In vitro synergism of rifampin-cephalosporin combinations againstHaemophilus influenzae type b

Abstract

The in vitro susceptibility of Haemophilus influenzae type b to rifampin, cefotaxime, ceftazidime, ceftriaxone and cefuroxime was examined at inocula of 10(5) and 10(7) CFU/ml. Time-kill curves were then obtained using antibiotic concentrations at one-half the MIC for each drug at the two inocula with combinations of rifampin plus each of the cephalosporins. There was a pronounced inoculum effect with all of the cephalosporins except for cefuroxime, but the MIC values were also higher for the latter drug. The rare failure of some cephalosporins to promptly sterilize the cerebrospinal fluid in meningitis should encourage investigation of the relationship between the inoculum effect, minimum bactericidal concentration and cerebrospinal fluid antibiotic levels in these clinical situations. A marked synergistic effect was noted for most of the isolates, and therefore, cephalosporin-rifampin combinations might show clinical utility.

Inoculum effect of β-lactam antibiotics

“…The inoculum effect of b-lactams against H. influenzae has been studied exclusively in the context of in vitro susceptibility testing or time-kill analyses. Substantial in vitro inoculum effects were noted for aminopenicillins [82][83][84][85][86][87] and cephalosporins, 81,84,86,[88][89][90][91] whereas carbapenems 87,92 and cefoxitin 88 were only evaluated in a few studies and did not demonstrate a substantial inoculum effect in vitro (Table 4). Two studies detected an in vitro inoculum effect for aminopenicillins against b-lactamase-producing strains of H. influenzae but did not observe an inoculum effect in b-lactamase-deficient strains.…”

“…83,85 In contrast, cephalosporins frequently demonstrated an inoculum effect regardless of b-lactamase production, with ceftriaxone, ceftazidime and cefaclor displaying a substantial inoculum effect in multiple studies. 81,84,86,88,89,91 In addition, b-lactamase-deficient strains of H. influenzae that were resistant to ampicillin mediated an in vitro inoculum effect during susceptibility testing of carbapenems, cephalosporins and aminopenicillins. 90,92 The authors attributed the ampicillin resistance and inoculum effects to mutations in the PBP3 enzyme that decrease the target affinities of cephalosporins and other b-lactams.…”