azlocillin and Sepsis

Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS).. This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates.. A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin.. Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

Topics: Anti-Bacterial Agents; Azlocillin; Humans; Infant, Newborn; Microbial Sensitivity Tests; Prospective Studies; Sepsis

In the four EORTC International Antimicrobial Therapy Cooperative Group trials, the frequency of gram-positive isolates has increased significantly from 29% of single-organism bacteraemias in trial I (1973-1976) to 41% in trial IV (1983-1985). In trial IV febrile and neutropenic (less than 1000 polymorphonuclear lymphocytes per microliter) cancer patients were randomized prospectively to receive either azlocillin plus a long course (at least 9 days) of amikacin, or ceftazidime plus a short course (3 days) of amikacin, or ceftazidime plus a long course of amikacin. Without modification of the allocated antibiotics, the overall response rates for gram-positive bacteraemias were similar for all three regimens (19/37 [51%], 8/23 [35%] and 14/30 [47%]), respectively. However, in patients with prolonged and severe neutropenia, treatment with azlocillin plus amikacin was significantly more effective than with ceftazidime plus 3 days' amikacin (7/10 vs. 0/7). The overall response rate for these infections was significantly lower than that observed in trial I (46% vs. 74%), but this was not associated with increased mortality. The response to treatment was significantly influenced by the susceptibility of the infecting strain to the beta-lactam. Multivariate analysis revealed that increasing age, presence of a central venous catheter and resistance to beta-lactam adversely affected outcome. Future studies should be designed to improve the outcome of gram-positive bacteraemia in neutropenic patients with cancer.

Topics: Agranulocytosis; Amikacin; Azlocillin; Bacterial Infections; Ceftazidime; Drug Therapy, Combination; Gram-Positive Bacteria; Humans; Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic; Sepsis

To determine whether combination antibiotic therapy including a short course of an aminoglycoside was as effective and less toxic than a conventional long course of the combination for the empirical therapy of gram-negative bacteremia in patients with cancer and granulocytopenia, we conducted a randomized multicenter trial comparing ceftazidime plus a short course (three days) of amikacin, ceftazidime plus a long course (nine days) of amikacin, and azlocillin plus a long course (nine days) of amikacin. Single-organism gram-negative bacteremia occurred in 129 of 872 evaluable patients. Without a change in antibiotics, the response rates were 81 percent with ceftazidime and long-course amikacin, 48 percent with ceftazidime and short-course amikacin (P = 0.002), and 40 percent with azlocillin and long-course amikacin (P less than 0.001). Among patients with fewer than 100 granulocytes per cubic millimeter throughout therapy, the response rates were 6 percent with ceftazidime and short-course amikacin and 50 percent with ceftazidime and long-course amikacin (P = 0.03). Linear logistic-regression analysis showed that therapy with ceftazidime and long-course amikacin was the most favorable prognostic factor of the response to infection, whereas the presence of leukemia or shock was the least favorable. We conclude that ceftazidime should be given in combination with a conventional full course of an aminoglycoside (amikacin) when used for the empirical treatment of gram-negative bacteremia in cancer patients with granulocytopenia.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amikacin; Azlocillin; Ceftazidime; Child; Child, Preschool; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Humans; Leukemia; Leukocyte Count; Male; Middle Aged; Neoplasms; Prognosis; Random Allocation; Regression Analysis; Sepsis

The standard regimen used by members of the European Organization for Research on Treatment of Cancer Antimicrobial Therapy Cooperative Group for empiric therapy of febrile neutropenic cancer patients has been treatment with ticarcillin plus amikacin. A three-arm prospective randomized controlled trial was performed to determine whether the extended-spectrum antipseudomonal penicillin azlocillin or the extended-spectrum cephalosporin cefotaxime had more or less efficacy than the beta-lactam in the ticarcillin-plus-amikacin regimen. A total of 742 patients from 22 institutions were evaluated. Single gram-negative rod bacteremias accounted for 83 episodes, and it was among these patients that the prognosis was least satisfactory, leading to a more intensive evaluation of this patient group. In these patients the azlocillin-plus-amikacin regimen resulted in a 66% response rate, compared with a 37% response rate for patients who received cefotaxime plus amikacin (P = 0.080) and a 47% response rate for patients who received ticarcillin plus amikacin (P = 0.207). The patients with gram-negative rod bacteremias and persistently profound granulocytopenia had substantially poorer response rates (37%) than the patients with rising granulocyte counts (73%; P = 0.004). A logistic regression analysis indicated that the following factors also affected infection resolution: beta-lactam utilization in the regimen (azlocillin was better than ticarcillin or cefotaxime), resolution of profound granulocytopenia (less than 100 cells per microliter) during therapy, and susceptibility to the beta-lactam antibiotic.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amikacin; Azlocillin; Cefotaxime; Child; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fever; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Kanamycin; Male; Middle Aged; Penicillins; Prospective Studies; Random Allocation; Regression Analysis; Sepsis; Ticarcillin

Azlocillin, an acylureidopenicillin particularly active against Pseudomonas aeruginosa, was used to treat 124 patients, 36 of whom were children, presenting with pulmonary infections (including cystic fibrosis), urinary, genital, intra-abdominal, osteoarticular and skin infections as well as septicaemia, otitis and meningitis. The causative agent in all cases was Ps. aeruginosa either alone or associated with other pathogens. Azlocillin was administered alone in 75% of the cases and in combination with an aminoglycoside in 25%. Dosage was 240 mg/kg/24 h in three intravenous infusions in adults and in children older than 3 months, and 75 to 225 mg/kg/24 h in two intravenous injections in neonates and prematures. The duration of treatment varied according to the site of infection, with a mean of 10 days. One-hundred and eight pathogenic organisms were isolated, including 114 strains of Pseudomonas, 43 of which were carbenicillin-resistant. A satisfactory clinical response was observed in 86.5% of the infections. The bacteriological response was similar to the clinical response, with 76.6% cures, 10% improvements and 13.5% failures. Microbiologically, 77.5% of the germs were eradicated, 7.5% reappeared and 15% persisted. Azlocillin was well tolerated systemically and biochemically and had no detrimental effect on renal function.

Topics: Adult; Azlocillin; Bacterial Infections; Child; Clinical Trials as Topic; Humans; Meningitis; Middle Aged; Otitis Media; Penicillins; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sepsis; Urinary Tract Infections

To assess the effectiveness of combined therapy with azlocillin and amikacin in a group of neonates with sepsis caused by multiresistant staphylococci who were hospitalized in the neonatal intensive care unit of Hospital Ginecobstétrico "America Arias" in Havana, Cuba, from 1998 to 2000.. A retrospective study was carried out of the clinical and laboratory results obtained in 15 patients with sepsis caused by multiresistant staphylococci who received combined therapy with azlocillin and amikacin, according to hospital guidelines on the use of antibiotics. We used a broth microdilution method to study the patterns of resistance shown by isolated strains to 10 of the antibiotics in use. In vitro synergy tests, specifically the checkerboard technique with microtitration plates, were used to observe the effects of treatment in 8 patients.. Twelve coagulase-negative staphylococci and three Staphylococcus aureus isolates showed five different patterns of resistance on the basis of their sensitivity to oxacillin, three aminoglycosides, and vancomycin. Six of the synergy tests showed a considerable synergistic effect, with an average three-fold reduction in the minimum inhibitory concentrations (MIC) of the two antibiotics used to treat the patients. No antagonistic effects were noted, and the combined antibiotics showed an overall clinical effectiveness of 91.7%.. The test showed that the therapeutic combination used was effective, but further studies are needed before conclusive results are obtained.

Topics: Amikacin; Anti-Bacterial Agents; Azlocillin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Microbial Sensitivity Tests; Models, Theoretical; Retrospective Studies; Sepsis; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus

The in-vitro susceptibility pattern to newer beta lactams namely Ticer/Clav, Azlocillin, Piperacillin and Imipenem was determined with 50 clinical strains isolated from neutropenic patients with strains isolated from neutropenic patients with sepsis, with an objective of evolving a strategy for empirical antibiotic therapy for febrile neutropenic patients. The MIC90 value for Imipenem for the Gram negative bacilli tested, other than Pseudomonas was < 0.25 mcg/ml therapy revealing a high degree of susceptibility, while for Ps. aeruginosa and related species MIC50 and MIV90 values were 2.0 and 64.0 micrograms/ml respectively. A comparatively lower degree of susceptibility was found among Gram negative bacilli included in the study to ticar/clavu, azlocillin and piperacillin indicating a moderate degree of resistance to these antibiotics. The data from this study suggests that (i) Ureidopenicillins with an aminoglycoside should be effective therapy for proven Pseudomonas and other Gram negative sepsis in febrile neutropenic patients. (ii) Imipenem would be the antibiotic of choice in Gram negative bacterial sepsis in febrile neutropenic patients where the organism is resistant to cephalosporins and ureidopenicillins.

Topics: Anti-Bacterial Agents; Azlocillin; Clavulanic Acid; Clavulanic Acids; Drug Evaluation; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Imipenem; Neutropenia; Piperacillin; Pseudomonas aeruginosa; Sepsis; Ticarcillin

In-vitro and clinical efficacy of a combination therapy consisting of 3 antibiotic agents was to be assessed in neonatal septicemia.. From 1980 to 1987, 152 newborns with septicemia as proven by blood culture were treated with an initial antibiotic regimen consisting of azlocillin (150 mg/kg bw), cefotaxime (100 mg/kg bw), and tobramycin (5 mg/kg bw).. According to the microbiologic testing, antimicrobic therapy was effective in each of the 152 organisms: 101/152 bacteria were susceptible to all 3 agents; resistance to 1 or 2 of the antibiotics was evident in 33/152 and in 18/152 organisms, respectively. Mortality due to septicemia was 7.2%.. As no difference was observed in the frequency in which one of the three antibiotic substances was the only effective drug, each of the 3 agents seemed to be necessary for clinical effectiveness of this antibiotic combination.

Topics: Azlocillin; Bacteriological Techniques; Cefotaxime; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Microbial Sensitivity Tests; Risk Factors; Sepsis; Staphylococcal Infections; Streptococcal Infections; Streptococcus agalactiae; Tobramycin

Topics: Anti-Bacterial Agents; Azlocillin; Bacteria; Ciprofloxacin; Clinical Trials as Topic; Critical Care; Drug Therapy, Combination; Humans; Intensive Care Units; Microbial Sensitivity Tests; Pneumonia, Bacterial; Sepsis

The efficacy of azlocillin, ticarcillin, and amikacin as single agents and the penicillin/amikacin combinations for treatment of Pseudomonas aeruginosa bacteremia during cyclophosphamide-induced severe neutropenia in a rat model were assessed. Equivalent antibiotic dosing was based on the time rat serum antibiotic levels were above the minimal bactericidal concentration for the challenge organism. Antibiotic therapy was administered for 62 hours after bacterial challenge. Antimicrobial efficacy was based on the rate of bacteremia, the emergence of resistant organisms during therapy, life-table survival analysis, and rat survival seventy-two hours after bacterial challenge. For infection with a P. aeruginosa strain susceptible to all study antibiotics, therapy with azlocillin and ticarcillin (given so as to be equipotent) were equivalent, as judged by bacteremia rates or rat survival. However, combination therapy prevented the emergence of organisms resistant to azlocillin, but not to ticarcillin. Amikacin-containing combinations were more effective than single-agent regimens.

Topics: Agranulocytosis; Amikacin; Animals; Azlocillin; Drug Therapy, Combination; Female; Kanamycin; Microbial Sensitivity Tests; Neutropenia; Penicillin Resistance; Penicillins; Pseudomonas Infections; Rats; Rats, Inbred Strains; Sepsis; Ticarcillin

Azlocillin was administered alone to seven patients without malignant or blood disease presenting with septicaemia caused by Pseudomonas aeruginosa. In 6 cases the infection developed after surgery and in 3 of these it was responsible for a state of shock, twice associated with acute anuric renal failure. The minimum inhibitory concentrations of azlocillin varied from 2 to 32 micrograms/ml; 5 strains were resistant to carbenicillin. The minimum inhibitory to minimum bactericidal concentrations ratio, measured on five occasions, was equal to 2. Bacterial eradication was obtained in 6 patients. One patient with multivisceral failure died during treatment and in this case the responsible organism had become resistant to azlocillin.

Topics: Adult; Aged; Azlocillin; Carbenicillin; Female; Humans; Male; Middle Aged; Penicillin Resistance; Penicillins; Postoperative Complications; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Shock, Septic

Of the pathogens causing septicaemia due to Gram-negative bacteria at Zentrum der Inneren Medizin, Frankfurt, over a 7-year period (1974-80), 16.8 per cent were due to P. aeruginosa. Analysis of all septicaemias over this period, however, shows a decrease from 13 per cent in the 3-year period 1974-76 to 8 per cent in 1977-79 and 5 per cent P. aeruginosa septicaemia in 1980. The overall mortality rate was 66 per cent, most of the patients dying within 24 hours. Azlocillin and Piperacillin are at present the drugs of choice for systemic therapy of pseudomonas infections, preferably in combination with an aminoglycoside.

Topics: Anti-Bacterial Agents; Azlocillin; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis

Clinical studies with azlocillin were conducted in North America and Europe to assess its efficacy and to monitor its safety. The results of studies from these two areas are compared retrospectively. In North America 631 multiple-dose courses were monitored, while 887 were given in Europe. The most frequently administered daily dose was 18 g in North America and 15 g in Europe. In 71% of the courses a Pseudomonas species was the causative infecting organism in the former area and 51% in the latter. Over 60% of the patients were seriously ill, and about a third were over 60 years of age. A satisfactory bacteriological response, as defined by the eradication or a marked reduction of the organism causing infection was obtained in 74% of patients in North America and in 75% in Europe. 89% of the patients in America responded clinically compared to 92% in Europe. Ps. aeruginosa was eradicated in over 70% of instances. Azlocillin, like other penicillins, possesses a low potential for toxicity. Hypersensitivity reactions and gastrointestinal effects were the most common adverse experiences. No serious problems were encountered with impairment of renal or hepatic function, or blood coagulation. Azlocillin was effective for treating serious infections caused primarily by Ps. aeruginosa.

Topics: Adolescent; Adult; Aged; Azlocillin; Bacterial Infections; Child; Child, Preschool; Humans; Infant; Middle Aged; Penicillins; Respiratory Tract Infections; Sepsis; Urinary Tract Infections

An 8-day-old, 2.48-kg, 35-week gestation infant developed neonatal sepsis and meningitis due to Flavobacterium meningosepticum serotype F. Treatment with a new antibiotic, azlocillin, in combination with chloramphenicol, led to complete recovery.

Topics: Azlocillin; Bacterial Infections; Chloramphenicol; Flavobacterium; Humans; Infant, Newborn; Male; Meningitis; Penicillins; Sepsis

The in vitro activities of azlocillin and cefotaxime in combination and of azlocillin and tobramycin in combination against 100 blood isolates and 50 multidrug-resistant isolates were compared. With both combinations, antibacterial spectrums were complementary. Although synergy against individual strains was infrequently observed (except for azlocillin-cefotaxime against Streptococcus faecalis and azlocillin-tobramycin against Pseudomonas aeruginosa), 97% of blood isolates and 76% of multidrug-resistant isolates were susceptible to azlocillin-cefotaxime, and 94% of blood isolates and 36% of multidrug-resistant isolates were susceptible to azlocyclin-tobramycin.

Topics: Anti-Bacterial Agents; Azlocillin; Bacteria; Cefotaxime; Drug Interactions; Humans; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Sepsis; Tobramycin

Topics: Azlocillin; Cephalosporins; Cephalothin; Humans; Mezlocillin; Penicillins; Sepsis; Splenomegaly