Hypoprothrombinemia in Febrile, Neutropenic Patients with Cancer: Association with Antimicrobial Suppression of Intestinal Microflora

Abstract

Serial, twice-weekly prothrombin times were determined in 108 febrile, granulocytopenic patients with cancer who were prospectively randomized to receive empiric antimicrobial therapy with moxalactam plus ticarcillin (M/T) or tobramycin plus ticarcillin (T/T). Thirty of 54 patients given M/T and 13 of 54 patients given T/T developed prothrombin times that were greater than or equal to 2 sec beyond control values (P less than .001) after a mean of 6.5 days of antimicrobial therapy. Serious bleeding episodes were more frequent in the group given M/T than in that given T/T (10 and two patients, respectively; P less than or equal to .05). Serial quantitative stool cultures revealed that both Escherichia coli and Bacteroides species were suppressed by greater than or equal to 5 log10 in eight of nine patients given M/T and in three of nine given T/T (P less than .05, Fisher's exact test). A significant reduction of the population of E. coli and Bacteroides fragilis, organisms that are major producers of bacterially synthesized menaquinones, was associated with a high incidence of hypoprothrombinemia. These observations support the hypothesis that menaquinones may play an important physiological role in the maintenance of blood coagulation during episodic dietary deficiency of phylloquinone.

Coagulopathy associated with extended-spectrum cephalosporins in patients with serious infections

“…Others have proposed a direct inhibition of fibrin formation by ,-lactam antibiotics through the inhibition of the final steps of blood coagulation (6,14). Conly and colleagues have recently proposed that the broad antimicrobial spectrum of the newer cephalosporins eliminates the menaquinone-producing bacteria in the intestinal lumen, thereby facilitating the development of vitamin K deficiency and hypoprothrombinemia in hosts already so predisposed because of pre-existing malnutrition and general debilitation (3,22).…”

Double-blind, prospective, multicenter trial comparing ceftazidime with moxalactam in the treatment of serious gram-negative infections

“…The search for a regimen which would be successful yet nontoxic has yielded several cephalosporins. When introduced, moxalactam appeared to be effective in this niche; however, it is not active against many strains of P. aeruginosa and is associated with prolongation of PT in some patients (2,4,12,15).…”

“…This double-blind, controlled trial suggests that ceftazidime is associated with a much lower incidence of prolonged PT than moxalactam. The potential for moxalactam to cause prolongation of PT has been the subject of much discussion in the recent medical literature (2,4,12,15). This adverse effect of moxalactam may be a result of the combination of the deficient dietary intake and the administration of a broad-spectrum antibiotic to severely ill individuals with resultant marked suppression of anaerobic and aerobic bacteria in the gut.…”

“…This adverse effect of moxalactam may be a result of the combination of the deficient dietary intake and the administration of a broad-spectrum antibiotic to severely ill individuals with resultant marked suppression of anaerobic and aerobic bacteria in the gut. Bowel flora such as E. coli, Bacteroides species, and some gram-positive anaerobic bacilli produce menaquinones that may be a source of vitamin K in patients who are deprived of exogenous dietary vitamin K. Therefore a combination of above factors can result in hypothrombinemia with its attendant risk of bleeding (4,15). b One patient each with obtundation, lethargy, and sleepiness which began 2 to 9 days after entry.…”

“…Ceftazidime is a promising cephalosporin with excellent in vitro activity against many such strains (3,16). Furthermore, therapy with ceftazidime has not been associated with bleeding and prolongation of prothrombin time (PT), as has occurred with moxalactam (2,4,12,15).…”