azlocillin and Agranulocytosis

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

Efficacy of the cephalosporin, ceftriaxone, was compared with that of the combination of the aminoglycoside, netilmicin, and the penicillin, azlocillin, in the treatment of febrile episodes in immunocompromised neutropenic children undergoing chemotherapy for neoplastic disease. During 100 separate febrile episodes, 40 strains of bacteria were isolated from the blood of 34 patients and a further 55 strains from other sites. Nine strains (four of which were staphylococci) to both netilmicin and azlocillin. There was no difference in clinical response between the two therapeutic regimens as assessed 4 and 7 days after treatment began. Ceftriaxone had the considerable practical advantages of once daily dosage without a need for blood monitoring. Ceftriaxone would appear to be effective as initial monotherapy in the treatment of bacterial infections in severely neutropenic children.

Topics: Adolescent; Agranulocytosis; Azlocillin; Bacteria; Bacterial Infections; Ceftriaxone; Child; Child, Preschool; Fever; Humans; Infant; Neoplasms; Netilmicin; Neutropenia; Randomized Controlled Trials as Topic

In a multicenter, randomized clinical trial, the efficacy of ciprofloxacin plus azlocillin was compared with that of a standard regimen of ceftazidime plus amikacin for the initial empiric treatment of fever in neutropenic cancer patients. In addition, the efficacy of early conversion from intravenous therapy to orally administered ciprofloxacin was compared with that of continued ceftazidime plus amikacin. Seventy-one oncology patients with 79 episodes of fever and neutropenia were randomly assigned to receive initial empiric antibiotic therapy with either intravenously administered ciprofloxacin and azlocillin followed by orally administered ciprofloxacin (regimen 1, 25 episodes); ceftazidime and amikacin (regimen 2, 30 episodes); or ceftazidime and amikacin followed by oral ciprofloxacin (regimen 3, 24 episodes). Microbiologically documented infections were the cause of fever in 10 (40 percent), seven (23 percent), and nine (38 percent) episodes in regimens 1, 2, and 3, respectively, including six, five, and four episodes of bacteremia. Patient survival was 90 to 92 percent in each regimen; however, some modification of antimicrobial therapy occurred in 65, 44, and 41 percent of surviving patients in regimens 1, 2, and 3, respectively. The rate of clearance of initial bacteremia was 67 percent (four of six) in regimen 1, 100 percent (five of five) in regimen 2 and 50 percent (two of four) in regimen 3. Patients in regimens 1 and 3 were able to convert to orally administered ciprofloxacin in 32 (65 percent) of 49 episodes after a mean of six days of intravenous therapy. Superinfections occurred in 24, 10, and 12 percent of patients receiving regimens 1, 2, and 3, respectively, and occurred similarly for patients receiving orally administered ciprofloxacin, 12 percent (four of 32), and intravenous therapy, 17 percent (eight of 47). Parenteral ciprofloxacin was generally well tolerated. One (4 percent) of 25 patients receiving regimen 1 experienced oto- or nephrotoxicity, compared with eight (15 percent) of 54 patients receiving regimens 1, 2, and 3 (p = 0.15), including three patients who required premature termination of aminoglycoside therapy. Our data suggest that the combination of ciprofloxacin and azlocillin is an effective alternative to ceftazidime and amikacin for the initial empiric therapy of febrile neutropenic patients, is generally well tolerated, and avoids the oto- and nephrotoxicity associated with aminoglycoside use. In addition, a majo

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Amikacin; Azlocillin; Bacterial Infections; Ceftazidime; Ciprofloxacin; Drug Therapy, Combination; Female; Fever; Humans; Male; Middle Aged; Multicenter Studies as Topic; Neutropenia; Random Allocation

One hundred and two patients with neutropenia (less than 1 x 10(9)/L) secondary to primary hematological disorders or chemotherapy for hematological malignancies were prospectively randomised, upon the development of fever or other signs of infection, to receive empirical antibiotic treatment with either ceftazidime (+/- flucloxacillin) (n = 52) or azlocillin plus amikacin (+/- flucloxacillin) (A&A, n = 50). The two groups were equivalent with respect to clinical and laboratory parameters prior to antibiotic therapy and flucloxacillin was added to approximately 25% of the patients in each group on the clinical suspicion of Gram positive infection. When assessed at 96 hours, the complete response rates were 59.6% for the ceftazidime treated patients and 44% for A&A treated patients. Partial response rates were 17% and 20% respectively. This difference was not statistically significant. Eight patients died whilst on the trial, three of those initially randomised to ceftazidime and five initially randomised to A&A. Moderate to severe hypokalemia was encountered significantly less often in the ceftazidime treated group (p less than 0.01), whilst other parameters of toxicity were equivalent. No primary or acquired resistance to ceftazidime was encountered. Separate analysis of those patients who did not receive flucloxacillin yielded identical results. We conclude that ceftazidime (+/- flucloxacillin) is as efficacious as azlocillin plus amikacin (+/- flucloxacillin) in the empirical antibiotic management of such patients and is associated with a lower incidence of moderate to severe hypokalemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Amikacin; Azlocillin; Bacterial Infections; Ceftazidime; Drug Therapy, Combination; Female; Fever; Floxacillin; Hematologic Diseases; Humans; Male; Middle Aged; Neutropenia; Randomized Controlled Trials as Topic; Remission Induction; Therapeutic Equivalency

We have evaluated the azlocillin-amikacin combination, given at a daily dose of 200 mg/kg and 15 mg/kg respectively, in the treatment of 62 consecutive febrile granulocytopenic patients (less than 500 PMN/microliters) affected by hematological disease. The effectiveness of the treatment was assessed in 60 patients, 44 (73%) of whom responded within 96 hours from the beginning. 36 of the responders showed microbiological and clinical infections, 2 had clinically documented pneumonia and 6 a possible infection. No improvement was obtained in 16 patients; 7 of whom suffered from clinical and microbiological infection, 2 from pulmonary mycosis, 4 from possible infection and 3 from doubtful infection. Seven of these patients subsequently responded to a proven antibiotic treatment, while only one of the remaining responded to a second-line empirical antibiotic schedule. These results suggest that the combination of azlocillin-amikacin was able to overcome about two-thirds of the infections, representing an effective remedy for the empiric treatment of febrile neutropenic patients.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amikacin; Azlocillin; Bacterial Infections; Child; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neutropenia

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

Topics: Agranulocytosis; Azlocillin; Child; Clinical Trials as Topic; Escherichia coli Infections; Female; Fever; Humans; Male; Neoplasms; Neutropenia; Penicillins; Pseudomonas Infections; Staphylococcal Infections; Ticarcillin

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

A multicentre clinical trial was organized by the International Antimicrobial Therapy Project Groups of the European Organisation for Research on the Treatment of Cancer (E.O.R.T.C.) to compare the effectiveness of three combinations of antibiotics (azlocillin + amikacin; cefotaxime + amikacin and ticarcillin + amikacin) in patients with malignant leukopenic and febrile diseases (polymorphonuclears less than 1000/mm3; temperature greater than 38.5 degrees C). Some 800 patients from 20 centres entered the study. Preliminary results in 421 assessable patients showed a 62% positive response rate. The response rate in patients with bacteraemia was twice as high in the azlocillin group than in the other groups, the difference being significant at p less than 0.02. This difference does not seem to be due to a distribution bias, since the responsible micro-organisms, the severity of granulopenia, the incidence of bacterial-resistant strains, etc., were similar in all three groups. Similarly, the death rate was 12% in the azlocillin-amikacin group as against 15% and 17% respectively in the other groups. It would appear from this trial that the azlocillin-aminoglycoside treatment is superior to the other antibiotic combinations tested in this category of patients.

Topics: Agranulocytosis; Amikacin; Azlocillin; Bacterial Infections; Cefotaxime; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Neoplasms; Penicillins; Ticarcillin

Fifty consecutive episodes of fever in neutropenic children with malignant disease or aplastic anaemia were randomized to treatment with either ceftazidime alone or a combination of azlocillin and tobramycin, pending the results of bacteriological investigation. More than 90% of organisms isolated from these episodes were sensitive to ceftazidime, which appears to be a non-toxic alternative to aminoglycosides in such circumstances.

Topics: Adolescent; Agranulocytosis; Anemia, Aplastic; Azlocillin; Bacterial Infections; Ceftazidime; Cephalosporins; Child; Child, Preschool; Drug Therapy, Combination; Fever; Humans; Infant; Neoplasms; Neutropenia; Penicillins; Random Allocation; Tobramycin

A significant decrease in resistance to infections caused by gramnegative pathogens was observed in mice with neutropenia induced by cytostatics. Efficacy of schemes for combined chemotherapy with beta-lactams, aminoglycosides and a novel peptide antibiotic was studied on model infections in mice with neutropenia. In the neutropenic mice with sepsis caused by Pseudomonas the peptide antibiotic administered parenterally in a single dose of 50 micrograms/kg provided high therapeutic activity. In combination with azlocillin, cefotaxime and amikacin the peptide antibiotic has a synergistic therapeutic action.

Topics: Agranulocytosis; Amikacin; Animals; Azlocillin; Cefotaxime; Drug Synergism; Drug Therapy, Combination; Escherichia coli Infections; Immune Tolerance; Klebsiella Infections; Mice; Neutropenia; Opportunistic Infections; Pseudomonas Infections

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

Neutropenic patients are at risk of serious infection caused by gram-negative bacilli and staphylococci. The mortality rate associated with gram-negative bacteremia in these patients is extremely high, especially in those with persistent and profound granulocytopenia. In these latter patients, the best results have been obtained by administering combinations of antibiotics in which both agents are active and/or show in vitro synergism against the infecting organism. Most combinations include an aminoglycoside such as amikacin and a broad-spectrum beta-lactam antibiotic, such as azlocillin, mezlocillin, piperacillin, or ceftazidime. The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer has completed several studies evaluating various antibiotic combinations in the empiric treatment of febrile neutropenic patients. These trials have evaluated cephalothin plus gentamicin, carbenicillin plus gentamicin, and cephalothin plus carbenicillin; carbenicillin plus amikacin and carbenicillin plus amikacin plus cefazolin; azlocillin plus amikacin, ticarcillin plus amikacin, and cefotaxime plus amikacin; and azlocillin plus amikacin versus ceftazidime plus long- or short-course amikacin. The preclinical evaluation of antibiotic combinations usually involves the in vitro testing of antibiotics alone and in combination by the checkerboard method or with the use of time-kill curves. However, these methods expose the bacterial culture to a static or constant concentration of the drugs. During the in vivo treatment of infections, bacteria are exposed to changing concentrations of antibiotics, which are contingent on the individual pharmacokinetics of these drugs. We have designed a two-compartment in vitro pharmacokinetic model that allows the simultaneous study of the activity of two antibiotics with similar or different half-lives against a number of bacteria. Amikacin and azlocillin have been studied alone and in combination in this model against Pseudomonas aeruginosa, a frequent cause of bacteremia in neutropenic patients. In pharmacologically relevant doses, amikacin alone produced rapid bacterial killing, followed by regrowth of resistant subpopulations. Azlocillin alone produced a more gradual reduction of the bacterial inoculum, with ultimate bacteriostasis. Amikacin plus azlocillin produced rapid and complete eradication of the organism. In vitro pharmacokinetic models may prove to be more predictiv

Topics: Agranulocytosis; Amikacin; Aminoglycosides; Anti-Bacterial Agents; Azlocillin; Bacterial Infections; Carbenicillin; Cefazolin; Cephalothin; Drug Therapy, Combination; Gentamicins; Humans; Models, Biological; Neutropenia; Pseudomonas Infections; Risk

The efficacy of beta-lactam antibiotics and amikacin alone and in various combinations against Pseudomonas aeruginosa was studied in a rabbit model simulating a closed-space infection in a locally neutropenic site. Six strains of P. aeruginosa were studied in semipermeable chambers placed subcutaneously in rabbits. Therapy was begun 4 h after inoculation of 5 X 10(4) CFU of bacteria per ml of pooled rabbit serum into the chambers. Antibiotics were administered intramuscularly every 6 h for 16 doses. Quantitative bacteriology was measured at the start of therapy and at 20, 44, and 92 h thereafter. Antibiotic concentrations were measured in blood and chamber fluid. Results were compared with in vitro tests of susceptibility and synergy. No single-agent therapy eradicated any of the six test organisms. Azlocillin (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated five of six organisms by 92 h, and ceftizoxime (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated three of six test strains. Azlocillin plus ceftizoxime (each 100 mg/kg per dose) failed to eliminate any of the six strains. To eliminate P. aeruginosa in this model, two drugs were required, with one being an aminoglycoside. In vitro susceptibility tests of synergy were predictive of successful therapy whenever the antibiotic concentrations (free and total) at the infection site exceeded the MBC for both the aminoglycoside alone and the beta-lactam when tested in combination with amikacin.

Topics: Agranulocytosis; Amikacin; Animals; Anti-Bacterial Agents; Azlocillin; Cefotaxime; Cefoxitin; Ceftizoxime; Disease Models, Animal; Drug Combinations; Female; Hydrogen-Ion Concentration; Kanamycin; Microbial Sensitivity Tests; Neutropenia; Penicillins; Protein Binding; Pseudomonas Infections; Rabbits

Studies of therapy for experimental pneumonia due to Pseudomonas aeruginosa have failed to document beta-lactam-aminoglycoside synergy for most antibiotics examined, in contrast to results usually observed with pseudomonas infections at other sites. The neutropenic guinea-pig model of pseudomonas pneumonia was modified to resemble more closely therapy for clinical infections. Animals were treated 16 hr after infection with ticarcillin, azlocillin, ceftazidime, tobramycin, and netilmicin, alone and in combination. As predicted by in vitro synergy testing, in all cases combination drug therapy was more effective than the corresponding drugs given alone (P less than .05), as assessed by quantitative lung culture. Among single-drug regimens, those in which peak antibiotic levels did not exceed the minimal bactericidal concentration for the organism were significantly less effective. Resistance to aminoglycosides did not develop during therapy, and therefore, in this study does not explain the mechanism of synergy observed with beta-lactam antibiotics.

Topics: Agranulocytosis; Aminoglycosides; Animals; Anti-Bacterial Agents; Azlocillin; Ceftazidime; Cephalosporins; Drug Synergism; Drug Therapy, Combination; Guinea Pigs; Netilmicin; Neutropenia; Penicillin Resistance; Penicillins; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Ticarcillin; Tobramycin