Antimicrobial agents are most often tested against bacteria in the log phase of multiplication to produce the maximum bactericidal effect. In an infection, bacteria may multiply less optimally. We examined the effects of several classes of antimicrobial agents to determine their actions on gram-positive and gram-negative bacteria during nongrowing and slowly growing phases. Only ciprofloxacin and ofloxacin exhibited bactericidal activity against nongrowing gram-negative bacteria, and no antibiotics were bactericidal (3-order-of-magnitude killing) against Staphylococcus aureus. For the very slowly growing gram-negative bacteria studied, gentamicin (an aminoglycoside), imipenem (a carbapenem), meropenem (a carbapenem), ciprofloxacin (a fluoroquinolone), and ofloxacin (a fluoroquinolone) exhibited up to 5.7 orders of magnitude more killing than piperacillin or cefotaxime. This is in contrast to optimally growing bacteria, in which a wide variety of antibiotic classes produced 99.9% killing. For the gram-positive and gram-negative bacteria we examined, antibiotic king was greatly dependent on the growth rate. The clinical implications of slow killing by chemotherapeutic agents for established bacterial infections and infections involving foreign bodies are unknown.

Treating the acute medical problems (mostly infectious diseases) in poor, undereducated, and often noncompliant intravenous drug users is far more complex than previously described. Although some features have remained constant, the emergence of human immunodeficiency virus infection and changes in patterns of drug use have radically altered patient management.

Ceftazidime-resistant KkebsieUla pneumoniae strains began to appear when ceftazidime usage was increased in two unrelated Chicago hospitals. These strains produced a P-lactamase with an isoelectric point of 5.6 (RP-5.6) and strong hydrolyzing activity against ceftazidime. Two different restriction digest profiles were associated with the ceftazidime resistance plasmids. A second P-lactamase with a pl of 5.2 (RP-5.2) was coproduced in two representative strains. The second ,-lactamase hydrolyzed ceftazidime, cefotaxime, and aztreonam with relative hydrolysis rates of <8% of that observed for benzylpenicillin. Both enzymes were inhibited by clavulanic acid and tazobactam. Nucleotide sequencing of the genes coding for RP-5.2 and RP-5.6 revealed sequences identical to those of the TEM-12 and TEM-10 I8-lactamase genes, respectively. Both genes were derived from a TEM-1 sequence related to that of the gene encoded on the Tn2 transposon. Single point mutations are required to progress from TEM-1 to TEM-12 and from TEM-12 to TEM-10. Extracts from broths grown from single cell isolates of the strain producing TEM-12 and TEM-10 were shown to contain both enzymes. Transconjugants producing either the TEM-12 or the TEM-10 j-lactamase were obtained. A significant finding was that both enzymes were encoded by plasmids with identical restriction digest patterns.These studies show that mutations leading to extended-spectrum ,-lactamases can occur sequentially in the same organism, with the genes encoding both enzymes maintained stably.

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The degree of the inoculum effect shown by the new beta-lactam antibiotics with Pseudomonas aeruginosa was investigated, and the aptibiotics were divided into three groups based upon the observations. The group 1 antibiotics (cefotaxime, moxalactam, cefoperazone, azlocillin, piperacillin, and aztreonam) demonstrated a large inoculum effect, were poorly bactericidal, produced aberrant, plongated bacilli, and did not inhibit the increase in turbidity of high inocula during an 18-h incubation. The group 2 antibiotics (ceftazidime and ticarcillin) were slowly bactericid&ll, caused minimal formation of aberrant, elongated bacillij, and slowly decreased the turbidity of high inocula. The group 3 antibiotics (imipepem and gentamicin) were bactericidal, did not cause the formation of elongated bacilli, and decreased the turbidity of high inocula rapidly. Data are presented which suggest that the inoculum effect seen with the group 1 beta-lactam antibiotics is related to (i) the poor intrinsic axitibacteriCidal activity of these antibiotics for P. aeruginosa at the inocula tested and (ii) failure of these antibiotics to inhibit the formation of aberrant and filamentous bacilli, which can result in increased bacterial mass and turbidity.The phenomenon of inoculum effect is described as the significant increase seen in the MIC of an antibiotic when the inoculum size used in the testing is increased. The importance of such a phenomenon was first stressed by Luria in 1946 (11). The inoculum effect has been studied most extensively in staphylococci, in which antibiotic destruction by beta-lactamase was largely responsible for this phenomenon (3,17). The inoculurp effect has recently attracted widespread interest tdue in part to the recent proliferation of new beta-lactam antibiotics which demonstrate a variety of degrees of the inoculumn effect (4, 6, 7, 17;

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