Ampicillin resistance was first reported among clinical isolates of Haemophilus influenzae in 1972. Reports of chloramphenicol resistance followed shortly thereafter. The principal mechanism of resistance to these two antibiotics is enzymatic. Although other mechanisms have been described, they are found in comparatively few strains. The genetic information for the inactivating enzymes is plasmid mediated and therefore readily transmissible to susceptible strains. Consequently, effective therapy for invasive disease caused by this pathogen has been seriously compromised. As antibiotic susceptibility became less predictable, in vitro testing became increasingly important. Unfortunately, the standardization of methods for laboratory testing has been slow and complicated by the fastidious nature of the organisms. This review traces the development of antibiotic resistance in H. influenzae, discusses the mechanisms which appear to be important in mediating resistance, explores newer antimicrobial agents which might be useful in the treatment of infection, and analyzes the various approaches to in vitro testing.

We questioned whether the apparent rarity of ampicillin-resistant, non-4-lactamase-producing (NBLP) Haemophilus influenzae was due to failure of detection. We identified ampicillin-resistant and ampicillinsusceptible H. influenzae by the agar dilution technique, using 105-and 103-CFU inocula. We compared the disk susceptibility of 18 ampicihlin-resistant NBLP strains, 13 ampicillin-resistant, (8-lactamase-producing strains, and 10 ampicillin-susceptible strains by using standard 10-and 2-,ug ampicillin disks on two different media. We also investigated the possibility that disks containing 10 ,ug of clavulanic acid and 2 ,ug of ampicillin could be used to distinguish between the two ampicillin-resistant populations. Using the disk containing 2 ,ug of ampicillin, we correctly differentiated all the ampiciflin-resistant isolates from the ampicillin-susceptible isolates on both media (a zone diameter of s15 mm was considered resistant). In contrast, the 10-,ug ampiciflin disk failed to detect 44% (8 of 18) of the ampicillin-resistant NBLP strains (a zone diameter of sl9 mm was considered resistant). The MIC of ampicillin with the 103-CFU inoculum correlated better with zone diameters than with the 105-CFU inoculum. A difference in zone diameters of .8 mm between the disk containing 10 ,g of clavulanic acid and 2 ,ug of ampicillin and the disk containing only 2 ,ug of ampicillin correctly identified all j3-lactamase-producing strains. We conclude that the 2-,ug ampicillin disk tests more readily identify ampicillin resistance in H. influenzae than do the 10-,ug ampicillin disk tests. Future investigation should determine whether this in vitro resistance correlates with clinical treatment failures.Although the most common mechanism of ampicillin resistance (Amp) in Haemophilus influenzae is plasmidmediated production of TEM P-lactamase (4,7,17, 32,37), pathogenic Ampr type b H. influenzae lacking detectable P-lactamase activity has been reported (12,14,24,26).Clinical isolates with this phenotype appear to be even more common among nontypable respiratory tract H. influenzae (1,29,37). Nontypable H. influenzae has been increasingly implicated in community-acquired and nosocomial pneumonia in adults (3,9,19,20,22,40,41)

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