Section: Methodsmentioning

confidence: 99%

“…This parenteral drug is a representative of a newer group of cephalosporin antibiotics which shows relative resistance to beta-lactamases of gram-negative bacilli. This group includes cefoxitin, cefamandole (CFM), cefuroxime, and ceforanide (CFN) (7)(8)(9)(10)(11)13). Due in part to this resistance, the newer cephalosporins may demonstrate activity against certain bacteria such as Enterobacter species, Seratia, and indole-positive Proteus strains, the majority of which are ordinarily resistant to other cephalosporin antibiotics.…”

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confidence: 99%

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Antibacterial Activity of a New Parenteral Cephalosporin—HR 756: Comparison with Cefamandole and Ceforanide

Counts

Turck

1979

Antimicrob Agents Chemother

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HR 756, a new parenteral cephalosporin that is beta-lactamase resistant, was tested against 271 bacterial isolates. Both agar and broth dilution testing were employed, using two media and two inoculum sizes of bacteria. Antibacterial activity of the drug was compared to that of cefamandole (CFM) and ceforanide (CFN) HR 756 is a new semisynthetic methoxyimino derivative of 7-amino-cephalosporanic acid (2). This parenteral drug is a representative of a newer group of cephalosporin antibiotics which shows relative resistance to beta-lactamases of gram-negative bacilli. This group includes cefoxitin, cefamandole (CFM), cefuroxime, and ceforanide (CFN) (7)(8)(9)(10)(11)13). Due in part to this resistance, the newer cephalosporins may demonstrate activity against certain bacteria such as Enterobacter species, Seratia, and indole-positive Proteus strains, the majority of which are ordinarily resistant to other cephalosporin antibiotics.The purpose of this study was to compare the in vitro antibacterial activity of HR 756 to that of ceforanide and cefamandole. Susceptibility testing. Agar dilution and broth dilution minimum inhibitory concentrations (MICs) were determined using Mueller-Hinton agar and broth (MHA, MHB; Difco Laboratories, Detroit, Mich.) and nutrient agar (NA) and broth (Difco) according to previously described methods (3, 13). Inoculum sizes of 104 and 106 colony-forming units were used. Minimum bactericidal concentrations (MBCs) were obtained with these two broth media. Agar dilution testing employed a Steers replicating device (15). Criteria for endpoints for MIC and MBC values were as previously described (3). A laboratory reference strain of Escherichia coli inhibited by 0.125 ,ug of HR 756, 0.5 jg of CFN, and 0.5 jg of CFM, respectively, per ml was used as a control organism in all experiments. MATERIALS AND METHODS RESULTSAgar dilution. Table 1 shows the range of agar dilution MICs found using MHA as well as the minimum drug concentration to inhibit 50 and 90% of tested isolates. There was no consistent difference in the results for various species of Enterobacter or indole-positive Proteus, and the results for each genera are presented in on April 27, 2019 by guest http://aac.asm.org/ Downloaded from

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β‐Lactamase Inhibitors

Stam

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The antibacterial effectiveness of penicillins, cephalosporins, and other β‐lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β‐lactam antibiotics often produce enzymes called β‐lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β‐lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β‐lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β‐lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β‐lactamases to inhibit clinically are the gram‐positive penases, the gram‐negative TEM, which are Richmond‐Sykes type III, and the gram‐negative chromosomal cephalosporinases–cephases which are Richmond‐Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β‐lactamases are serine proteases that form an acyl enzyme intermediate with β‐lactam substrates and β‐lactam‐derived β‐lactamase inhibitors. A number of β‐lactamase‐resistant penicillins and cephalosporins were found to be β‐lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β‐lactamases, including penases and Richmond‐Sykes types II, III, IV, V, VI ( Bacteroides ). Carbapenems are another class of natural product β‐lactamase inhibitors. Many penem β‐lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2( S )‐ cis )‐3,3‐dimethyl‐7‐oxo‐4,4‐dioxide‐4‐thia‐1‐azabicyclo [3.2.0]heptane‐2‐carboxylic acid (sulbactam) ( , ), C 8 H 11 NO 5 S, is a weak antibacterial, but is a potent irreversible inactivator of many β‐lactamases, including penases and Richmond‐Sykes type II, III, IV, V, and VI ( Bacteroides ) β‐lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β‐lactamase inhibitors. Among penam β‐lactamase inhibitors, of 6‐β‐bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β‐lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C 15 H 16 N 2 O 6 S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β‐lactam antibiotic as Betamaze.

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Beta-Lactamase Stability of HR 756, a Novel Cephalosporin, Compared to That of Cefuroxime and Cefoxitin

Cited by 122 publications

References 14 publications

HR 756, a New Cephalosporin Active Against Gram-Positive and Gram-Negative Aerobic and Anaerobic Bacteria

HR 756, a New Cephalosporin Active Against Gram-Positive and Gram-Negative Aerobic and Anaerobic Bacteria

Antibacterial Activity of a New Parenteral Cephalosporin—HR 756: Comparison with Cefamandole and Ceforanide

β‐Lactamase Inhibitors

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