The Hemostatic Defect Produced by Carbenicillin

Brown, Clarence H.; Natelson, Ethan A.; Bradshaw, Wendi; Williams, Temple W.; Alfrey, Clarence P.

doi:10.1056/nejm197408082910601

Cited by 188 publications

(53 citation statements)

References 11 publications

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“…This is in close agreement with the observations of Ueo et al (14). Ninety percent of isolates were inhibited at a concentration of 50 ,ug/ml, a concentration readily achieved in human serum after intravenous administration of doses of 1 323,1977). Piperacillin also possessed bactericidal activity against a majority ofP.…”

Section: Discussionsupporting

confidence: 92%

In Vitro Activity of Piperacillin Compared with That of Carbenicillin, Ticarcillin, Ampicillin, Cephalothin, and Cefamandole Against Pseudomonas aeruginosa and Enterobacteriaceae

Shah

Briedis

Robson

et al. 1979

Antimicrob Agents Chemother

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Piperacillin (T-1220), a semisynthetic derivative of aminobenzylpenicillin, was more active than either carbenicillin or ticarcillin against Pseudomonas aeruginosa; over 60% of isolates were inhibited at a concentration of 6.3 ug/ml. Piperacillin was bactericidal for 84% of Pseudomonas strains at 100 ,ug/ml, carbenicillin killed 60%, and ticarcillin killed 68% at that concentration. Piperacilhin was also more active than the other penicillins against isolates of Escherichia coli, Enterobacter, and Proteus mirabilis. The combination of piperacillin and tobramycin, demonstrating synergistic inhibition of 87% of strains of P. aeruginosa, was the most active of the penicillin-aminoglycoside combinations tested for synergism.Piperacillin sodium (T-1220) is a new semisynthetic penicillin with a broad spectrum of activity against gram-negative bacteria. In recent studies, many isolates of Pseudomonas aeruginosa and members of the Enterobacteriaceae were noted to be more susceptible to piperacillin than to carbenicillin (6,14,15). In the current study, the in vitro activity of piperacillin was compared with that of carbenicillin and ticarcillin against P. aeruginosa, and with that of carbenicillin, ticarcillin, ampicillin, cephalothin, and cefamandole against various Enterobacteriaceae. In addition, we compared combinations of piperacillin or carbenicillin with gentamicin or tobramycin for synergistic activity against P. aeruginosa. MATERIALS AND METHODSBacterial isolates. Fifty isolates each of Escherichia coli, Klebsiellapneumoniae, Proteus mirabilis, and P. aeruginosa, 37 of Enterobacter spp., 28 indolepositive Proteus, 13 Providencia stuartii, and 5 Serratia marcescens constituted the 283 bacterial isolates obtained from the diagnostic microbiology laboratory of the Royal Victoria Hospital. The identity of all isolates was confirmed by standard methods (3, 9). Not more than one isolate of a given species per patient was included.Culture medium. Mueller-Hinton broth was supplemented with calcium chloride and magnesium chloride (12). The final calcium concentration was 5.4 to t Present address: Division of Virology, New Addenbrooke's Hospital, Cambridge, England.6.0 mg/dl, and the magnesium concentration was 2.2 to 2.5 mg/dl in the various batches used.Determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). A microtitration broth dilution technique similar to that described by Harwick et al. was employed (8). Stock solutions of piperacillin, carbenicillin, and ticarcillin were prepared in Mueller-Hinton broth at a concentration of 533 ,g/ml. After appropriate dilutions in Mueller-Hinton broth and addition of the bacterial inoculum, the antibiotic concentrations ranged from 400 to 0.8 ,ug/ml, in a final volume of 200 ,ul. For ampicillin, cephalothin, and cefamandole, stock solutions were prepared at a concentration of 266 ,ug/ml, yielding antibiotic concentrations of 200 to 0.4 'Ug/ml.

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Section: Discussionsupporting

confidence: 92%

In Vitro Activity of Piperacillin Compared with That of Carbenicillin, Ticarcillin, Ampicillin, Cephalothin, and Cefamandole Against Pseudomonas aeruginosa and Enterobacteriaceae

Shah

Briedis

Robson

et al. 1979

Antimicrob Agents Chemother

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“…Several studies (1,3,6,7,10) have indicated that patients receiving carbenicillin may exhibit a bleeding disorder. Most, but not all, of those patients had renal insufficiency and exceedingly high serum levels of carbenicillin.…”

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confidence: 99%

Study of the Effects of Ticarcillin on Blood Coagulation and Platelet Function

Brown

Natelson

Bradshaw

et al. 1975

Antimicrob Agents Chemother

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Ticarcillin is a new semisynthetic penicillin similar to carbenicillin. Since carbenicillin has been shown to inhibit platelet function to such an extent that bleeding may accompany its use, an investigation of the effects of ticarcillin on hemostasis was made. The drug was administered to 17 human volunteers for periods of 3 to 10 days in intravenous doses of 100, 200, or 300 mg/kg per day (7 to 21 g/day). Serial studies of blood coagulation and platelet function indicated that coagulation was unaffected by ticarcillin but that platelet function became defective in all subjects. Abnormal platelet function was evidenced by lengthening of bleeding time (17 of 17 volunteers), depressed adenosine diphosphate-induced platelet aggregation (17 of 17), defective collagen-induced aggregation (15 of 17), and abnormal epinephrine-induced aggregation (10 of 17). Prothrombin consumption, due to reduced platelet procoagulant activity, was significantly decreased with a dose of 300 mg/kg per day. Comparison of results from this study with those from an earlier carbenicillin study revealed that ticarcillin at 300 mg/kg per day produces the same defects in hemostasis as does carbenicillin at 300 mg/kg per day, but that lower doses (100 or 200 mg/kg per day) of ticarcillin result in only a mild defect in platelet function. If the effective dose of ticarcillin is proven to be lower than the doses of carbenicillin currently employed for treatment of certain gram-negative infections, bleeding should not be a frequent complication of ticarcillin administration, when the drug is given to patients with normal renal function.

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“…First, these antibiotics inhibit platelets immediately in vitro, whereas they appear to prolong the bleeding time only after 12-24 h of parenteral administration (2)(3)(4). Second, the peak serum concentration of either antibiotic achieved when high doses are given to man (1 mM) is several-fold lower than that necessary to inhibit platelet aggregation and secretion in vitro (Figs.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…These drugs presumably do so by impairing platelet function because they prolong the bleeding time of human volunteers (3,4). Moreover, platelets from individuals taking these antibiotics aggregate poorly in response to several aggregating agents (3,4) and they agglutinate poorly in response to ristocetin (2). Platelets incubated with carbenicillin or penicillin G in vitro also respond poorly to a variety ofplatelet agonists, although larger concentrations of antibiotic are required to demonstrate this effect (5).…”

Section: Introductionmentioning

confidence: 99%

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