Mecillinam-Ampicillin Synergism in Experimental Enterobacteriaceae Meningitis

Abstract

The in vitro activities of mecillinam, a new f)-amidinopenicilhin, and ampicillin, alone and in combination, against an Escherichia coli strain and a Klebsiella pneumoniae strain were compared, and these results were correlated with their respective activities in vivo in experimental meningitis. The mecillinam-ampicillin combination was synergistic in vitro against both strains when tested by a modified checkerboard technique (bacteriostatic synergy). However when quantitative bactericidal synergy studies were made, the relative bactericidal rate of the combination was more rapid than that of either drug alone ("bactericidal synergy") against the Escherichia coli isolate only. In a rabbit model of Enterobacteriaceae meningitis, in vivo bactericidal activity correlated with results obtained in vitro. Both drugs were administered by continuous intravenous infusion for 8 h. Serum and cerebrospinal fluid antibiotic levels were similar to those achieved in humans. Cerebrospinal fluid bacterial concentrations (colonyforming units [CFU] per milliliter) were quantitatively titrated at 2-h intervals. Both drugs, alone or the combination, were ineffective against the K. pneumoniae strain in vivo (change in titer <1 log in 8 h). In contrast, the combination produced a markedly enhanced bactericidal effect against the E. coli strain (mean + standard deviation, decrease of log1o CFU per milliliter of 3.65 ± 1.02) compared with those of ampicillin alone (decrease of log1o CFU per milliter of 0.07 ± 0.8) and mecillinam alone (decrease of logio CFU per milliliter of 1.6 ± 0.05) (P < 0.001). When bactericidal synergism can be demonstrated for mecillinam-ampicillin in vitro in a case of gram-negative-bacillary meningitis this combination may be useful in the therapy of the illness.

Bactericidal versus Bacteriostatic Antibiotic Therapy of Experimental Pneumococcal Meningitis in Rabbits

“…The results strongly support the conclusion that when CSF antibiotic levels exceeded the MBC for the test strain, the results of therapy were significantly better by all parameters than the results achieved with regimens that did not attain CSF antibiotic concentrations above this level. The need for bactericidal antibiotics for optimal therapy of bacterial meningitis is suggested by several lines of evidence: (a) the disease represents an infection in an area of impaired host resistance (7-9, 13, 24), and may, like bacterial endocarditis and bacteremia in the neutropenic host (15,16), require bactericidal antibiotics for cure; and (b) most studies of experimental meningitis in animals suggest that CSF antibiotic concentrations must exceed the MBC of the test strain by severalfold to achieve rapid bacterial killing in vivo (17)(18)(19)(25)(26)(27)(28).…”

“…CSF aminoglycoside levels greatly exceeding the minimum bactericidal concentration (MBC) were necessary for effective reduction in bacterial titers in vivo in experimental meningitis induced by gram-negative bacilli (17), where chloramphenicol, a static agent, was without effect (18). In another study, a bactericidal, but not a bacteriostatic, combination regimen was effective in reducing numbers of viable bacteria in experimental Escherichia coli meningitis (19). Comparable information for pneumococcal meningitis in either animals or man is not available, and the requirement for bactericidal therapy in any form of meningitis remains unproven.…”

Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone.

“…After withdrawal of CSF (0.3 ml), the inoculum (0.25 ml) was introduced, the needle withdrawn, and the animal returned to its cage. All animals developed meningitis as manifested by fever (>39°C), lethargy, and a CSF pleocytosis with positive cultures, as shown (22)(23)(24)(25). These models result in a uniformly fatal infection within 2-5 d if untreated.…”

“…After insertion of the pressure screw and preparation of the inoculum, meningitis was induced in the rabbits as described (22)(23)(24)(25). The animal was again mildly anesthetized with 30Imig of sodium pentobarbital and positioned in the stereotaxic frame.…”

“…Overnight (16 h) growth in trypticase soy broth (Difco Laboratories, Detroit, Mich.) supplemented with 5% defibrinated sheep's blood at 37°C was centrifuged (1,000 rpm for 5 min to remove erythrocytes), recentrifuged (3,000 rpm for 15 min), washed in physiological saline twice, and resuspended in 2.0 ml of 0.9% NaCl. The E. coli clinical isolate (k,+) has also been characterized in this laboratory (25). A 10-4 dilution of an overnight growth in tripticase soy broth was centrifuged, washed, and resuspended as described above.…”