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Stability in aqueous solution of two monocyclic beta-lactam antibiotics: aztreonam and nocardicin A.

The catalytic effect of various buffer systems (citrates, acetates, phosphates, borates and carbonates) on the degradation of aztreonam and nocardicin A in aqueous solution was studied at 35 degrees C and a constant ionic strength of 0.5 mol.dm-3 over a pH range of 3.50 to 10.50. The observed degradation rates, obtained by measuring the remaining intact antibiotic, were shown to follow pseudo-first-order kinetics with regard to antibiotic concentrations and to be influenced by general acid and general base catalysis. The changes in the concentration of intact beta-lactam antibiotic in the solutions were established by reverse-phase HPLC with UV-detection. In general the buffer systems employed in the kinetic studies showed a very weak catalytic effect on the degradation of aztreonam and nocardicin A. The pH-rate profiles for these antibiotics showed degradation minimums at pH 5.38 and 6.13, respectively. Aztreonam is slightly more reactive with hydrogen ions than nocardicin A and is much more reactive with hydroxide ions. In comparison with other beta-lactamic antibiotics, aztreonam and nocardicin A are much more stable in aqueous solution, except for aztreonam in a base solution, which is just as unstable as penicillins and cephalosporins. The Arrhenius activation energies were determined for aztreonam and nocardicin A at pH's 4.23, 6.59 and 8.60.

Anti-Bacterial Agents↗

Role of aztreonam in the treatment of nosocomial pneumonia in the critically ill surgical patient.

In 1995 the American Thoracic Society issued an official consensus statement on the treatment of hospital-acquired pneumonia (HAP). Classes of antimicrobials included in the list of antimicrobials deemed to be suitable for the empiric treatment of severe HAP were the aminoglycosides, quinolones, antipseudomonal penicillins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations. Aztreonam, a monobactam, was also listed and is unique among these agents based on its spectrum of activity being limited to the gram-negative bacillary bacteria combined with an excellent safety profile. This review focuses on the role of aztreonam in the treatment of nosocomial pneumonia in the critically ill patient.A review of the literature was performed using PubMed and secondary literature sources as to the clinical efficacy of aztreonam in the treatment of lower respiratory tract infections as well as its pharmacokinetic and safety profiles. An analysis of aztreonam's potential pharmacoeconomic advantages compared with other agents was also performed. Numerous studies have documented that aztreonam has effectiveness that is equal or superior to that of other suitable antibiotics in the treatment of nosocomial pneumonia. Its excellent safety profile makes it a particularly attractive agent compared with the aminoglycosides. Considering the potential costs of bacterial resistance from the use of broader-spectrum alternatives, a case can be made that aztreonam is a pharmacoeconomically sound choice as well.

Aztreonam↗

Antipseudomonal effects of selected dithiocarbamates alone and in combination with gentamicin or aztreonam.

The antipseudomonal effects conferred by combinations of substituted dithiocarbamates, gentamicin or aztreonam (Azactam) were measured and compared to those produced by single agents alone in female BALB/C mice bearing overwhelming Pseudomonas aeruginosa infections. Dimethyldithiocarbamate (DMDTC), diethyldithiocarbamate (DEDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMGDTC) were chosen as representative substituted dithiocarbamates. All three dithiocarbamates rescued some cisplatin-immunosuppressed mice from pseudomonal infections but DMDTC and NMGDTC produced better results than DEDTC. Single daily injections of DMDTC at doses of 5 mg/kg/day or higher for a total of 7 days rescued 14 of 18 mice given 10(6) viable Pseudomonas aeruginosa by tail vein inoculation. Similar dose regimens of 10 mg/kg/day or higher NMGDTC for a total of 7 days rescued 15 of 18 mice. DEDTC at doses of 5 mg/kg/day or higher for 7 days rescued 7 of 18 mice. Combinations of DMDTC or NMGDTC with gentamicin failed to produce better results than each agent alone in mice immunosuppressed with methyl-prednisolone (Solumedrol) at the dose range evaluated in mice inoculated with 10(6) viable organisms via tail veins. Combinations of DMDTC and aztreonam were effective in mice immunosuppressed with methylprednisolone and given overwhelming numbers of viable Pseudomonas aeruginosa (10(7) or more, ip). Combinations of 6 mg/kg/day or higher of each agent with multiple daily injections rescued 11 of 18 mice. The results yielded by either agent alone were not impressive. Similar results were obtained when mice immunosuppressed with cisplatin were given ip injections of 10(8) or more viable bacteria. No mice were rescued by the use of DMDTC, NMGDTC, aztreonam or gentamicin only. Combinations of DMDTC (6 mg/kg) and aztreonam (6 mg/kg) with multiple daily injections for seven days rescued 11 of 20 infected mice while combinations of NMGDTC with aztreonam were less effective (3 of 20 rescued). The concurrent administration of DMDTC and aztreonam offers considerable promise in the treatment of overwhelming pseudomonal infections in mice and may prove to be of value in human patients as well.

Animals↗

Microbiology and pharmacology of aztreonam.

Aztreonam, the first monobactam antibiotic, represents a significant evolutionary advance in antimicrobial therapy. Aztreonam is stable in the presence of the hydrolytic beta-lactamase enzymes; as such, it is effective against most Gram-negative aerobes, including Pseudomonas aeruginosa, Escherichia coli, Klebsiella, and Enterobacter. Due to its specific spectrum of activity, aztreonam does not disturb the normal Gram-positive and anaerobic intestinal flora. The safety profile of aztreonam is superior: unlike the aminoglycosides, aztreonam does not cause nephrotoxicity or ototoxicity, and no routine monitoring of serum levels is required with its use. The pharmacokinetics of aztreonam after intravenous infusion or intramuscular dosing are presented as well as the dosage adjustments for hemodialysis and chronic ambulatory peritoneal dialysis (CAPD).

Aztreonam↗

Aztreonam in the treatment of serious gram-negative infections in the elderly.

The efficacy and safety of aztreonam in the treatment of serious gam-negative infections were investigated in 20 patients, 19 of whom were more than 60 years old. There were 13 cases of upper urinary tract infection, 6 of septicemia and one of peritonitis. Half the patients were in a critical clinical condition with significant severe underlying disease. Aztreonam was given i.v. or i.m. in doses ranging from 1.5 to 4 g/day according to the severity of the infection. The duration of treatment ranged from 7 to 20 days. In 5 patients with mixed infections due to gram-positive and anaerobic organisms in addition to gram-negative pathogens, aztreonam was given in combination with clindamycin and metronidazole as appropriate. Clinical and bacteriological cures were observed in all 20 patients. There were two cases of reinfection and 3 of superinfection--all occurred in patients with severe underlying disease. Untoward effects were few and of minor severity. Creatinine clearance remained stable or improved during aztreonam treatment, even in patients with significant renal impairment. In conclusion, aztreonam was shown to be both effective and safe in the treatment of serious gram-negative infections in elderly patients--even those with impaired renal function. In such indications aztreonam appears to be a good alternative to potentially toxic drugs such as the aminoglycosides.

Aged↗

[Diffusion of aztreonam in the tissues and biological fluids of the female genital tract].

Diffusion of aztreonam into female genital tract tissues was investigated. After a single IV injection of 1 g, aztreonam was assayed in uterine tissue, uterine tube tissue and peritoneal fluid in 15 patients undergoing coelioscopy or hysterectomy. In addition, to evaluate placental transfer of aztreonam, maternal blood, amniotic fluid and cord blood samples were collected in five women undergoing cesarean section. Concentrations of aztreonam were determined using a microbiologic method. Mean concentrations 1 to 2 hours after administration of the drug were 11 to 25 micrograms/g in the endometrium and uterine tube tissue and 18 to 30 micrograms/g in the myometrium. Concentrations in peritoneal fluid samples were lower, ranging from 4.7 micrograms/ml (0.5 h) to 16 micrograms/ml (1 to 2 hours after the injection). The ratio of tissue concentrations to serum concentrations found at the same time, expressed as a percentage, ranged from 50 to greater than or equal 100%. Placental transfer of aztreonam proved comparable to that of other recently studied beta-lactams: the amniotic fluid/maternal blood and cord blood/maternal blood ratios ranged from 27 to 33% thirty minutes after administration of the antibiotic. No adverse effects were recorded in the offspring. These results indicate that diffusion of aztreonam into female genital tract tissues is good, producing concentrations capable of preventing or curing gynecologic and obstetrical infections caused by Gram negative bacilli.

Aztreonam↗

A comparison of aztreonam and two regimens of gentamicin in a rabbit model of intra-amniotic infection and sepsis.

OBJECTIVE: To compare aztreonam in a standard dose with two gentamicin doses in the early treatment of experimental intra-amniotic infection in rabbits induced by intracervical inoculation with Escherichia coli. METHODS: Timed pregnant rabbits on day 21 (70% of gestation) were inoculated intracervically with 10(4)-10(5) colony-forming units of E coli. After inoculation, the animals were treated with one of three regimens: 1) aztreonam at 90 mg/kg/day ("standard" dose in humans), 2) gentamicin at 4.5 mg/kg/day ("standard" dose in humans), or 3) higher-dose gentamicin at 6.0 mg/kg/day, each given in three divided doses daily. Outcomes included fever, delivery, and presence of a live fetus. At necropsy, cultures were taken from endometrium, amniotic fluid, and blood. Data were analyzed by Fisher exact test because the expected cell size was fewer than five. RESULTS: Compared with rabbits treated with aztreonam, those treated with gentamicin 4.5 mg/kg/day delivered significantly more often (P = .002), had more positive cultures (P < .001), and had significantly fewer live fetuses (P < .001). Compared with rabbits treated with gentamicin 6.0 mg/kg/day, those treated with gentamicin 4.5 mg/kg/day delivered more often (P = .003), had fewer live fetuses (P = .02), and had more positive cultures (P = .02). There were no significant differences between the aztreonam and gentamicin 6.0 mg/kg/day groups. CONCLUSIONS: This study demonstrates in an animal model that aztreonam and gentamicin at 6.0 mg/kg/day are more effective than gentamicin at 4.5 mg/kg/day (a dose that is widely used empirically in humans) in the early treatment of experimental intra-amniotic infection in rabbits. Aztreonam was as effective as gentamicin at 6.0 mg/kg/day. In this rabbit model, in which intra-amniotic infection is accompanied by maternal sepsis, 4.5 mg/kg/day of gentamicin was not adequate for the treatment of severe maternal infection.

Amnion↗

Role of aztreonam in the treatment of nosocomial pneumonia in the critically ill surgical patient.

In 1995 the American Thoracic Society issued an official consensus statement on the treatment of hospital-acquired pneumonia (HAP). Classes of antimicrobials included in the list of antimicrobials deemed to be suitable for the empiric treatment of severe HAP were the aminoglycosides, quinolones, antipseudomonal penicillins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations. Aztreonam, a monobactam, was also listed and is unique among these agents based on its spectrum of activity being limited to the gram-negative bacillary bacteria combined with an excellent safety profile. This review focuses on the role of aztreonam in the treatment of nosocomial pneumonia in the critically ill patient.A review of the literature was performed using PubMed and secondary literature sources as to the clinical efficacy of aztreonam in the treatment of lower respiratory tract infections as well as its pharmacokinetic and safety profiles. An analysis of aztreonam's potential pharmacoeconomic advantages compared with other agents was also performed.Numerous studies have documented that aztreonam has effectiveness that is equal or superior to that of other suitable antibiotics in the treatment of nosocomial pneumonia. Its excellent safety profile makes it a particularly attractive agent compared with the aminoglycosides. Considering the potential costs of bacterial resistance from the use of broader-spectrum alternatives, a case can be made that aztreonam is a pharmacoeconomically sound choice as well.

Journal Article↗

A comparison of aztreonam plus vancomycin and imipenem plus vancomycin as initial therapy for febrile neutropenic cancer patients.

BACKGROUND: The improved efficacy of imipenem over other beta-lactam antibiotics in the treatment of febrile neutropenic patients has been attributed to its broad spectrum of activity. METHODS: A prospective, randomized, clinical trial was performed comparing vancomycin 1 g every 12 hours plus imipenem/cilassatin 500 mg every 6 hours and the same dose of vancomycin plus aztreonam 2 g every 6 hours for empiric treatment of febrile episodes in neutropenic patients with cancer. RESULTS: The imipenem regimen cured 76% of the 148 evaluable episodes compared with a 67% cure rate for the 152 episodes treated with the aztreonam regimen (p = 0.1). Most of the polymicrobial infections (77% or 10/13) treated with the imipenem responded, whereas only 38% (5/13) of these infections responded to the aztreonam regimen. Although the cost of the imipenem regimen was less than the cost of the aztreonam regimen, it was associated significantly more with skin rashes (12/194 vs 3/189, p = 0.02). In a multivariate analysis, a poor outcome was independently associated in both instances with the persistence of neutropenia and the presence of pneumonia (p < 0.001). CONCLUSIONS: Overall, in a multifactorial analysis that included efficacy, toxicity, and cost, the imipenem and aztreonam regimens were comparable.

Adolescent↗

Pharmacokinetic interaction of aztreonam with other antibiotics.

The pharmacokinetic interaction of the monobactam antibiotic aztreonam with cephradine, clindamycin, gentamicin, metronidazole, and nafcillin was investigated in five separate studies in 48 healthy male volunteers. All drugs were administered by 30-minute intravenous infusions in single-dose, three-way balanced cross-over studies. Drug levels were measured in serum, protein-free filtrate of serum, and urine. Small changes of no clinical significance were seen when aztreonam was given simultaneously with another antibiotic as compared with each drug alone. Maximum serum concentrations of aztreonam were reduced by 12.6 and 9.8 per cent when it was given with gentamicin and metronidazole, respectively. The percentage of serum aztreonam bound to protein fell by a maximum of 5.0 per cent when the monobactam was given in conjunction with nafcillin and rose by 5.1 per cent when accompanied by cephradine. Twenty-four-hour cumulative urinary excretion of aztreonam and clindamycin rose by 5.2 and 10.9 per cent, respectively, when they were administered simultaneously.

Adult↗

Aztreonam.

Aztreonam is a new, totally synthetic beta-lactamase agent--the first monobactam. It is highly resistant to hydrolytic inactivation caused by plasmid-mediated (except PSE-2 enzyme found in some Pseudomonas species) or chromosomally mediated beta-lactamases (except for K1 produced by rare strains of Klebsiella oxytoca). Accordingly, aztreonam remains active against many pathogens that are resistant to other beta-lactam antibiotics. The drug exhibits directed antibacterial activity against gram-negative organisms and is effective as monotherapy against most Enterobacteriaceae and Hemophilus and Neisseria species, including beta-lactamase-producing strains; it is not active against anaerobes or gram-positive organisms. Before culture results are known, it may be necessary to administer the agent empirically in combination with other antibiotics. Aztreonam is rapidly distributed to most body tissues and fluids when administered parenterally. Its serum half-life is 1.7 hours, suggesting a dosing interval of 6-8 hours for severe or life-threatening infections and 8-12 hours for moderately severe infections and urinary tract infections. It is primarily eliminated unchanged in the urine and in much lesser amounts as a microbiologically inactive metabolite; slight biliary excretion may occur. Aztreonam is well-tolerated, lacking any serious adverse hematologic, otic, or renal system effects. Its lack of effect on anaerobes helps to maintain resistance against colonization. Particularly in light of its safety and unique properties, aztreonam promises to be a useful alternative to aminoglycoside therapy.

Aztreonam↗

Effects of granulocyte colony stimulating factor and monobactam antibiotics (Aztreonam) on neutrophil functions in sepsis.

Possible clinical use of a recombinant human granulocyte colony stimulating factor (rG-CSF) and a newly developed monobactam antibiotics (Aztreonam) for the treatment of gram-negative sepsis was investigated. Gram-negative sepsis was induced in male WKA rats by cecal ligation and puncture (CLP). Untreated CLP rats all died by septicemia with severe peripheral blood leukocytopenia within 5 days after the operation. When we administered 2.0 micrograms/kg of rG-CSF and/or 20 mg/kg of Aztreonam intravenously just after the operation, the rats survived longer than the untreated CLP rats. These drugs were found to be more effective when used in combination. Since these rats showed an increase in leukocyte counts, we next examined the changes in the functions of polymorphonuclear leukocytes (PMNs, mainly neutrophils) after the treatment. PMNs from untreated CLP rats at 24 hr after the operation exhibited enhanced plastic-dish adherence, suppressed chemotaxis, and depressed O2 production when compared with PMNs from control animals. A single injection of rG-CSF restored both the depressed chemotaxis and the O2 production to levels greater than those of controls. Although a single injection of Aztreonam could not improve the suppressed O2 production, it could restore the depressed chemotaxis. Interestingly, simultaneous injection of Aztreonam with rG-CSF significantly enhanced the effect of rG-CSF on the PMN functions. These data suggest that the Aztreonam and rG-CSF may be useful for the treatment of gram-negative sepsis, especially when used in combination.

Animals↗

Enzymatic inactivation of aztreonam by faecal enzyme preparations from healthy volunteers.

The enzymatic inactivation of aztreonam by the faecal flora was investigated in 25 healthy human volunteers. Ten volunteers received aztreonam orally and 15 volunteers did not receive antibiotic treatment. Residual aztreonam and its inactivated open ring form were simultaneously detected by an HPLC-assay. Independent of aztreonam treatment, beta-lactamase activity was detected in the faecal flora of 20 volunteers. The inactivation of aztreonam by the faecal supernatants was inhibited by clavulanic acid.

Adult↗

Aztreonam can safely be used in combination with cyclosporin without aggravating nephrotoxicity.

The administration of antibiotics to renal transplant patients using cyclosporin can be difficult because of the risk of severe nephrotoxicity. An investigation was therefore carried out to determine whether aztreonam, a synthetic monocyclic beta-lactam antibiotic, can safely be combined with cyclosporin. In this retrospective study 68 renal transplant patients who received preoperative antibiotic prophylaxis consisting of aztreonam, ampicillin, and lincomycin were compared with 68 patients who received ceftazidime instead of aztreonam. Both groups were treated with cyclosporin and prednisolone and followed for 3 months. After transplantation 28.7% of the patients suffered from an acute renal failure and 1.5% had a wound infection. There were no significant differences between the two groups in acute renal failure, would infections, other infections, incidence of rejections, duration of admission, or graft survival. We therefore conclude that aztreonam can safely be administered together with cyclosporin. We also conclude that the combination of aztreonam, ampicillin, and lincomycin is a good preoperative antibiotic prophylaxis in renal transplant patients.

Acute Kidney Injury↗

A comparative trial of aztreonam versus gentamicin in the treatment of urinary tract infections.

A prospective, randomized trial was conducted to compare the efficacy of aztreonam, a monobactam antibiotic, and gentamicin in the treatment of serious urinary tract infections. Fifty-five patients with a suspected or confirmed infection were randomized, 28 received aztreonam and 27 received gentamicin. Both antibiotics had a high clinical response rate (aztreonam 92%, gentamicin 85%). However, the duration of treatment was significantly shorter (p = 0.037, Wilcoxon Rank Sum Test) when aztreonam was used. There were no cases of toxicity with either antibiotic but 5 patients who received gentamicin required dose alteration. Aztreonam is well tolerated and is no less effective than gentamicin in the treatment of urinary tract infections and has advantages in convenience of use and duration of treatment.

Adult↗

The combination of aztreonam and cefozopran against Stenotrophomonas maltophilia.

Aztreonam is suited for combination chemotherapy because it could be a potent Beta-lactamase inhibitor. We designed a study to show the inhibitory activity of aztreonam, using Stenotrophomonas maltophilia, which produces both carbapenemase L1 and penicillinase L2. Aztreonam showed considerable synergy with cefpirome and contributed to a decrease in minimum inhibitory concentrations of cefozopran. In further examinations, the mean viable bacterial counts in cultures treated with aztreonam-cefozopran were 1 log lower than those in cultures treated with cefozopran alone. These results confirm that inhibition of penicillinase L2 occurred. We hope that a combination chemotherapy using aztreonam and cefozopran will be used to prevent the emergence of penicillinase-producers.

Anti-Bacterial Agents↗

Review of the clinical pharmacology of the monobactam antibiotic aztreonam.

Serum and urine levels of aztreonam after 0.5, 1, and 2 g doses are potentially therapeutic for susceptible gram-negative organisms. Aztreonam is widely distributed in body fluids and tissues, and concentrations exceeding the minimal inhibitory concentrations of important gram-negative pathogens are attained in those compartments in which infections are most common. Aztreonam is eliminated primarily in the urine in unchanged form, although it is also secreted into the bile and is metabolized to a minor extent. Renal insufficiency may significantly impair the elimination of aztreonam, thus requiring modification of the dosage regimen. The monobactam can be cleared by hemodialysis but is only minimally cleared by peritoneal dialysis. Parenterally and orally administered aztreonam can selectively reduce the population of aerobic gram-negative bacteria in the gut without notably altering the number of anaerobic organisms.

Anti-Bacterial Agents↗

Aztreonam in the treatment of urinary tract infection.

The possible advantages of the monobactam antibiotic aztreonam in the treatment of hospital-acquired urinary tract infection were assessed in a study comparing aztreonam (0.5 to 1 g twice daily or three times daily) to cefamandole (1 g three times daily) in 159 patients. Initial pathogens were eradicated in 91.7 percent of the patients of the aztreonam group who were treated three times daily, in 82.7 percent of the group treated twice daily, and in 78.3 percent of the patients receiving cefamandole. Reinfection and superinfection were most commonly caused by enterococci in the aztreonam groups and by Pseudomonas aeruginosa in the cefamandole group. In a second study, 35 patients infected with organisms resistant to other antibiotics were treated with aztreonam 1 to 6 g per day for eight days. The overall cure rates were 93 percent for Pseudomonas infections, 87.5 percent for Escherichia coli infections, and 100 percent for other pathogens.

Anti-Bacterial Agents↗