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New therapies for vancomycin-resistant Enterococcus faecium (VREF) infections are urgently needed. We describe the treatment of 15 patients with VREF infection with quinupristin/dalfopristin (RP 59500), a new injectable streptogramin antibiotic. Primary infections treated were bacteremia (4), urinary tract (4), intraabdominal (5), otitis externa (1), and meningitis (1). Minimum inhibitory concentrations for quinupristin/dalfopristin ranged from 0.5 microgram/ml or less to 2 micrograms/ml, and minimum bactericidal concentrations were greater than 64 micrograms/ml for all VREF isolates tested. Peak serum inhibitory titers following infusion of quinupristin/dalfopristin ranged from 1:8 to 1:64; all bactericidal titers were less than 1:2. Development of resistance to quinupristin/dalfopristin during therapy was not observed. The only drug-related adverse effect noted was phlebitis in 4 patients; all had received quinupristin/dalfopristin by peripheral venous infusion. Three patients had clinical and bacteriologic cures. Relapses occurred in 5 patients with recovery of VREF from infected sites in post-treatment cultures. Ten patients died of severe underlying disease; VREF was believed to contribute directly to the death of only 1 patient. While evaluation of clinical efficacy was complicated by the severity of underlying disease in patients with VREF infection, our experience suggests that quinupristin/dalfopristin is a safe and potentially useful agent for the treatment of VREF infections.

The minimum inhibitory concentrations of antibiotics for bacterial pathogens are derived from broth suspensions (broth dilution) and from nutrient surfaces (agar dilution). These concentrations may not apply when bacteria are on a nonnutrient surface such as in a foreign body infection. We compared bacteria (Staphylococcus epidermidis and Escherichia coli) broth suspension MBCs with MBCs of the same bacteria when on a nonnutrient surface in broth the growing and nongrowing phases. Bacteria growing on cotton surfaces were much less susceptible to antibiotic killing than when freely suspended in the liquid nutrient. These results alone, independent of host factors, would explain the failure of antibiotics to eradicate infections involving bacteria on foreign body surfaces. The resistance of bacteria to antibiotic killing is not caused by a lack of antibiotic penetration to the site of the bacteria, but by an altered state of the bacteria when they are associated with a surface.

Antibiotics may inhibit bacterial growth or may kill bacteria by inhibiting cell wall synthesis or protein synthesis. The amount of endotoxin released during antibiotic action has been found to be clinically important. Nine antibiotics, representing seven classes, were studied for the amounts of endotoxin released during their action on susceptible strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. Staphylococcus aureus, which produces no endotoxin, was used as a control organism. Aztreonam induced the highest release of endotoxin, whereas other antibiotics such as imipenem and the quinolones induced the lowest release of endotoxin. Although the quantities of endotoxin released are not easily explained from the established mechanisms of antibiotic action, our findings may have implications for therapy of the acutely ill, septic patient in whom release of large quantities of endotoxin may be catastrophic.

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 killing 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.

Most bacteria at an infection site obtain energy by the breakdown of glucose via microaerophilic or anaerobic pathways and in the process yield various end products. In this study, production of D-lactic acid by Staphylococcus aureus and Escherichia coli was correlated with glucose utilization by bacteria during exposure to antibiotics at subinhibitory, inhibitory, and suprainhibitory concentrations. D-Lactic acid production was further correlated with production of a tissue-destroying enzyme, hyaluronidase, by S. aureus. For E. coli, all agents tested showed dose-related bacterial killing, with the most noticeable being with ampicillin, piperacillin, and ciprofloxacin. Imipenem, ciprofloxacin, and chloramphenicol had the most dose-related effects on D-lactic acid production. With few exceptions, hyaluronidase production correlated well with D-lactic acid production in S. aureus. Subinhibitory concentrations of erythromycin and clindamycin effectively decreased accumulation of D-lactic acid and hyaluronidase. Determination of D-lactic acid production may perhaps serve as a means of independently monitoring the effects of antimicrobial agents on bacterial metabolic activity, which is an important aspect of antimicrobial action that remains relatively unexplored.

The effectiveness of antibiotic removal by the BACTEC aerobic resin-containing blood culture medium (16B) and the Antimicrobial Removal Device (ARD) was compared for 12 antibiotics: ampicillin, cephalothin, cefoperazone, cefotaxime, moxalactam, nafcillin, gentamicin, tobramycin, azlocillin, mezlocillin, piperacillin, and ticarcillin. The ability to recover eight commonly encountered species of bacteria from antibiotic-containing serum by these two systems showed that recovery of antibiotic-exposed bacteria was dependent not only upon the amount and rate of the antibiotic removal but also upon the kinetics of bacterial killing by the antibiotic(s). The 16B medium had difficulty recovering organisms exposed to ticarcillin and moxalactam, whereas the ARD had difficulties with moxalactam and sometimes with cefotaxime and cefoperazone. Although neither system was able to recover all species of microorganisms tested, these in vitro results suggest that to use optimally these new culture systems, knowledge of the suspected pathogen(s), the amount and kind of antibiotic(s) administered, and the rate of bacterial killing by the antibiotic(s) is required.

Aztreonam was administered as a single, 2-g intravenous dose to 25 patients with noninflamed meninges and to 9 patients with inflamed meninges. It was well tolerated and was detected in the cerebrospinal fluid at the initial sampling period at 1 h after the end of infusion. Aztreonam levels in the cerebrospinal fluid of patients with inflamed meninges were four times higher than those recorded for the same time period in patients with noninflamed meninges. Aztreonam concentrations in cerebrospinal fluid in the presence of normal and inflamed meninges exceeded the inhibitory and bactericidal concentrations for most gram-negative bacteria. Thus, a multiple-dose treatment regimen with 2-g intravenous doses every 6 h appears to be appropriate for clinical trials of aztreonam for the treatment of gram-negative bacillary meningitis which is caused by susceptible organisms.

Because of the emergence of drug-resistant Klebsiella strains in many hospitals, the distribution of the serotypes was reexamined to determine whether there was any correlation between the serotype and the site of isolation from the body, the antimicrobial susceptibility pattern, or the place of acquisition of the organism (hospital or community). One hundred consecutive isolates of Klebsiella pneumoniae from different patients were typed as 1, 2, 3, 4, 5, 6, or greater than 6. Of these, 8 of 28 strains isolated from respiratory secretions were serotype 2 (9 typable strains), 6 of 24 wound isolates were serotype 3 (8 typable strains), and the urine isolates varied in their serotypes. Regardless of serotype, most strains appeared mucoid on blood and MacConkey agars. Twenty-six percent of the isolates were resistant to at least one antimicrobial agent. No correlation was found between the serotypes and the antibiotic resistance; however, strains isolated within 25 days of admission to the hospital from the community were all susceptible. It appears that although there may be a correlation between the serotype and isolation from some sites of the body, knowledge of the serotype of the organism cannot predict the antimicrobial susceptibility pattern. The clinician's choice of antibiotic therapy should depend largely on whether the Klebsiella strain was acquired by the patient in the community (0% resistant) or in the hospital (31% resistant).

The degree of the inoculum effect shown by the new beta-lactam antibiotics with Pseudomonas aeruginosa was investigated, and the antibiotics 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, elongated 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 bactericidal, caused minimal formation of aberrant, elongated bacilli, and slowly decreased the turbidity of high inocula. The group 3 antibiotics (imipenem 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 antibactericidal 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.

Rifampicin resistance developed easily in methicillin-susceptible and methicillin-resistant strains of Staphylococcus aureus during an overnight incubation in broth containing 0.1 mg/l of rifampicin. Incubation of methicillin-susceptible Staph. aureus and 0.1 mg/l of rifampicin with 1 mg/l of nafcillin reduced the emergence of rifampicin resistance with only 5 of 50 strains (10%) becoming rifampicin-resistant. However, incubation of the methicillin-susceptible or methicillin-resistant strains with 0.1 mg/l of rifampicin and 1 mg/l of vancomycin did not prevent the development of rifampicin resistance. Rifampicin resistance developed in 25 of 50 (50%) of methicillin-susceptible and 32 of 50 (64%) methicillin-resistant Staph. aureus strains tested. These data would suggest that differences exist in the abilities of nafcillin and vancomycin to suppress the development of rifampicin resistance in Staph. aureus (P less than 0.01). Caution should be exercised when the combination of vancomycin and rifampicin is used for infections caused by Staph. aureus and Staph. aureus isolates recovered during therapy should be monitored for the development of rifampicin resistance.

Seven beta-lactam antibiotics were studied for both their antimicrobial activity and the degree to which they produced inoculum effect on Escherichia coli, Klebsiella pneumoniae, and Salmonella typhimurium. Aztreonam, cefoperazone, and ceftazidime were poorly bactericidal, caused marked bacterial filamentation, and exhibited a large inoculum effect on E. coli, K. pneumoniae, and S. typhimurium. Cefotaxime and ceftriaxone were more rapidly bactericidal, caused only a moderate amount of filamentous forms, and exhibited a modest inoculum effect, while cefoxitin and imipenem both were rapidly bactericidal and exhibited only a minimal-to-no-inoculum effect. The inoculum effect did not correlate with drug stability during incubation with the bacteria. Inoculum effect on these species of the family Enterobacteriaceae appears to be a manifestation of increase in optical density secondary to the development of filamentous bacterial forms with an increase in bacterial mass during exposure to antibiotics which are not rapidly bactericidal. These observations have a clear significance for the susceptibility testing of beta-lactam antibiotics when turbidity is used as a parameter to determine presence of bacterial growth.

Seven quinolone antibiotics were tested against 115 isolates of methicillin-resistant Staphylococcus aureus. The MICs for 90% of the strains tested were 0.5 microgram/ml for A-56619, A-56620, ciprofloxacin, and ofloxacin; 2.0 micrograms/ml for amifloxacin and enoxacin; and 4.0 micrograms/ml for norfloxacin. Killing kinetic studies showed a similar killing rate for all seven antibiotics.

Amdinocillin was studied alone and in combination with three other beta-lactam antibiotics (aztreonam, cefoperazone, and ceftriaxone) for activity against gram-negative bacilli. These antibiotic combinations failed to show synergy by the checker-board double-dilution test or by killing kinetic studies. However, amdinocillin did show additive killing action when combined with the other beta-lactam antibiotics studied. Amdinocillin failed to induce or inhibit beta-lactamase production in species of Enterobacteriaceae, but with Pseudomonas aeruginosa, beta-lactamase production was induced. It is concluded that the activity of amdinocillin alone or in combination with another beta-lactam antibiotic should not be more effective in the treatment of infections by gram-negative bacilli than just using the beta-lactam antibiotic alone at a higher dose.

The frequency with which resistant variants could be found in Pseudomonas aeruginosa ATCC 27853 during growth in media with and without antibiotics was determined for ticarcillin, piperacillin, cefotaxime, latamoxef, cefoperazone, ceftriaxone, ceftazidime, aztreonam and imipenem. The resistance frequency was highest for ceftriaxone, cefotaxime, cefoperazone and piperacillin (up to 2 X 10(-4)) and lowest for ticarcillin, latamoxef, ceftazidime, aztreonam and imipenem (less than 10(-8)). The resistant variants showed cross-resistance to all of the beta-lactam antibiotics tested with the exception of imipenem. The MIC profiles of all variants were similar regardless of which antibiotic the cultures had been exposed to previously. Although all resistant variants produced and excreted cephalosporinases, increased resistance was demonstrated to both cephalosporinase-susceptible and cephalosporinase-stable beta-lactam antibiotics.