Intravenous Compatibility of Ceftazidime-Avibactam and Aztreonam Using Simulated and Actual Y-site Administration.

PURPOSE: The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration. METHODS: Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate. FINDINGS: Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments. IMPLICATIONS: Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.

Repurposing an old drug: aztreonam as a new treatment strategy for gonorrhoea.

Objectives: To determine whether aztreonam is still an effective drug for the treatment of gonorrhoea. Methods: Observational study of patients with gonorrhoea diagnosed by urine multiplex PCR, with a past medical history of allergy to ß-lactams or relapse after treatment with a third-generation cephalosporin. Patients received a single 1 g dose of aztreonam in accordance with the manufacturer's instructions. Results: Five patients (four males, one female) were enrolled, comprising two who were allergic to ß-lactams and three previously treated with cephalosporins who relapsed. Median age was 38 years (range 23-51). Following treatment with aztreonam all were cured without any adverse event. All the men were free of symptoms, and the woman tested negative for gonorrhoea 1 month after treatment. Conclusion: Aztreonam appears to be an effective alternative to cephalosporins in the treatment of uncomplicated gonorrhoea, particularly when patients are suspected of being infected by strains with reduced susceptibility to ceftriaxone or are known to be allergic to penicillin.

A review of the pharmacokinetics and pharmacodynamics of aztreonam.

The monobactam aztreonam is currently being re-examined as a therapeutic agent in light of the global spread of carbapenem resistance in aerobic Gram-negative bacilli and aztreonam's stability to Ambler class B metallo-ß-lactamases. Of particular interest are the pharmacokinetic and pharmacodynamic properties of aztreonam alone and in combination with ß-lactamase inhibitors. The choice of inhibitor may vary depending on the spectrum of ß-lactamases produced by Enterobacteriaceae. The monobactam ring is also being used to produce new developmental monobactams. Thus, a greater understanding of aztreonam pharmacokinetics and dynamics is of great relevance in drug development. This review summarizes the pharmacokinetic profile of aztreonam in man and its pharmacodynamics in human and pre-clinical studies when studied alone and with ß-lactamase inhibitors.

Effectiveness of antibiotic combination therapy as evaluated by the Break-point Checkerboard Plate method for multidrug-resistant Pseudomonas aeruginosa in clinical use.

Multidrug-resistant Pseudomonas aeruginosa (MDRP) strains are defined as having resistance to the following 3 groups of antibiotics: carbapenems, aminoglycosides, and fluoroquinolones. Antibiotic combinations have demonstrated increased activity in vitro compared with a single agent. As an in vitro method of determining the combination activity of antibiotics, the Break-point Checkerboard Plate (BC-plate) can be used routinely in clinical microbiology laboratories. We evaluated the effectiveness of the BC-plate for MDRP infections in clinical settings. We retrospectively selected cases of MDRP infection treated with combination therapy of antibiotics in Tokyo Medical University Hospital (1015 beds), Tokyo, Japan, from November 2010 to October 2012. A total of 28 MDRP strains were clinically isolated from 28 patients during the study period. This study design is a case series of MDRP infection. Six infections among the 28 patients were treated based on the results of the BC-plate assay, and the 6 strains tested positive for MBL. One patient had pneumonia, 3 had urinary tract infections, 1 had vertebral osteomyelitis, and 1 had nasal abscess. The combination of aztreonam with amikacin demonstrated the most frequently recognized in vitro effect (5 patients). Next, aztreonam with ciprofloxacin and piperacillin with amikacin revealed equivalent in vitro effects (3 patients, respectively). The clinical cure rate was 83.3% (5/6 patients). Antibiotic combination therapy based on the results of the BC-plate assay might indicate the effective therapy against MDRP infection in clinical settings.

[Antibacterial therapy in surgery of patients with acute destructive appendicitis].

Character of microflora of exsudate of abdominals and mucosis microflora of vermicular appendix is studied for patients with the destructive forms of appendicitis with the purpose of development of variants of antibacterial therapy at surgical treatment of patients with acute appendicitis. The patients with the destructive forms of appendicitis, which were on treatment in a municipal clinical hospital N 4 Kyiv for period 2004-2010. An Inflammatory-destructive process in an appendix is conditioned by both aerobic (Escherichia coli - 46,6 %, Enterobacter - 4,2 %, Citrobacter - 4,2 %, Klebsiella - 3,3 %, Pseudomonas aeruginosa - 5,8 %, Staphylococcus - 4,2 %) and anaerobic microorganisms (Bacteroides - 100 %) and increase Candida - 17,5 %. Antibacterial therapy is effective at 46,7 % patients with acute appendicitis. At 49,6 % patients acute appendicitis develops on a background dysbiotic intestinal disturbances. Clinically the effective charts of empiric antibacterial monotherapy 6 days it is been: Moxifloxacini intravenously 400 mgs one time in twenty-four hours during, Ertapenemi for a 1 g one time in twenty-four hours intravenously and combined - Aztreonami for a 1 g twice in twenty-four hours and of Clindamycini for 600 mgs twice in twenty-four hours, intramuscular during; Cefepimumi for a 1 g twice in twenty-four hours and of Clindamycini for 600 mgs twice in twenty-four hours, intramuscular.

Efficacy of aerosol MP-376, a levofloxacin inhalation solution, in models of mouse lung infection due to Pseudomonas aeruginosa.

Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.

[Infection treatment caused by multiple-drug-resistant Pseudomonas aeruginosa in a patient undergoing allogeneic hematopoietic stem cell transplantation].

Infections caused by multiple-drug-resistant Pseudomonas aeruginosa (MDRP) are a clinically significant problem. We reported here the effective use of combination therapy in a patient with infection caused by MDRP according to an interventional treatment strategy suggested by a pharmacist. The patient was a 70-year-old male who underwent allogeneic hematopoietic stem cell transplantation. On day 45 after transplant, MDRP was newly isolated from urine, but the diagnosis at that time was colonization. On day 61, the patient developed a fever (> or =38.0 degrees C). In addition, laboratory data showed that C-reactive protein (CRP) was also increased. At the medical team conference, the pharmacist proposed the following treatment strategy for this infection. Aztreonam and amikacin were intravenously administered at doses of 2 g/day and 800 mg/day, respectively. The subsequent clinical course was well controlled, but the infection recurred and was aggravated. Aztreonam and ciprofloxacin were then intravenously administered at doses of 4 g/day and 600 mg/day, respectively, resulting in the alleviation of fever in the patient as well as a decrease in CRP and disappearance of MDRP isolates from urine on day 67; that is, MDRP infection was consequently well controlled. In conclusion, the combination therapy between aztreonam and amikacin, or ciprofloxacin may be clinically useful for severe infections of MDRP in compromised hosts.

Susceptibility of Streptococcus mutans and Streptococcus sobrinus to cell wall inhibitors and development of a novel selective medium for S. sobrinus.

Representative strains of Streptococcus mutans and Streptococcus sobrinus showed differences in susceptibility to members of the monobactam group of beta-lactam antibiotics: S. sobrinus was less sensitive than S. mutans. The minimum inhibitory concentrations of aztreonam (AZT) and carumonam, both of which belong to this group, were 2,000 microg/ml for S. sobrinus and 125 microg/ml for S. mutans. Further addition of fosfomycin, bacitracin and sodium chloride to Mitis Salivarius agar (MS) supplemented with AZT resulted in growth inhibition of S. mutans and oral streptococci other than S. sobrinus, and was therefore used as a selective medium for S. sobrinus (MS-SOB medium). The average growth recovery of laboratory and clinically isolated strains of S. sobrinus on MS-SOB medium was 74.1% compared to that on MS medium. Seventy-eight percent of clinical samples in which S. sobrinus was detected yielded pure growth of S. sobrinus on MS-SOB medium.

Comparative epileptogenic properties of two monobactam derivatives in C57, Swiss and DBA/2 mice.

The behavioural and electrocortical effects of two monobactam derivatives were studied after intraperitoneal (ip) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures, and in C57 and Swiss mice, two strains not prone to seizure. DBA/2 mice were more susceptible than Swiss and C57 mice to seizures induced by aztreonam or carumonam. No significant differences were observed between seizures elicited by aztreonam and carumonam in animals (DBA/2 only) administered intracerebroventricularly or ip. Although the main mechanism for seizure-like activity of monobactams cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of aztreonam and carumonam from the CNS may be postulated.

[Antibiotic treatment for pneumonia caused by Flavobacterium meningosepticum].

Two cases of critical nosocomial pneumonia caused by flavobacterium meningosepticum (FM) were reported and both of them were successfully cured. There were 2 other cases of FM pneumonia reported in Chinese literature previously, but none of them survived. It has been found that the treatment for FM respiratory infection was very difficult because of its resistance to majority of antibiotics, including the third generation cephalosporins. The symptoms of FM pneumonia are similar to those of other gram-negative bacillus pneumonias, such as Klebsiella pneumoniae pneumonia. Definite diagnosis depends principally on etiological examination and clinical manifestations of pneumonia. Cefoperazone, Cefsulodin, Astreonam and Ciprofloxacin are valuable drugs in saving the lives of patients with FM Pneumonia.

Comparison of imipenem versus cefuroxime plus tobramycin as empirical therapy for febrile granulocytopenic patients and efficacy of vancomycin and aztreonam in case of failure.

143 aplastic episodes with fever in 91 haematological patients with granulocytopenia were treated empirically in a randomized prospective study using either imipenem (Imi) or a combination of tobramycin and cefuroxime (T/C). Response after 72 h was significantly better in patients receiving Imi (44/75 vs 27/68, p < 0.05). This was seen especially in patients with bacteriologically proven infections where the isolated staphylococci and streptococci were more susceptible to Imi. In both groups, patients who failed to respond to the initial antibiotic therapy were given vancomycin and aztreonam (V/A). The response rate after another 72 h, measured using the same criteria as after the first 72 h, did not differ statistically between the groups. One patient in each study group died from the bacterial infection, both from Gram-positive bacteraemia. Duration of fever was significantly shorter in the Imi group (4 days vs 7 days, p < 0.04). Serum peak and trough concentrations of the antibiotics were comparable. Both regimens were well tolerated. Our results show that monotherapy with imipenem is superior to the combination of tobramycin and cefuroxime during the first 72 h of therapy and can be safely administered to neutropenic patients with predominantly Gram-positive infections. A combination of vancomycin and aztreonam, given when initial imipenem treatment has failed, was effective in only a few patients. Adjuvant glycopeptide therapy from the outset in the treatment of febrile granulocytopenic patients did not seem worthwhile.

Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer.

BACKGROUND: Hospitalization and intravenous (IV) broad-spectrum antibiotics are the standard of care for all febrile neutropenic patients with cancer. Recent work suggests that a low-risk population exists who might benefit from an alternate approach. METHODS: A prospective randomized clinical trial was performed comparing oral ciprofloxacin 750 mg plus clindamycin 600 mg every 8 hours with IV aztreonam 2 g plus clindamycin 600 mg every 8 hours for the empiric outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer. RESULTS: The oral regimen cured 35 of 40 episodes (88% response rate), whereas the IV regimen cured 41 of 43 episodes (95% response rate, P = 0.19). Although the cost of the oral regimen was significantly less than that of the IV regimen (P < 0.0001), it was associated with significant renal toxicity (P < 0.05), which led to early termination of the study. Overall, combining its safety and efficacy, the IV regimen was superior (P = 0.03). CONCLUSIONS: This prospective study suggested that outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer is safe and effective. Better oral regimens are needed.

[Aztreonam, a new approach in the therapy of gonorrhea]. / Aztreonam, eine neue Möglichkeit in der Gonorrhoe-Therapie.

The isolated gonococcal strains cultured from 99 patients (64 men and 35 women) with uncomplicated genital gonorrhoea were tested with regard to their susceptibility to aztreonam. No resistant strain was found. The bacteriological evaluation of 50 of these strains showed a minimum inhibitory concentration (MIC) of 0.0075 to 3.906 mcg/ml. Four of the tested strains were penicillinase-producing strains of N. gonorrhoeae. 95 patients (95.9%) were cured after administration of a single dose of 1 g aztreonam by intramuscular injection. It was not possible to exclude reinfection of the 4 remaining patients. No side effects were reported.

Antipseudomonal therapy in cystic fibrosis: aztreonam and amikacin versus ceftazidime and amikacin administered intravenously followed by oral ciprofloxacin.

In order to determine the optimal antipseudomonal therapy in patients with cystic fibrosis aztreonam plus amikacin was compared to ceftazidime plus amikacin, and these two-week hospital regimens were followed by oral ciprofloxacin given for four weeks. Fifty-six cases of acute pulmonary exacerbation of the disease in 42 patients associated with isolation of Pseudomonas aeruginosa from the sputum were randomly treated with either aztreonam or ceftazidime (300mg/kg/day i.v.; maximum daily dose 12g) in combination with amikacin (36mg/kg/day i.v.; maximum daily dose 1,500mg). Other aspects of the two-week treatment were constant. The two therapy groups were comparable in all respects. Both regimens were well tolerated and resulted in similar improvements in clinical, bacteriologic, radiologic and laboratory findings, and pulmonary function. Fifty patients could be reevaluated after subsequent outpatient therapy consisting of oral ciprofloxacin (30mg/kg/day; maximum daily dose 1,500mg) given for four weeks. During this period, the clinical and laboratory improvements persisted, and the rate of eradication of Pseudomonas aeruginosa from sputum decreased from 62% to 34%. Ciprofloxacin was well tolerated and there was no drug toxicity or serious adverse effect. In the 25 prepubertal patients there was neither subjective nor objective evidence of skeletal drug toxicity. In patients with cystic fibrosis, aztreonam or ceftazidime in combination with amikacin represents an effective and safe systemic anti-pseudomonal therapy. Subsequent oral ciprofloxacin therapy for four weeks prolongs the beneficial effects and is well tolerated.

A comparative analysis of aztreonam + clindamycin versus tobramycin + clindamycin or amikacin + mezlocillin in the treatment of gram-negative lower respiratory tract infections.

One hundred ten patients were randomized to receive one of the following antibiotic combinations: aztreonam + clindamycin, tobramycin + clindamycin, or amikacin + mezlocillin for the treatment of lower respiratory tract infections (LRTI) caused by gram-negative bacilli. Of the 68 patients who received aztreonam + clindamycin, 60 were clinically evaluable and 50 were bacteriologically evaluable. Of the 60 clinically evaluable patients, 54 were cured and 5 were treatment failures or died during the study period. Of the 50 bacteriologically evaluable patients, 46 were cured and 3 failed to respond to therapy. Of the 26 clinically evaluable patients in the tobramycin + clindamycin group, 22 were cured and 4 either failed to respond or died during the study period. Of 18 bacteriologically evaluable patients in this group, 16 were cured and 2 failed to respond. In the amikacin + mezlocillin group, 14 of the 15 clinically and bacteriologically evaluable patients were cured, and 1 failed to respond. The most commonly isolated pathogens were Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. The very few adverse drug reactions that were seen were transient and comparable in all three groups except for renal function parameters, which deteriorated in 6-8% of patients receiving the aminoglycoside combination. All three antibiotic combinations were similar in effectiveness and safety.

In vivo significance of the inoculum effect of antibiotics on Escherichia coli.

The minimum dosage of antibiotics which reduced mortality in rats intraperitoneally inoculated with an Escherichia coli isolate was determined. Low mortality rates (0-10%) were obtained when antibiotics with minimal or no inoculum effect (cefoxitin, cefmetazole and gentamicin) were administered to yield serum levels 3 to 20 times the MIC, while antibiotics with a pronounced inoculum effect (cefotaxime and aztreonam) had to be administered to yield serum levels 200 to 1,000 times the MIC determined with a standard (low) inoculum. Thus, it seems that the inoculum effect observed in vitro with some antibiotics for Escherichia coli may have clinical significance.

[Aztreonam treatment of severe infections caused by gram-negative aerobic bacilli]. / Le traitement par aztréonam d'infections sévères à bacilles à Gram négatif aérobies.

Twenty nine patients of an intensive care unit (9 women and 20 men), aged 63.9 +/- 15.8 years, with a mean body weight of 62.5 +/- 11.8 kg were treated during 9.4 +/- 2.1 days by aztreonam (2 x 1 g/24 h) administered by short infusion (30 min) for a severe infection due to a Gram-negative bacilli. The primary (n = 25) or nosocomial (n = 4) infection sites were a peritonitis (14), a septicaemia (6), a cholecystitis (6), a pyelonephritis (5), a cholangitis (2), a subphrenic abscess (1) or a pneumonia (2). The isolated Gram-negative bacilli were all susceptible to aztreonam, their MIC being less than or equal to 0.5 micrograms/ml, except for a Pseudomonas aeruginosa (MIC = 4 micrograms/ml). Aztreonam was administered as a single therapy to 7 patients and in association with metronidazole (18) and/or penicillin G (14) to 22 patients; in fact, anaerobes were isolated in ten patients. The mean serum concentrations of aztreonam, as measured by HPLC, before and after the 7th administration respectively were 83.2 +/- 17.5 and 6.1 +/- 5.5 micrograms/ml for peak and through levels. The treatment of the 29 infections was a success in all the cases. No complication occurred due to the presence of Gram positive cocci (n = 4) in the first bacteriological sample, or due to the emergence (n = 12) of Gram positive cocci, except for one case of sepsis of the abdominal wall by Staphylococcus aureus. Aztreonam (2 x 1 g/24 h) may be a suitable alternative for the treatment of severe infections of intensive care units, mostly due to Gram-negative bacilli.

Single dose aztreonam in treating gonorrhoea.

Of 108 consecutive patients with urogenital gonorrhoea treated with a single 1 g intramuscular dose of aztreonam, 102 were suitable for evaluation. There was 100% cure at urogenital sites but treatment failed at three of 14 (21%) rectal or pharyngeal sites. In vitro resistance to aztreonam was not noted.