azlocillin and Neutropenia

The clinical efficacy and toxicity of once-daily compared with multiple-daily gentamicin dosing, in combination with azlocillin, were studied retrospectively in febrile neutropenic episodes following intensive chemotherapy. Fifty-two episodes were studied in 28 patients with acute myeloid leukaemia. Reasons for initiation of antibiotic therapy, dose, duration of treatment, organism isolation rates, response, cost comparison and toxicity were studied in the two treatment groups. The main indication for initiation of antibiotic therapy was neutropenic fever without a documented infection (80.8% of episodes). The response rate to once-daily gentamicin dosing and azlocillin was three times higher than to multiple-daily gentamicin dosing and azlocillin (P = 0.0112). The incidence of toxicity was low overall and was slightly but not significantly higher in the once-daily group. In this clinical context once-daily gentamicin at a dose of 7 mg/kg/day is more effective than a multiple-daily dosing regimen but may be more toxic.

Topics: Adult; Aged; Anti-Bacterial Agents; Antineoplastic Agents; Azlocillin; Bacterial Infections; Female; Gentamicins; Humans; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Neutropenia; Penicillins; Treatment Outcome

A prospective, randomized trial comparing monotherapy with high-dose ciprofloxacin versus a standard combination regimen of azlocillin and netilmicin in the empirical treatment of febrile episodes in neutropenic patients was performed. One hundred and forty-six patient episodes were randomized, but ten (seven ciprofloxacin and three azlocillin/netilmicin) were considered unevaluable for efficacy, and three episodes were withdrawn due to incorrect randomization or non-neutropenia. Of the remaining 133 episodes, infections resolved without modification of therapy in 25/66 (38%) versus 28/67 (42%) of ciprofloxacin and azlocillin/netilmicin treated groups respectively (P = 0.72). Considering all randomized episodes, therapy was modified in 46/73 (63%) episodes with ciprofloxacin and 39/70 (56%) with azlocillin/netilmicin (P = 0.40). Of 73 patient episodes randomized to ciprofloxacin, 25 (34%) received oral follow-on therapy after a median of three days of intravenous therapy. Infections were microbiologically documented in 31/73 (42%) ciprofloxacin and 32/70 (46%) azlocillin/netilmicin, of which 8/27 (30%) and 14/31 (45%) of evaluable episodes resolved without modification of therapy respectively (P = 0.28). Gram-positive organisms accounted for 78% of all organisms cultured with 36% coagulase-negative staphylococci. Bacteriological eradication was recorded in 18/24 (75%) and 26/29 (90%) evaluable patient episodes treated with ciprofloxacin and azlocillin/netilmicin respectively (P = 0.27). Superinfections were seen in 14% of episodes in both groups, and subsequent infections in 12% ciprofloxacin and 14% azlocillin/netilmicin treated patients. Two patients (one ciprofloxacin and one azlocillin/netilmicin) died within 48 h of randomization, and a further 13 patients (four ciprofloxacin and nine azlocillin/netilmicin) died before resolution of neutropenia. Adverse events were recorded in 9% and 15% of ciprofloxacin and azlocillin/netilmicin treated patients respectively, with skin rash (five ciprofloxacin and four azlocillin/netilmicin), nephrotoxicity (two azlocillin/netilmicin), abnormal liver function tests (two azlocillin/netilmicin), ototoxicity (one azlocillin/netilmicin) and nausea (one ciprofloxacin) being the major events recorded. It was concluded that monotherapy with ciprofloxacin at this dosage is a safe alternative to combination therapy with azlocillin/netilmicin, and has the advantages of twice daily administration, iv and oral presentations, no

Topics: Adolescent; Adult; Aged; Azlocillin; Ciprofloxacin; Double-Blind Method; Drug Therapy, Combination; Female; Fever; Humans; Male; Middle Aged; Netilmicin; Neutropenia

Topics: Azlocillin; Ciprofloxacin; Drug Therapy, Combination; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Netilmicin; Neutropenia; Prospective Studies

The authors report treatment of eighteen haematologic patients (twelve male, six female, age between 21 and 78 years), suffering from upper respiratory tract (ten patients) and/or lower urinary tract (eight patients) infections caused by Gram-negative germs, with a combination of ciprofloxacin-azlocillin in the ratio 1:10. Before treatment, the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Fractional Inhibitory Concentration (FIC) index of Gram-negative isolates from patients for the ciprofloxacin-azlocillin combination were evaluated. The in vitro experiments revealed a synergistic activity of the combination for 85% of isolates, while at the same concentration ciprofloxacin alone was 100% effective, and azlocillin alone was 50% effective. The combination was administered to patients as follows: ciprofloxacin: 750 mg "per os" every 12 h; azlocillin 5 g intravenously every 8 h for a therapeutic cycle of 8 days. Seventeen of the eighteen patients that were treated with the combination showed complete eradication of the causative pathogen, sixteen of the eighteen patients recovered fully, whereas the other two showed significant improvements. The tolerability of the combination was excellent in seventeen patients and only one patient developed symptoms of mild gastric intolerance. The results presented here warrant further interest in studies of this antibiotic combination.

Topics: Adult; Aged; Azlocillin; Ciprofloxacin; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hematologic Diseases; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Opportunistic Infections; Prospective Studies

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 randomized multicentre study ciprofloxacin combined with azlocillin was compared with gentamicin and azlocillin for the treatment of febrile episodes in neutropenic patients. In 147 evaluable episodes in 108 patients, 80 patients received ciprofloxacin/azlocillin and 67 received gentamicin/azlocillin. The two treatment groups were comparable in terms of age, underlying diagnosis, and duration of neutropenia. Microbiologically documented infections were the cause of fever in 34 (42.5%) and 29 (43.3%) episodes in the ciprofloxacin/azlocillin and gentamicin/azlocillin groups respectively. At the end of therapy, 46 patients (57.5%) receiving ciprofloxacin/azlocillin showed complete resolution compared with 30 (44.7%) for the gentamicin/azlocillin group (P = 0.14). The clinical response rate for microbiologically documented episodes was 58.8% and 48.3% respectively (P = 0.45). Among the microbiologically documented infections with follow-up cultures available, 24 (92.3%) of 26 isolates from patients receiving ciprofloxacin/azlocillin were eradicated, in comparison with 19 (86.4%) of 22 in the gentamicin/azlocillin group (P = 0.65). There were five superinfections, all in the gentamicin/azlocillin group. Significant resistance to the study drugs was not seen. Of all evaluable patients, including those subsequently withdrawn because of early modification of therapy, there were 12 deaths within the study period; six (6.8%) of these occurred in 88 patients randomized to the ciprofloxacin/azlocillin group, compared with two of 80 (2.5%) in the gentamicin/azlocillin group. Both treatments were generally well-tolerated; one patient in the ciprofloxacin/azlocillin group developed convulsions, probably related to ciprofloxacin. The combination of ciprofloxacin and azlocillin is as effective as gentamicin plus azlocillin and offers a useful alternative for the empirical treatment of febrile neutropenic patients.

Topics: Adolescent; Adult; Azlocillin; Bacterial Infections; Ciprofloxacin; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Neutropenia; Remission Induction; Superinfection

In a randomized trial ceftazidime plus piperacillin or azlocillin, and netilmicin plus piperacillin or azlocillin were used as initial empirical therapy in 202 febrile neutropenic episodes. Netilmicin plus azlocillin was the most effective combination with a clinical response rate of 81% in clinically and microbiologically documented infections compared with 63% for ceftazidime plus piperacillin. All of the episodes of Gram-negative bacteraemia treated with azlocillin responded compared with 43% of those treated with piperacillin. Gram-positive organisms accounted for 52% of all bacteriologically documented infections and 40% of the febrile episodes were treated with vancomycin for presumptive or documented Gram-positive infection. Patients treated with netilmicin had significantly more nephrotoxicity than those given the double beta-lactam combinations (14.8% vs 3.5%; P less than 0.05). However, this difference was not shown in those patients who did not receive concurrent vancomycin or amphotericin. The double beta-lactam combinations were associated with more hypokalaemia (58.2% vs. 37.7%; P less than 0.05) and more colonization with yeasts (24% vs. 10.4%; P less than 0.05) but there was no evidence that their use was associated with prolongation of neutropenia. These results indicate that ceftazidime plus a ureidopenicillin would be adequate empirical therapy in situations where the concomitant use of nephrotoxic agents precludes the use of aminoglycoside containing combinations.

Topics: Adult; Anti-Bacterial Agents; Azlocillin; Bacterial Infections; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fever; Humans; Male; Microbial Sensitivity Tests; Netilmicin; Neutropenia; Penicillin G; Piperacillin; Random Allocation

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

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

Seven febrile neutropenic adults with normal renal function were treated with intravenous gentamicin 4.5 mg/kg once a day in combination with azlocillin. Gentamicin serum concentrations 1, 2, 4, 8, and 24 h after a 30 min infusion were 10.9 +/- 0.6, 7.1 +/- 0.4, 4.2 +/- 0.2, 1.8 +/- 0.1 and 0.16 +/- 0.003 mg/L respectively. The pharmacokinetics were best described by a triphasic plot including a distribution phase (about 1/2 h) and two elimination phases, an early and late.

Topics: Adolescent; Adult; Aged; Azlocillin; Female; Gentamicins; Humans; Leukemia; Lymphoma; Male; Middle Aged; Neutropenia

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

A granulocytopenic mouse model was used to elucidate the impact of dose spacing on the activity of netilmicin against Pseudomonas aeruginosa. A thigh infection was produced and then treated with netilmicin combined with azlocillin. Netilmicin was injected subcutaneously at decreasing doses every 20 min to result in plasma-concentration-time curves similar to those observed in patients on intravenous netilmicin treatment. A once-daily regimen was simulated and compared to a simulated conventional schedule of every 8 h. Identical total amounts of drug were used in both groups of comparatively treated mice. Therapeutic efficacy was quantitated by repeated determinations of surviving organisms in thigh homogenates. Combination therapy was significantly more effective than azlocillin treatment alone. In combination regimens the simulated once-daily netilmicin schedule killed the target organisms faster than the simulated thrice-daily regimen and was significantly more efficacious by 24 and 32 h in two out of three strains of Pseudomonas aeruginosa tested. It is concluded that the results of combination therapy of severe Pseudomonas aeruginosa infections in the immunocompromised host might be improved by choosing an aminoglycoside dosage interval of 24 h instead of the conventional 8 h.

Topics: Animals; Azlocillin; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppression Therapy; Mice; Netilmicin; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

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

Closed-space neutropenic infection sites were simulated in rabbits by subcutaneous semipermeable chambers that were inoculated with 5 X 10(4) CFU/ml of various strains of Streptococcus pneumoniae, Streptococcus faecalis, and Streptococcus avium. Four hours after inoculation, treatment was begun with ciprofloxacin, 10 or 30 mg/kg, azlocillin, 100 mg/kg, amikacin, 15 mg/kg, procaine penicillin G, 300 U/dose, or gentamicin, 2 mg/kg, alone and in two-drug combinations. Antimicrobials were given intramuscularly every 6 hr for 16 doses. Extravascular chambers were sampled throughout the treatment course for bacterial counts and antimicrobial concentration. In vivo results were compared to in vitro tests of inhibition, killing, and synergism. Ciprofloxacin alone had little effect on the animal infection sites. Azlocillin alone reduced, in vivo, eight of 12 isolates greater than or equal to 5 log10 CFU/ml by 92 hr as compared to control. Azlocillin plus ciprofloxacin reduced all 12 isolates greater than or equal to 5 log10 CFU/ml by 92 hr, whereas amikacin plus azlocillin reduced only three and penicillin plus gentamicin only one of the six group D streptococcal isolates greater than or equal to 5 log10 CFU/ml.

Topics: Amikacin; Animals; Azlocillin; Ciprofloxacin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enterococcus faecalis; Female; Gentamicins; Kinetics; Neutropenia; Penicillin G; Rabbits; Streptococcal Infections; Streptococcus; Streptococcus pneumoniae

Combinations of ciprofloxacin with azlocillin, piperacillin and ticarcillin were tested in vitro against clinical isolates. Azlocillin plus ciprofloxacin showed synergy against 30% of Pseudomonas aeruginosa isolates; it was either synergistic or additive against 78% of all isolates tested even those resistant to the beta-lactam. Synergism was rarely noted for Klebsiella pneumoniae, Escherichia coli, Enterobacter spp. or Branhamella spp. isolates. Minimum inhibitory concentrations of ciprofloxacin plus azlocillin, plus piperacillin and plus ticarcillin against Pseudomonas spp. were reduced 4 or 2 fold, respectively. However, the combination azlocillin plus ciprofloxacin showed primarily indifference against gram-positive strains. Neutropenic mice infected with a lethal challenge of Pseudomonas spp. were protected by a combination of azlocillin and ciprofloxacin. Its additive and/or synergistic effects and expanded spectrum of activity against streptococci, methicillin-resistant staphylococci and JK corynebacteria may provide an alternative to traditional therapy.

Topics: Animals; Azlocillin; Bacteria; Carbenicillin; Ciprofloxacin; Drug Synergism; Drug Therapy, Combination; Enterobacteriaceae; Gentamicins; Humans; Listeria monocytogenes; Male; Mice; Neisseriaceae; Neutropenia; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolines; Staphylococcus aureus; Streptococcus; Ticarcillin

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 antibacterial efficacy of azlocillin against Pseudomonas aeruginosa was quantitatively assessed in short-term growth curves in vitro and in a short-term thigh muscle infection in granulocytopenic mice. Ticarcillin was used as the reference drug. The antibacterial effect in vitro was expressed as the difference between the logarithms of the numbers of cfu in the presence and absence of antibiotics (log ratio). The log ratio-time curves could be described by a concentration-dependent parameter, i.e., the inhibition constant (i). According to a standard parallel line bio-assay, based on values of i, azlocillin was 3.80 times more active than ticarcillin (coefficient of variation 27%). Tobramycin in a concentration of 0.19 mg/l, which is not effective in itself, potentiated both drugs by a factor of 3.85 (coefficient of variation 26%). In the in vivo model ticarcillin showed a dose-dependent antibacterial effect, whereas the effect of azlocillin was limited and not dose dependent. The effect of tobramycin in a dose of 4 mg/kg was additive for both penicillins. The results obtained in vivo were less favourable for azlocillin than would be predicted on the basis of the in-vitro results.

Topics: Animals; Azlocillin; Bacteria; Kinetics; Male; Mice; Microbial Sensitivity Tests; Neutropenia; Penicillins; Pseudomonas aeruginosa; Pseudomonas Infections; Ticarcillin; Whole-Body Irradiation

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