netilmicin and Neutropenia

The authors had for aim to assess the effectiveness and toxicity of a piperacillin-tazobactam-netilmicin combination, and the possibility of avoiding using glycopeptide, in children with febrile neutropenic episodes induced by chemotherapy.. A retrospective study was made, including children treated for a febrile neutropenic episode (absolute neutrophile count < 0.5 x 10(9)/l) by a piperacillin-tazobactam-netilmicin combination. If fever persisted 48 hours after the beginning of antibiotic therapy, a glycopeptide could be added. The responses to the treatment were defined as follows: 1) total success (no fever or documented infection) at 48 hours and at 72 hours following the beginning of treatment; 2) partial success (apyrexia beyond 72 hours without any therapeutic change); 3) failure (persistent infectious signs 48 hours after the introduction of glycopeptide).. Sixty-nine episodes were assessable, corresponding to 41 patients, treated for a solid tumour (29), an acute leukaemia in remission (11), or a metabolic disease (1). The febrile episodes were divided into fever of unknown origin (71%), microbiologically documented fever (12%), and clinically documented fever (17%). No death occurred, no toxicity was reported. With this antibiotic therapy, total success at 72 hours was observed in 72% in case of fever of unknown origin and 45% in case of documented infections. The success rate reached 84% when a glycopeptide was added (30% of the cases).. The piperacillin-tazobactam-netilmicin combination is very effective and well tolerated in probabilistic treatment of febrile neutropenia induced by chemotherapy, but does not allow to decreasing the frequency of glycopeptide administration.

Topics: Adolescent; Anti-Bacterial Agents; Antineoplastic Agents; Bacterial Infections; Child; Child, Preschool; Clinical Trials as Topic; Drug Combinations; Drug Evaluation; Escherichia coli Infections; Female; Fever; Fever of Unknown Origin; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Male; Neoplasms; Netilmicin; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Postoperative Complications; Retrospective Studies; Treatment Outcome; Urinary Tract Infections

The prevention and treatment of infections are major issues of supportive care in patients with haematological malignancies. Because of their broad antimicrobial activity, the use of fluoroquinolones for prophylaxis in neutropenic patients has been extensively studied. In comparison with placebo, norfloxacin reduces the incidence of Gram-negative infections, whereas Gram-positive bacterial and fungal infections remain unaffected. Ofloxacin and enoxacin also bacterial and fungal infections remain unaffected. Ofloxacin and enoxacin also produce a reduction in fever and documented infections. In randomized studies comparing ciprofloxacin with cotrimoxazole (trimethoprim/sulfamethoxazole) plus colistin (each in combination with nonabsorbable antifungal agents), conflicting results were obtained. The incidence of documented Gram-negative bacterial infections was markedly reduced by ciprofloxacin prophylaxis; however, the number of Gram-positive infections may increase dramatically. Combining ciprofloxacin with a macrolide antibiotic in an attempt to prevent streptococcal infections can result in breakthrough bacteraemias due to resistant Gram-positive pathogens. Empirical antimicrobial therapy after quinolone prophylaxis should also be directed against microorganisms susceptible to quinolones, since sustained eradication by oral administration cannot be assumed with certainty. Clinical trials comparing intravenous quinolones in combination with aminoglycosides with widely used standard regimens for the treatment of infections in cancer patients indicate equivalent efficacy; however, in studies of ciprofloxacin alone, response rates were significantly lower compared with standard combinations. Therefore, quinolone monotherapy as empirical treatment in febrile neutropenic patients cannot be recommended.

Topics: Anti-Infective Agents; Drug Therapy, Combination; Fluoroquinolones; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Netilmicin; Neutropenia; Penicillins

We evaluated piperacillin-tazobactam in association with netilmicin (TN) in the early empirical treatment of neutropenic children, as data are limited in number.. In 1996, an observational study was initiated to assess the efficacy and safety of this association, with a glycopeptide (TNG) if needed. The impact on the bacterial ecology of our unit was also observed. Children were treated for hematological malignancy or solid tumor between September 1996 and December 1998 and presented a febrile neutropenia.. There were 148 evaluable febrile neutropenic episodes in 104 patients. Median age was 7 years, 55% of the episodes were fever of unknown origin, 22% were clinically documented and 23% microbiologically documented (27 bacteriemia). A glycopeptide was added in 67 episodes. The initial unmodified treatment was successful in 114 episodes (77%): 75/81 episodes in the TN group and 39/67 in the TNG group. For successful episodes, median treatment duration was 6 days. There were 22 febrile recurrences. These patients, as well as initial failures, always responded to a second-line treatment. One child was considered a failure because he developed a skin rash probably due to piperacillin-tazobactam and required another beta-lactamase.. This study suggests that piperacillin-tazobactam in association with netilmicin presents a satisfactory efficacy and a good tolerance as empirical therapy for febrile neutropenic children. It allowed us to maintain the bacterial ecology of our unit.

Topics: Adolescent; Anti-Bacterial Agents; Antineoplastic Agents; Child; Child, Preschool; Drug Therapy, Combination; Enzyme Inhibitors; Female; Fever; Follow-Up Studies; Humans; Infant; Male; Netilmicin; Neutropenia; Penicillanic Acid; Piperacillin; Recurrence; Tazobactam; Treatment Outcome

The aim of this study was to evaluate the efficacy and safety of meropenem plus amikacin compared with piperacillin-tazobactam plus netilmicin for initial empirical antibiotic treatment of high-risk febrile neutropenia in children with cancer. Patients with hematologic malignancy (leukemia or stage III/IV non-Hodgkin lymphoma) who presented with fever and neutropenia (ANC < 500/mm3) and patients with solid tumors who presented with fever and severe neutropenia (ANC < 100/mm3) were considered to be at high risk and eligible for this study. In this prospective study, 33 patients with 50 febrile neutropenic episodes received i.v. neropenem (20 mg/kg every 8 h) plus amikacin (15 mg/kg/d in 2 divided doses) (in 31 episodes) or piperacillin/tazobactam (100 mg/4 mg/kg every 8 h) plus netilmicin (7 mg/kg every 24 h) (in 19 episodes). Clinical response was determined at 72 h and at completion of the therapy. The groups were comparable in terms of age, sex, initial ANC, use of growth factors, and classification of the infections. An infection was documented microbiologically in 12 episodes (39%) in the meropenem plus amikacin group and in 8 episodes (42%) in the piperacillin/tazobactam plus netilmicin group. Of the 22 microbiological isolates, 37% were gram-positives, 45% were gram-negatives, and 18% were fungi. Most of the clinically documented infections were of lower respiratory tract, gastrointestinal mucosa, or urinary tract origin. The mean duration of neutropenia was 9 days in both groups. Fever persisted for 1-30 days (mean 3 vs. 5 days). The success rate with initial empiric therapy was 52% in the meropenem plus amikacin and 42% in the piperacillin/tazobactam plus netilmicin group, respectively (p = .5). Total success rate (with or without modification) was 97% vs. 90% in the episodes. Three patients died due to infection (1 vs. 2 patients). No major adverse effects were observed in each group. Empirical therapy with meropenem plus amikacin or piperacillin/tazobactam plus netilmicin for high-risk febrile neutropenia is equally effective and safe in pediatric cancer patients.

Topics: Amikacin; Anti-Bacterial Agents; Drug Therapy, Combination; Fever; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Hematologic Neoplasms; Humans; Infections; Meropenem; Neoplasms; Netilmicin; Neutropenia; Penicillanic Acid; Piperacillin; Tazobactam; Thienamycins

Infection remains the major cause of morbidity and mortality in immunocompromised children with malignancy. In addition, the economic impact of antibiotic treatment should always be evaluated, especially in developing countries. In our center between January 1998 and January 1999, 73 children with hematological malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML)]; 9 children with solid tumors (rhabdomyosarcoma, neuroblastoma) had 87 febrile neutropenic episodes (related to chemotherapy). These children were randomized prospectively into three treatment groups. The first group (n: 28) received cefepime plus netilmicin, while the second group (n: 29) was treated with ceftazidime plus amikacin and the third (n: 30) with meropenem as monotherapy. The aim of the study was to compare the success rates and cost of fourth generation cephalosporin plus aminoglycoside and monotherapy of meropenem with ceftazidime plus amikacin, which is the standard therapy for febrile neutropenia. Microbiologically documented infections were 29.9%, clinically documented infections were 9.2% and 60.9% of the febrile neutropenic episodes were considered to be FUO. Gram-positive microorganisms were the most commonly isolated agents from blood cultures [MRSA (Methicillin Resistant Staphylococcus aureus) in 6 patients and MSSA (Methicillin Sensitive Staphylococcus aureus) in 4 patients]. The success rates were 78.5%, 79.3% and 73.3 % for the 1st, 2nd and 3rd groups respectively. In 4 patients (4.5%) fever responded only to amphotericin-B therapy. There was no statistically significant difference between the three treatment regimens with respect to efficacy, safety and tolerance (chi2 test, p>0.05), but while the third and fourth generation cephalosporins + aminoglycosides were comparable for cost, the monotherapy regimen was the most expensive. The main determining factors for the choice of treatment of febrile neutropenic children, especially in a developing country, are cost, presence of indwelling catheter and the bacterial flora of the unit, as well as efficacy.

Topics: Adolescent; Adult; Amikacin; Cefepime; Cephalosporins; Child; Child, Preschool; Cost-Benefit Analysis; Drug Therapy, Combination; Female; Fever; Humans; Infant; Male; Meropenem; Neoplasms; Netilmicin; Neutropenia; Prospective Studies; Thienamycins; Turkey

To reduce drug acquisition costs, the clinical and bacteriological efficacy of low-dose ceftazidime i.v. (1 g tid) was compared with cefotaxime i.v. (2 g tid). Both regimens were combined with netilmicin i.v. (2 mg/kg bodyweight tid), in an open, randomized, multicentre trial in febrile neutropenic patients. The addition of antibiotics for gram-positive coverage was part of the protocol; alteration in the antibiotics for gram-negative cover or premature discontinuation of the study antibiotics were judged as failure. One hundred and eighty six patients were randomized by nine German centres, the patients matched for age, underlying diseases and duration of neutropenia (median duration 14 days) in both treatment arms. Infections were documented microbiologically in 29% of the patients, clinically in 16% and suspected (fever of unknown origin) in 102/186 patients (55%). The 82 pathogens isolated were predominantly gram-positive bacteria. In an intent-to-treat analysis, the overall response rate without modification at the final evaluation was 58% in the ceftazidime group and 34% in the cefotaxime group (P < 0.01). The success rates with modification were 84% and 64%, respectively. The failure rate in a highly immunosuppressed subgroup of the patients (bone marrow transplant recipients) was higher for cefotaxime (53%) than for the ceftazidime arm (14%) (P < 0.001). Response rates were significantly higher in the ceftazidime group for patients with microbiologically documented and possible infections. No major bacterial superinfections occurred in the low-dose treatment arm. The tolerability was good for both regimens. Low-dose ceftazidime combined with netilmicin proved to be superior to recommended doses of cefotaxime/netilmicin in febrile neutropenic patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Cefotaxime; Ceftazidime; Cephalosporins; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Male; Middle Aged; Netilmicin; Neutropenia; Superinfection; Treatment Outcome

The aim of this study was to compare the clinical and microbiological efficacy of netilmicin plus imipenem-cilastatin (Net + Imi) vs netilmicin plus ceftazidime (Net + Cef) as empiric antimicrobial therapy in bone marrow transplant (BMT) febrile neutropenic patients (pts). Sixty-six pts undergoing BMT for hematological malignancies and solid tumors were randomized to receive Net + Imi or Net + Cef as first-line antibiotic therapy. A lasting return of temperature to normal and complete disappearance of either clinical or cultural signs of infection without any modification of therapy was considered as improvement; the persistence of fever after 72 hours, the addition of a third antibiotic or a protocol change was considered as failure. Sixty-nine episodes were randomized during the course of the trial; bacteriological evidence of infection was obtained in 17 (25%) febrile episodes. Overall outcome based on clinical responses was as follows: 80% of pts on Net + Imi responded compared to 73% of those on Net + Cef. For microbiologically documented infections response rates were 70% in Net + Imi group and 43% in the Net + Cef group (p = ns). Neither septic death nor toxicity were observed. Both empiric regimens were shown to be effective; Net + Imi appeared to be more effective in microbiologically documented infections but there was no statistical significance. In conclusion, both Net + Imi and Net + Cef are active and safe as empirical treatment of febrile episodes in neutropenic BMT pts.

Topics: Adolescent; Adult; Bacteria; Bacterial Infections; Bone Marrow Transplantation; Ceftazidime; Cephalosporins; Child; Cilastatin; Drug Synergism; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Imipenem; Male; Middle Aged; Netilmicin; Neutropenia; Postoperative Complications; Protease Inhibitors; Thienamycins; Treatment Outcome

A prospective, randomized study was conducted to determine if recombinant human granulocyte-macrophage colony-stimulating factor (rh-GMCSF) (Escherichia coli-derived) could improve response rates to antibiotic therapy and shorten the duration of neutropenia in cancer patients.. A total of 107 febrile neutropenic cancer patients were randomly assigned to empiric therapy with ticarcillin-clavulanate (4 g ticarcillin + 0.1 g clavulanate i.v. every 4 hours) plus netilmicin (2 mg/kg i.v. every 8 hours) with or without rh-GMCSF (3 micrograms/kg per day i.v.). Clinical improvement, duration of neutropenia, and toxicity were monitored.. Addition of rh-GMCSF to the antibiotics significantly improved the response rate (96% versus 82%, P = 0.03), but not the survival rate (93% versus 93%), in the evaluable patients. This difference in response rate was not significant when considering all patients in an intent-to-treat analysis. The number of patients who recovered from severe neutropenia ( < 100 cells/microliter) during the period of observation in the study was significantly greater among patients receiving the colony-stimulating factor, although the median duration of neutropenia was not affected. Superinfections and subsequent infections were not significantly different among the two treatment regimens. Side effects were more common among patients treated with the colony-stimulating factor.. Our data do not support the routine administration of rh-GMCSF with antibiotics for patients with fever and neutropenia. Further studies should be conducted to identify those patients most likely to benefit from rh-GMCSF therapy, such as patients with persistent profound neutropenia and refractory infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Clavulanic Acid; Clavulanic Acids; Drug Administration Schedule; Drug Combinations; Escherichia coli; Fever; Gentamicins; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Middle Aged; Neoplasms; Netilmicin; Neutropenia; Penicillins; Prospective Studies; Remission Induction; Superinfection; Survival Rate; Ticarcillin

Topics: Adult; Anti-Bacterial Agents; Anti-Infective Agents; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Male; Neoplasms; Netilmicin; Neutropenia; Pefloxacin; Teicoplanin

In a comparative randomized trial, teicoplanin 5 mg/kg plus either netilmicin 5 mg/kg or pefloxacine 10 mg/kg was administered in a once daily empiric therapy to 40 cancer patients with fever and neutropenia after cytotoxic chemotherapy. Both regimens were analyzed with respect to the localisation of the underlying disease, catheter presence and agents isolated from blood culture. The cure and improvement rate were 80% (teicoplanin plus netilmicin) and 85% (teicoplanin plus pefloxacin), with no statistically significant difference between the groups. Teicoplanin with either an aminoglycoside or a quinolone administered once daily seems to be a suitable approach in empiric therapy for fever in neutropenia and may prevent catheter insertion in cancer patients.

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Humans; Leukemia, Myeloid, Acute; Male; Neoplasms; Netilmicin; Neutropenia; Pefloxacin; Teicoplanin

In a prospective, randomized trial, netilmicin given once daily (OD) was compared in terms of efficacy and safety with the conventional 8-hourly dosing regimen (TD), both in combination with a broad spectrum beta-lactam, as initial empirical therapy for febrile neutropenic patients; the total daily dosage of netilmicin in each group was 6 mg/kg body weight. Twenty-nine of the 116 (25%) evaluable patients had microbiologically documented septicaemia, most of which were caused by Gram-positive bacteria, 41 (35%) had microbiologically documented infection without bacteraemia and 46 (40%) had possible infection. Highest peak serum concentrations of netilmicin in the OD group were significantly higher and trough serum concentrations significantly lower than in the TD group. A multivariate analysis revealed that neither the dosage regimen nor the peak serum concentration of netilmicin were determinants of a favourable outcome. The response rates of both groups to the initial treatment regimens were comparable and increased similarly following modification of the initial therapy. Response rates were particularly poor in patients with lower respiratory tract infection and in those who remained neutropenic throughout the course of treatment. The incidence of nephrotoxicity was low and did not differ significantly between groups. Once-daily dosing of netilmicin appears to be as effective and as safe as thrice-daily dosing, but is unlikely to further improve the response of febrile neutropenic patients to empirical therapy.

Topics: Anemia, Aplastic; Anti-Bacterial Agents; beta-Lactams; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Neoplasms; Netilmicin; Neutropenia; Prospective Studies

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

We examined the efficacy of ciprofloxacin as an empirical treatment for fever in 97 neutropenic patients in a randomized study of ciprofloxacin and benzylpenicillin versus netilmicin and piperacillin. Benzylpenicillin was included because of evidence of in-vitro resistance to ciprofloxacin in some streptococci. Clinical response rate was similar in the two groups (46% resolution for ciprofloxacin/benzylpenicillin and 52% for netilmicin/piperacillin). Microbiological assessment revealed more pathogens eradicated by ciprofloxacin and benzylpenicillin (66%) and fewer persisting (3%) than in patients receiving netilmicin and piperacillin (52% and 13% respectively). Staphylococcus epidermidis was the commonest pathogen, accounting for 38% of all isolates and 30% of all treatment failures. There were no treatment failures or superinfections due to streptococci. More therapy-related adverse reactions were seen in patients on netilmicin and piperacillin (28%) compared with those on ciprofloxacin and benzylpenicillin (10%). The combination of ciprofloxacin and benzylpenicillin is as effective as a standard regimen of netilmicin and piperacillin, with fewer adverse effects, and is highly attractive as empirical therapy for the febrile, neutropenic host. The inclusion of benzylpenicillin prevents streptococcal-associated treatment failure.

Topics: Adult; Bacterial Infections; Ciprofloxacin; Drug Therapy, Combination; Fever; Humans; Injections, Intravenous; Middle Aged; Netilmicin; Neutropenia; Penicillin G; Piperacillin; Prospective Studies; Randomized Controlled Trials as Topic

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

A randomized study of treatment with ciprofloxacin combined with benzylpenicillin (CB) versus a standard regimen of netilmicin combined with piperacillin (NP) as first-line empiric therapy was conducted in febrile neutropenic patients. Ninety-six patients were evaluable for determination of efficacy: 50 patients received CB and 46 patients received NP. There was no significant difference between the two groups in terms of age or primary diagnosis. Overall clinical response rate at the end of therapy was 66 percent for CB and 65 percent for NP. Microbiologic assessment revealed more pathogens eradicated by CB (64 percent) and fewer persisting (4 percent) than in the NP group (52 percent eradicated, 13 percent persisting). Only 10 percent of patients in the CB group had treatment-related adverse reactions as opposed to 28 percent of the NP-treated patients; these were predominantly renal impairment and were likely to have been due to the aminoglycoside. Staphylococcus epidermidis was the most commonly isolated pathogen, accounting for 38 percent of all isolates and 30 percent of all patients in whom treatment failed. Although streptococci accounted for 18 percent of the isolated pathogens, no treatment failures or superinfections were due to these organisms. This indicates an advantage of combining ciprofloxacin with benzylpenicillin. We conclude that the CB regimen is as effective as the NP treatment and is associated with fewer side effects.

Topics: Adult; Agranulocytosis; Bacteria; Bacterial Infections; Ciprofloxacin; Drug Therapy, Combination; Fever; Humans; Infusions, Intravenous; Middle Aged; Netilmicin; Neutropenia; Penicillin G; Piperacillin; Random Allocation

To assess the efficacy of ciprofloxacin in neutropenic patients, we conducted a randomized prospective trial comparing the combination of ciprofloxacin and netilmicin against piperacillin plus netilmicin as an empiric treatment of fever in cancer patients with neutropenia. Of 214 evaluable episodes, 115 and 99 were randomly assigned to the ciprofloxacin and the piperacillin arms, respectively. The overall response rates were very similar (59 and 62% for the ciprofloxacin and piperacillin arms, respectively). The response for the gram-positive bacteremias was almost identical (around 40%); this low response was due in part to an outbreak of infection by a multiply resistant strain of Staphylococcus epidermidis (for which the ciprofloxacin MIC was greater than or equal to 128 micrograms/ml) which occurred during the second half of the trial. Among gram-negative bacteremias, 9 of 11 infections (82%) responded to the ciprofloxacin combination compared with 3 of 7 (43%) that responded to the piperacillin combination (P = 0.23). The incidences of persistent, profound neutropenia were comparable in both treatments, but the susceptibility of the gram-negative organism to ciprofloxacin and netilmicin was significantly higher than was susceptibility to the other combination. Ciprofloxacin was well tolerated, and patients were able to convert from intravenous to oral therapy in 64 of 115 episodes.

Topics: Administration, Oral; Adolescent; Adult; Aged; Agranulocytosis; Bacterial Infections; Bone Marrow Transplantation; Ciprofloxacin; Drug Therapy, Combination; Female; Fever; Humans; Infusions, Intravenous; Injections, Intravenous; Leukemia; Lymphoma; Male; Middle Aged; Netilmicin; Neutropenia; Piperacillin; Prospective Studies; Random Allocation

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

Ceftazidime in doses of 100 mg/kg/day was used, combined with netilmicin 6 mg/kg/day, as first-line treatment in two successive studies conducted on febrile neutropenic children (neutrophils less than 500/mm3). Study n. 1, performed at the Infantile Haematology unit of Saint Louis hospital, Paris, included 75 children. Study n. 2 was a multicentre study involving 88 children from 11 medical centres. The children's age in both studies ranged from 2 months to 16 1/2 years (mean 7 years). The percentage of bacteriologically documented febrile episodes was 45 per cent (34/75 and 39/88), and the most frequent infections were those caused by Gram-positive cocci (56 and 58 per cent respectively of the cases). Vancomycin 40 mg/kg/day was introduced if fever was still present 48 hours after the beginning of the antibiotic therapy. Effective treatments were continued until the neutropenia was corrected. These children were being treated for acute leukaemia, lymphoma, solid tumours or bone marrow aplasia. In study n. 1 apyrexia was obtained in 85 per cent of the cases with the ceftazidime-netilmicin combination and in 91 per cent of the cases after addition of vancomycin. The initial therapy was effective in all patients with a documented infection. There were tow super-infections with septicaemia: one due to Streptococcus D, the other to Staph. epidermidis. In study n. 2 73 per cent of the patients were apyretic after the first combination and 85 per cent after vancomycin was introduced. In proven infections the ceftazidime-netilmicin combination was effective in 30 cases and in another 6 cases after addition of vancomycin. Three patients remained febrile until they came out of aplasia. In all cases the bacterial cultures were sterilized by the ceftazidime-netilmicin combination. There was no superinfection. The mean duration of antibiotic therapy was 21 days in study n. 1 and 14 days in study n. 2. The drugs were perfectly tolerated both clinically and biochemically. No death occurred in the two studies. Thus, owing to its broad spectrum, effectiveness and safety ceftazidime is a very useful antibiotic when combined with netilmicin as first-line treatment of febrile neutropenic children.

Topics: Adolescent; Agranulocytosis; Bacterial Infections; Ceftazidime; Child; Child, Preschool; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Humans; Infant; Multicenter Studies as Topic; Netilmicin; Neutropenia

Over a two year period 174 evaluable episodes of fever in neutropenic patients were treated in a randomized study comparing four beta-lactam antibiotics, each given in combination with netilmicin. Exclusions included episodes due to viral or fungal infection, and trial violations. Most patients were receiving treatment for leukaemia, including 18% undergoing bone marrow transplantation. The overall response rate (EORTC criteria) was 66%, ranging from 56% for cefoperazone to 76% for mezlocillin. Microbial documentation was obtained in 31% of episodes; Gram-positive isolates were most frequent but Pseudomonas aeruginosa was found in 18 patients. In patients with microbiologically documented infection 70% improved, overall--from 40% with cefoperazone to 80% with piperacillin (P less than 0.05). Nephrotoxicity was seen in 6.7% and was associated with severe documented sepsis. Hypokalaemia was seen in 29% and was most marked in patients receiving ticarcillin. Rashes occurred in 6.6% overall, with no difference between the groups. Ototoxicity, shown by serial audiograms, was seen in 4.7% of patients. No evidence of vestibular dysfunction was seen in 62 patients studied. Of thirteen deaths due to the primary infection, seven were caused by Ps. aeruginosa and five by fungi.

Topics: Agranulocytosis; Anti-Bacterial Agents; Cefoperazone; Clinical Trials as Topic; Drug Therapy, Combination; Feces; Fever; Gram-Negative Bacteria; Humans; Mezlocillin; Microbial Sensitivity Tests; Netilmicin; Neutropenia; Piperacillin; Random Allocation; Respiratory System; Superinfection; Ticarcillin

Topics: Adult; Agranulocytosis; Amikacin; Bacterial Infections; beta-Lactamase Inhibitors; Child; Clavulanic Acids; Clinical Trials as Topic; Drug Therapy, Combination; Fever; Fever of Unknown Origin; Humans; Netilmicin; Neutropenia; Penicillins; Retrospective Studies; Sepsis; Ticarcillin; Tobramycin

During a randomized clinical trial comparing tobramycin plus ticarcillin to netilmicin plus ticarcillin as empiric therapy of febrile neutropenic patients, Staphylococcus epidermidis emerged as the predominate superinfecting pathogen in tobramycin recipients. Overall clinical response was 68% (44/65 responding) in tobramycin/ticarcillin recipients and 73% (45/62) in netilmicin/ticarcillin recipients. However, 5/65 tobramycin/ticarcillin treated episodes were complicated by bacteremic superinfection with Staphylococcus epidermidis, as compared to 0/62 netilmicin/ticarcillin treated episodes (p less than 0.05). Four of the five bacteremic strains produced aminoglycoside adenylating enzyme ANT 4', 4''. Prior colonization of patients with identical strains was demonstrated by plasmid profile analysis, antibiograms and biotyping with the API Staph-Ident system. During the trial, 36 consecutive patients were studied for colonization patterns with coagulase-negative staphylococci. S. epidermidis accounted for 566/831 (68%) isolates of coagulase-negative staphylococci recovered from surveillance cultures. Tobramycin-resistant strains were acquired in 2/17, 4/12 and 9/14 patients during trimethoprim/sulfamethoxazole, netilmicin/ticarcillin and tobramycin/ticarcillin therapy, respectively. Prior to aminoglycoside therapy, 77% of strains were susceptible to less than or equal to 8 micrograms/ml of tobramycin, but only 35% and 28% were susceptible to tobramycin after initiation of tobramycin/ticarcillin and netilmicin/ticarcillin therapy, respectively. In contrast, greater than or equal to 93% of isolates were susceptible to netilmicin before and after aminoglycoside therapy. Absence of several sites susceptible to modification by aminoglycoside inactivating enzymes produced by staphylococci may give netilmicin a therapeutic advantage in the therapy of febrile neutropenic patients.

Topics: Adult; Agranulocytosis; Aminoglycosides; Clinical Trials as Topic; Cross Infection; Drug Therapy, Combination; Ear; Humans; Kidney; Netilmicin; Neutropenia; Penicillin Resistance; Random Allocation; Sepsis; Staphylococcal Infections; Staphylococcus epidermidis; Ticarcillin; Tobramycin

Fifty patients with acute non-lymphocytic leukaemia were treated by random allocation with either ceftazidime alone or a combination of piperacillin, netilmicin and cefotaxime for 65 febrile neutropenic episodes. Nineteen of 33 patient episodes (58%) responded to ceftazidime alone compared with 21 of 32 episodes (66%) treated with the combination. There was one infective death in a patient given the combination; rates of documented superinfection were low. The treatment groups appeared identical in terms of patient demography, underlying disease and other risk factors, though patients with a clinical site of infection responded more slowly than those without. Bacteraemia per se did not appear to influence outcome. Bactericidal serum concentrations greater than or equal to 8 X the minimum bactericidal concentration were predictive of a rapid response (within 4 days) to antibiotics. Furthermore, serum from patients treated with ceftazidime maintained adequate cidal activity against Pseudomonas aeruginosa for longer than that obtained from patients treated with the three-drug combination. Ceftazidime was shown to be a safe and effective alternative to the three-drug combination for the initial management of febrile neutropenic episodes in leukaemic patients.

Topics: Adolescent; Adult; Bacterial Infections; Cefotaxime; Ceftazidime; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Middle Aged; Netilmicin; Neutropenia; Penicillin Resistance; Piperacillin; Random Allocation; Sepsis

Topics: Agranulocytosis; Amikacin; Aminoglycosides; Anti-Bacterial Agents; Drug Therapy, Combination; Gentamicins; Humans; Netilmicin; Neutropenia; Sepsis

To establish the safety and efficacy of single daily intravenous netilmicin 6 mg/kg with piperacillin 100 mg/kg every 8 h for empirical, first-line management of children with neutropenic pyrexia following cytotoxic chemotherapy.. Observational study of children admitted to a regional oncology unit from October 1999-April 2002. Primary outcome measure was temperature 72 h after commencing antibiotic therapy; secondary measures were mortality, nephrotoxicity, symptomatic ototoxicity and serum netilmicin levels.. 280 episodes for 128 patients (median age 7.1 y) were documented, and 248 episodes were evaluated and compared with a previous cohort of 100 episodes for which the only difference was administration of netilmicin three times daily. Twenty-seven per cent of single-dose netilmicin episodes remained febrile at 72 h compared to 32% in the comparator group (difference -4.7%; 95 % CI: -6.8% to 16.2%; p = 0.41). No patients died and we were unable to find evidence of nephrotoxicity or ototoxicity. Eighty-nine per cent of "peak" serum netilmicin levels measured 30 min after infusion were 10 mg/l or greater, and 94% and 86% measured 12-16 h after the first and third dose, respectively, were 1 mg/l or less. Peak serum netilmicin level measurements and 12-16-h measurements after the first dose were abandoned after the first 180 episodes.. Netilmicin can safely be given as a single daily dose to children with febrile neutropenia who do not have biochemical evidence of nephrotoxicity. Monitoring peak serum levels of netilmicin is unnecessary. Levels taken 12-16 h after the third dose are adequate to monitor therapy if used in conjunction with a therapeutic guideline detailing the response to abnormal serum creatinine and netilmicin levels.

Topics: Adolescent; Anti-Bacterial Agents; Antineoplastic Agents; Brain Neoplasms; Child; Drug Monitoring; Female; Fever; Humans; Infant; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Netilmicin; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

In a prospective observational study of 133 neutropenic episodes, interleukin (IL)-8 serum levels > 2000 pg/mL at the onset of fever had a sensitivity of 53% and a specificity of 97% as a predictor of gram-negative bacteremia (GNB; positive predictive value, 73%; negative predictive value, 94%). The rates of early death differed significantly between patients with high and those with low IL-8 levels (3/11 vs. 1/122; P< .01). Serum IL-8 levels at the onset of fever define a low-risk subgroup of patients who can safely be treated with monotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bacteremia; Cefepime; Cephalosporins; Drug Therapy, Combination; Fever; Gentamicins; Gram-Negative Bacterial Infections; Humans; Interleukin-8; Leukemia; Lymphoma; Male; Middle Aged; Netilmicin; Neutropenia; Predictive Value of Tests; Prospective Studies

The object of this work is to study in neutropenic mice the in vivo postantibiotic effect (PAE) of isepamicin, a new aminoglycoside, gentamicin and netilmicin on Staphylococcus aureus and Escherichia coli and in vivo killing kinetics using two different schedules (A and B) of isepamicin and gentamicin administration against S. aureus: (A) at time zero and every hour up to the 7th or 9th hour and (B) two doses only, at time zero and at the end of the PAE. The PAE of the three aminoglycosides was long (3-5 h), showing that of isepamicin to be the largest, especially on S. aureus. Both A and B treatment models show the same effectiveness for the two tested drugs. These results support the idea that the major significance of the PAE is in its application to dosing regimens.

Topics: Animals; Bacterial Infections; Disease Models, Animal; Escherichia coli; Female; Gentamicins; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Netilmicin; Neutropenia; Staphylococcus aureus; Thigh; Time Factors

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

Infection is the most important cause of mortality in leucopenic patients. A broad spectrum antibiotic therapy is imperative in febrile and neutropenic patients. In a multicentric study we have used ceftazidime (100 mg/kg/d) and netilmicin (6 mg/kg/d) in 88 children (fever greater than or equal to 38.5 degrees C, neutropenia less than 500/mm3) treated for acute leukemias (59), non Hodgkin lymphomas (13) or solid tumors (16). Median age was 7 years (2 months-16 years). In patients who continued to remain febrile, vancomycin (40 mg/kg/d) was added after 48 hours. The effective treatment was continued until a neutrophil count greater than 1,000/mm3. The first combination (ceftazidime + netilmicin) was effective in 64 children (73%) and the second combination (ceftazidime + netilmicin + vancomycin) in 11 patients. Bacteria were isolated in 39 children: Escherichia coli: 9, Staphylococcus epidermidis: 9, Staphylococcus aureus: 8, Streptococcus: 6, Pseudomonas aeruginosa: 3, Streptococcus pneumoniae: 1, Haemophilus: 1, Klebsiella pneumoniae: 1, Proteus: 1, Serratia: 1, Flavobacterium: 1. In these 39 patients, 30 became apyretic with ceftazidime and netilmicin and 6 after vancomycin. All blood culture were negative after the first combination. The median duration of antibiotic therapy was 14 days (5-9 days: 28, 10-20 days: 43, greater than 20 days: 17). There were no death, no superinfection. Tolerance was good without kidney or liver or biological perturbation. We conclude that the combination ceftazidime and netilmicin is effective in neutropenic children.

Topics: Adolescent; Agranulocytosis; Bacterial Infections; Ceftazidime; Child; Child, Preschool; Drug Therapy, Combination; Fever; Humans; Infant; Netilmicin; Neutropenia; Vancomycin

No preventive treatment other than intestinal decontamination with oral colimycin was given. Antibiotic therapy with piperacillin 200-300 mg/kg, netilmicin 6-7.5 mg/kg and cloxacillin 50-100 mg/kg was initiated within 6 to 12 hours of clinical onset, using a central catheter. Twenty-nine children with bone marrow aplasia and less than 1000 leucocytes/mm3 were treated: 20 had acute lymphoblastic leukaemia or lymphoma (first episode 13, relapse 7, including 3 undergoing bone marrow transplantation), 6 had acute myeloblastic leukaemia (first episode 4, relapse during transplantation 2), and there was 1 case each of idiopathic bone marrow aplasia, metastatic sympathico-blastoma and lymphohistiocytosis. Mean age was 9 years (range: 2-19 years). The combined antibiotic therapy was continued until recovery from aplasia in case of success and discontinued after 48 hours in case of failure. Bacteriological examinations were negative in 19 patients and positive in 10; 13 strains were isolated, mostly staphylococci and streptococci. Apyrexia was obtained in 24 patients, 11 of whom had a rise of temperature with negative bacteriology about 10 days later. There were 4 initial failures and one unassessable result. An atopic patient developed a skin rash on the 3rd day of treatment. There was no death, no superinfection and non clinical or biochemical side-effect. It is concluded that the piperacillin-netilmicin -cloxacillin combination, which gave a high success rate and was well tolerated, can be recommended in neutropenic children with febrile episodes.

Topics: Adolescent; Adult; Agranulocytosis; Bacterial Infections; Child; Child, Preschool; Cloxacillin; Drug Therapy, Combination; Fever; Humans; Netilmicin; Neutropenia; Piperacillin

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