Amikacin therapy for serious gram-negative bacillary infections.

Amikacin is a new aminoglycoside antibiotic pharmacologically similar to kanamycin. It has a wide range of activity against Gram-negative bacilli, including many resistant to gentamicin. Thirty-six serious Gram-negative bacillary infections were treated with amikacin. Twenty-nine patients (80-6%) responded (cured or improved). Twelve of 13 patients with gentamicin-resistant pathogens responded. Minor ototoxicity occurred in 6 patients and was associated with prolonged therapy or previous aminoglycoside therapy. Possible nephrotoxicity with amikacin was found in 6 patients. Amikacin should be used primarily to treat suspected or known gentamicin-resistant pathogens.     

Treatment of serious gram-negative infections with aztreonam

Aztreonam (SQ 26,776) is the first parenteral monobactam agent to be used in patient trials. The agent has significant activity in vitro against facultative aerobic gram-negative bacteria but not against gram-positive or anaerobic bacteria. Aztreonam was used for a year to treat 106 hospitalized patients with a total of 131 documented gram-negative infections. Important exclusion criteria included granulocytopenia, hyperbilirubinemia, meningitis, patients less than 13 years of age, pregnancy, and history of anaphylaxis to penicillin. In this study of 35 men and 71 women, there were 67 cases of pyelonephritis (25% bacteremic), 19 of pneumonia (16% bacteremic), 10 of skin or soft-tissue infections, 9 cases of osteomyelitis, and 6 cases of postpartum endometritis. During the study period, 159 facultative aerobic gram-negative bacteria were tested for aztreonam susceptibility, and 144 (91%) were found to be susceptible. Eighty percent of infections were cured by both clinical and microbiological criteria and each of the other 26 infections showed clinical improvement. Eradication of the infecting organism was achieved in 89% of infections without adverse reaction or drug toxicity.     

New treatment options for infections caused by multiresistant strains of Pseudomonas aeruginosa and other nonfermenting gram-negative bacilli

Hospital-acquired infections are one of the most important challenges to patient safety, especially in critical care units. The use of broad-spectrum antibiotics results frequently in multidrug-resistant pathogens. Therefore, we are attending to increased rates of multidrug-resistant microorganisms, especially gram-negative bacilli, that have been associated with prolonged hospital stays, higher costs, and increased mortality. The most important multidrug-resistant pathogens are PSEUDOMONAS AERUGINOSA and ACINETOBACTER BAUMANNII. There has been an important but as yet unsuccessful effort to develop new drugs to treat these pathogens. Nevertheless, old, very well known drugs, such as polymyxins, administered intravenously and aerosolized, have been revisited. Future options include immunotherapy or the continuous infusion of antibiotics. It is also important to emphasize the rational use of antibiotics to diminish the appearance of multiresistant pathogens.     

Use of aztreonam in the treatment of serious infections due to multiresistant gram-negative organisms, including Pseudomonas aeruginosa

Aztreonam is a novel antimicrobial agent belonging to the monobactam class of antibiotics. It inhibits both beta-lactamase-producing and non-beta-lactamase-producing aerobic gram-negative bacilli, but it has no activity against gram-positive species or against anaerobic species. The efficacy of aztreonam in the treatment of infection in 76 patients and its safety in 87 patients was evaluated. The majority (91 percent) of patients had significant underlying disease, and 47 percent were critically ill. Aztreonam produced an overall clinical response of 86 percent, with 10 of 11 cases of bacteremia cured, including four due to Pseudomonas aeruginosa, seven of eight cases of pneumonia, and seven of nine episodes of osteomyelitis. Infections due to bacteria resistant to ampicillin, carbenicillin, cefazolin, cefamandole, cefoxitin, and gentamicin were cured. Although 15 of 18 patients with exacerbations of pulmonary infection due to P. aeruginosa showed clinical improvement, bacteriologic cure was not achieved, as has been noted with other drugs. Similarly, patients with major underlying structural abnormalities of the urinary tract showed early relapses of bacteriuria. Aztreonam combined with antistaphylococcal, antistreptococcal, or antianaerobic agents provided an alternative to aminoglycoside use in these non-neutropenic patients. Administration of 1 or 2 g every eight hours yield serum bactericidal levels well in excess of 1:8 against all Enterobacteriaceae and some P. aeruginosa strains. There was a low incidence of adverse side effects, none serious. Overall, aztreonam is a useful alternative to the drugs available for use in hospital-acquired gram-negative infections and provides a chance for more directed therapy.     

Emergence of beta-lactam multiresistant variants of gram-negative bacilli in the presence of cefotaxime

88 clinical isolates of gram-negative bacilli (23 Enterobacter, 23 Klebsiella, 21 E. coli, and 21 Pseudomonas) all showed susceptibility to one or more cephalosporins and were nitrocefin test negative. When cultured overnight in the presence of 1, 10, or 100 mg/l of cefotaxime, 19 Enterobacter strains grew beta-lactamase-producing variants, 15 of them at concentrations less than or equal to 10 mg/l of cefotaxime. All enzyme-producing variants showed resistance to a number of cephalosporins including non-hydrolyzable cephalosporins and other beta-lactam antibiotics, except mecillinam and thienamycin. With the other gram-negative bacilli resistant mutants did not emerge in the presence of cefotaxime. These findings are discussed in relation to use of third generation cephalosporins as first hand monotherapy in patients.     

Nosocomial bloodstream infections caused by gentamicin-resistant gram-negative bacilli

Gentamicin resistance has emerged since 1971 among gram-negative bacilli isolated at the University of Virginia Hospital. Of 9,169 gram-negative bacilli isolated in 1971, 0.8 per cent were resistant to gentamicin by disc sensitivity testing. Of 7,817 isolates in 1975, 7.7 per cent were resistant. Approximately 20 per cent of the Klebsiellae had a minimum inhibitory concentration (MIC) ≥ 16 μg/ml of gentamicin.     

Amikacin treatment of pulmonary infections involving gentamicin-resistant gram-negative bacilli

Twelve patients with pulmonary infections presumably involving gentamicin-resistant gram-negative bacilli were evaluated for their response to amikacin therapy. All patients had hospital-acquired infections for which they had been previously treated and were considered therapeutic failures with gentamicin or tobramycin. Assessment of response to amikacin therapy showed objective evidence of clinical improvement in 11. The gentamicin-resistant organism was eradicated in nine patients although, in the majority, other gram-negative bacilli persisted in respiratory tract secretions both during and after treatment. There was one clinical failure.     

A comparative study of ticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram-negative bacilli.

The combination of ticarcillin plus tobramycin (TT) or carbenicillin plus gentamicin (CG) was used to treat 82 patients with severe systemic gram-negative infection in a prospective, randomized study. Pseudomonas aeruginosa was the primary pathogen in 7 (93 per cent) of these patients. Patients treated with TT responded more frequently (92 per cent or 37 of 40) than patients treated with CG (71 per cent or 30 of 42) (p is less than 0.05). This difference was primarily due to a greater response to TT in patients with pulmonary infections (93 per cent versus 68 per cent) and infections due to Pseudomonas (92 per cent versus 70 per cent). Severity of underlying disease was also an important determinant of response. Except for a greater incidence of hepatotoxicity with CG (23 per cent versus 3 per cent; p is less than 0.02), there was no difference in toxicity, colonization with drug-resistant microorganisms or superinfection between the two treatment groups. The combination of TT appears to be superior to CG for the treatment of pulmonary infections due to Pseudomonas aeruginosa.     

Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline.

Eighteen patients received tigecycline as treatment for infection due to multidrug-resistant gram-negative bacilli, including Acinetobacter baumannii and Klebsiella pneumoniae carbapenemase- and extended-spectrum beta-lactamase-producing Enterobacteriaceae. Pretherapy minimum inhibitory concentration values for tigecycline predicted clinical success. Observed evolution of resistance during therapy raises concern about routine use of tigecycline in treatment of such infections when other therapies are available.     

Clinical efficacy of ceftazidime. Treatment of serious infection due to multiresistant Pseudomonas and other gram-negative bacteria

Ceftazidime, a beta-lactamase stable cephalosporin, was administered to 57 patients. Substantial underlying disease was present in the majority of patients, and 50% were in critical or poor condition. Ceftazidime inhibited all initial isolates of Enterobacteriaceae at 8 mg/L or less, regardless of resistance to other antibiotics and the majority of Pseudomonas aeruginosa at 12 mg/L or less. The mean serum level after infusion of 1 g during 30 minutes was 62 mg/L. Overall clinical response was 84%, and the bacteriological response was 72% excluding cystic fibrosis patients. No major adverse effects were encountered. Resistance developed in Pseudomonas from patients with cystic fibrosis and in Enterobacter from two other patients. Ceftazidime was an effective, safe therapy for serious infection due to multiply resistant Pseudomonas and other aerobic gram-negative bacilli including aminoglycoside-resistant Serratia and Klebsiella.     

Intestinal decontamination for control of nosocomial multiresistant gram-negative bacilli. Study of an outbreak in an intensive care unit

STUDY OBJECTIVE: To study the efficacy of intestinal decontamination by oral nonabsorbable antibiotic agents to control a nosocomial outbreak of intestinal colonization and infection with multiresistant Enterobacteriaceae, and to examine its effects on endemic nosocomial infection rates. DESIGN: A 10-week prospective incidence study (group 1), and then an 8-week randomized, open trial of intestinal decontamination (groups 2 and 3). SETTING: A medical intensive care unit of a tertiary care university hospital. PATIENTS: Consecutive patients with unit stay of over 2 days and a severity score at admission of more than 2; 124 patients were included in group 1, 50 in group 2 (control), and 36 in group 3 (intestinal decontamination). INTERVENTIONS: Neomycin, polymyxin E, and nalidixic acid were given to group 3 patients throughout their stay in the unit. MEASUREMENTS AND MAIN RESULTS: Intestinal colonization with multiresistant strains occurred in 19.6% of patients in group 1, at a mean of 16 days after admission, and preceded detection in clinical samples by a mean of 11 days. During the decontamination trial, intestinal colonization rates decreased to 10% (group 2), and 3% (group 3) (P = 0.12 and P less than 0.01, compared with group 1, respectively). Corresponding infection rates were 9% (group 1), 3% (group 2), and 0 (group 3). No new cases were detected in the following 4 months. The intestinal colonization rate with gram-positive cocci was higher in group 3 than group 2 (P less than 0.001). The overall rate of nosocomial infections was at 28% (group 1), 33% (group 2), and 32% (group 3). CONCLUSIONS: Intestinal decontamination can help to control an outbreak of intestinal colonization and infection with multiresistant gram-negative bacilli in the intensive care unit, but should not be recommended for routine prevention of endemic nosocomial infections.     

Mezlocillin in the therapy of serious infections

Mezlocillin, a new semisynthetic penicillin chemically related to ampicillin which is more active than carbenicillin against Ps. aeruginosa, B. fragilis and Strep. faecalis and which inhibits many Klebsiella, was evaluated in the therapy of 34 episodes of infection in 26 patients. Infection sites included pulmonary, urinary tract and tissue infections, including peritonitis. Seven patients had bacteremia. Clinical cures were achieved in 83 per cent and bacteria cures in 76 per cent of infections. Cure was achieved with mezlocillin in patients with infections caused by carbenicillin-resistant species. Adverse effects of therapy were minimal, one rash and one episode of reversible neutropenia. Serum and body fluid levels were easily maintained above the inhibitory levels of susceptible organisms. Mezlocillin was a safe, well tolerated and effective antibiotic in the treatment of infections due to susceptible organisms.     

Efficacy and safety of aztreonam in the treatment of serious gram-negative bacterial infections

Aztreonam was used in the initial treatment of infection of the urinary tract (23 cases), respiratory tract (17 cases), skin and soft tissue (12 cases), abdominal cavity (three cases), endocarditis (two cases), septicemia (eight cases), and osteomyelitis (two cases). In 26 of 60 evaluable infectious episodes, aztreonam was used alone. Clinical cure was observed in 35 of 60, improvement in 24 of 60, and failure in one of 60 cases. Ten patients developed subsequent superinfection. Aztreonam was well tolerated, although one case of exfoliative dermatitis and one of pseudomembranous colitis occurred. However, these cases were complicated by proximal administration of other antibiotics.     

Piperacillin and gentamicin v carbenicillin and gentamicin for treatment of serious gram-negative infections

Piperacillin sodium, a new penicillin with remarkable in vitro activity against Pseudomonas aeruginosa and other Gram-negative bacilli, and gentamicin sulfate were compared with carbenicillin disodium and gentamicin in a prospective, randomized, double-blind comparison for treating serious Gram-negative infections. Of the 32 patients whose courses were "evaluable" for efficacy, 12 of 14 who received piperacillin and gentamicin and 13 of 18 who received carbenicillin and gentamicin had favorable outcomes. Of the 99 patients whose courses were evaluable for toxicity, nine of 51 recipients of piperacillin and gentamicin and 15 of 48 recipients of carbenicillin and gentamicin suffered clinical reactions possibly, probably, or definitely related to the penicillin. No statistically significant differences were found in the two groups in the frequencies of biochemical abnormalities, including hypokalemia, that occurred in 19 or 44 recipients of piperacillin and gentamicin and 16 of 45 recipients of carbenicillin and gentamicin. Thus, this study did not prove differences in efficacy of toxicity for piperacillin and gentamicin plus carbenicillin and gentamicin for serious Gram-negative infections.     

Use of cefotaxime, a beta-lactamase stable cephalosporin, in the therapy of serious infections, including those due to multiresistant organisms

Cefotaxime is a cephalosporin active against most gram-positive and gram-negative organisms, including streptococci, Staphylococcus aureus, Enterobacteriaceae, Proteus, and many Pseudomonas and Bacteroides fragilis--all but the latter two are inhibited at concentrations below 0.5 micrograms/ml. We evaluated cefotaxime as the sole therapy for 32 infections in 31 patients. Infection sites included 18 bacteremias; pulmonary, urinary tract, deep tissue infections; and meningitis. Clinical cures were achieved in 88 percent and bacteriologic cures in 86 percent of the patients--including those with infections due to organisms resistant to cephalosporins, chloramphenicol, carbenicillin and aminoglycosides; and in two patients with meningitis due to multiresistant Klebsiella pneumoniae. Serum and cerebrospinal levels were readily maintained above the inhibitory levels of susceptible organisms. Adverse reactions were minimal. Cefotaxime was a safe, effective antibiotic in the treatment of infections due to susceptible organisms, including those resistant to other agents.