Synergy Between Cephalosporin and Aminoglycoside Antibiotics Against Providencia and Proteus

Abstract

Clinical isolates of Providencia and Proteus with relative aminoglycoside resistance were tested for susceptibility to combinations of gentamicin or tobramycin with cephalothin or cefazolin. The minimal bactericidal concentration of aminoglycoside for one-third of the strains was reduced by fourfold or more in the presence of one-fourth of the minimal bactericidal concentration of either cephalosporin. This effect was achieved by clinically attainable concentrations of cephalothin or cefazolin.Although Providencia has been an uncommon cause of clinical infections, recent epidemics have been described in hospitalized patients, particularly in burn units (5,14,15). We have noted a gradually increasing incidence of clinical isolates of Providencia in our hospital, although serious infections have remained rare. In vitro studies on these strains have indicated relative resistance to all aminoglycoside antibiotics. Most strains have required minimal inhibitory and bactericidal concentrations of 12.5 to 50 gg of gentamicin per ml. A synergistic effect of penicillins or cephalosporins with aminoglycosides has previously been demonstrated against Enterobacteriaceae (3, 4, 10) and Pseudomonas (6,12,17). We have therefore studied nine strains of Providencia and seven strains of the related genus, Proteus, which were moderately or highly resistant to gentamicin. Our purpose was to evaluate two cephalosporins, cephalothin and cefazolin, in crossover combination with two aminoglycosides, gentamicin and tobramycin, for possible in vitro synergy against these organisms.MATERIALS AND METHODS Providencia and Proteus strains were collected from the clinical microbiology laboratory on the basis of gentamicin resistance by routine disk sensitivity testing. Tube dilution assays were done in MuellerHinton broth as previously described (9). Grid studies were performed so that double dilutions of cephalothin, and cefazolin were combined with double dilutions of gentamicin or tobramycin. This resulted in duplicate minimal inhibitory and bactericidal concentration values for each drug against each strain. Of the 144 such duplications, four differed by two tube dilutions and the remainder differed by one dilution or less. Synergy was defined as a fourfold decline in minimal inhibitory concentrations (MIC) or minimal bactericidal concentration (MBC) of gentamicin or tobramycin after the addition of one-fourth of the MIC or MBC of a cephalosporin antibiotic to each tube. RESULTSThe MIC and MBC values of each drug against the nine strains of Providencia and seven strains of Proteus tested are shown in Fig. 1

Synergy of Mecillinam, a Beta-Amidinopenicillanic Acid Derivative, Combined with Beta-Lactam Antibiotics

“…This approach has been used with 13-lactam antibiotics such as ampicillin and cloxacillin (16,19). A third approach is that of combining carbenicillin and amino-glycosides to effect killing of Pseudomonas (3,20) or combining cephalosporins with aminoglycosides to react against indole-positive Proteus (5). The mechanism used to explain this synergy is the increased entry of the aminoglycoside to reach its receptor site.…”

<i>In vitro</i> Sensitivity of <i>Proteus</i> Organisms to Gentamicin and Sisomicin

“…Synergism of sisomicin with ticarcillin against Proteus is similar to that seen in the responses of carbenicillin and gentamicin, amikacin, sisomicin or tobramycin against Pseudomonas [12,13], cephalosporins and aminoglycoside antibiotics against Proteus and Providencia [9], ticarcillin and gentami cin against Pseudomonas [15,26] and clin damycin and gentamicin against E. coli [16].…”