Pharmacokinetics of ceftazidime in febrile neutropenic patients

Eight patients with fever and neutropenia were given 2 g of ceftazidime i.v. as a bolus injection over the course of 3 min. The pharmacokinetic variables for ceftazidime were similar to those found previously in febrile, acutely ill, non-neutropenic patients. The area under the plasma-concentration-time curve was significantly smaller, and the terminal half-life (t1/2lambda(z)) significantly shorter, compared with elderly, healthy subjects (p < 0.005). Three patients survived long enough to be assayed after normalization of temperature and neutrophil counts. Glomerular filtration rates and clearances tended to be higher and the area under the curve and half-life lower on the day of fever and neutropenia. When considering our data in relation to known MIC values for common pathogens, ceftazidime administered intermittently every 6 h seems an appropriate regimen in patients with febrile neutropenia. Larger studies are needed to confirm this.     

Interventional antimicrobial therapy in febrile neutropenic patients

Summary In this prospective multicenter trial, treatment strategies for 1573 patients with neutropenia <1000/l and fever 38.5° C after cytotoxic chemotherapy were compared. Patients with unexplained fever were randomized to a three-phase sequential study for different established drug regimens. If an infection could be defined microbiologically or clinically, treatment modifications were determined. In phase I, treatment for all patients consisted of acylaminopenicillin (PEN) plus aminoglycoside (AMG); or third-generation cephalosporin (CEPH) plus AMG; or PEN plus CEPH. In 800 patients with unexplained fever the response rates were: PEN/AMG (n=258): 74.4%, CEPH/AMG (n=252): 73.4%; PEN/CEPH (n=290): 70.0%. Total response rate was 72.5%. In phase II, patients not responding after 3 days received PEN/CEPH/vancomycin (n=70) or PEN/CEPH/AMG (n=74). The respective response rates were 52.9% and 55.4%, total 54.2%. If fever did not resolve, the patients received either PEN/CEPH (n=40) or imipenem/cilastatin (n=59) both in combination with amphotericin-B/5-flucytosin/ rifampin. The response rates were 62.5% and 79.7%, respectively (p=0.07), total 72.7%. No significant differences between the treatment modalities compared were found. Analyzing all three phases together, 91.3% of patients with unexplained fever were cured. The response rate was also analyzed according to patients with gram-positive bacteremia (n=183), response rate =82.5%; gram-negative organisms (n=145) 78.6%; fungemia (n=51) 43.1% (p<0.001); lung infiltrates (n=269) 61.3% (p< 0.001); clinically documented infections (n=198) 84.4%; and clinically and microbiologically documented infections (n=84) 82.1%. If infections were diagnosed after at least 5 febrile days, more lung infiltrates and fungal infections occurredp<0.001). Leukocytes rising above 500/ during the infection predicted better response rates (p<0.001): in unexplained fever 97.8% vs 86.5% and lower death rates 1.5% vs 8.5%. In documented infections the response rates were then 89.9% vs 62.3% and the death rates 7.0% vs 20.5%. Therapy of neutropenic fever and infections must be adapted according to risk factors and should include early empiric antifungal therapy. The therapeutic and prophylactic use of hematopoietic growth factors to overcome neutropenia should be evaluated.     

The role of the chest roentgenogram in febrile neutropenic patients

In a retrospective review of patients with neutropenia and fever, we sought to determine how often roentgenograms detected pulmonary disease, especially pneumonia, not suggested by signs and symptoms. Further, we sought to determine how often therapy was changed as a result of roentgenographic findings. Overall, 41 (22%) of 187 chest roentgenograms obtained during initial febrile episodes, recurrent fevers, or persistent fevers were abnormal. While most patients had signs and symptoms suggesting the presence of pulmonary disease, 17% had roentgenographic abnormalities detected in the absence of such findings. During initial febrile episodes, therapy was not changed in response to findings on the chest roentgenogram. However, during episodes of persistent or recurrent fever, findings on chest roentgenograms led to changes in therapy in eight (61%) of 13 episodes of which six (40%) resulted in clinical improvement. Chest roentgenograms were therefore found to be an important diagnostic tool in evaluating recurrent or persistent fever in the neutropenic patient but of little use during initial febrile episodes.     

Piperacillin and netilmicin combination therapy for febrile episodes in neutropenic patients

Summary We assessed the efficacy of a piperacillin (3×4 g/d) and netilmicin (5 mg/kg/d) combination therapy for infections in febrile neutropenic patients. The study was conducted over a 30-month period and 203 patients were included. Bone marrow transplant recipients were not included in this study. Origin of infection was documented in 101 (50%) episodes: 33 fungal, viral or parasitic infections and 68 bacterial infections mainly composed of septicemia. Of the 169 evaluable patients with proved bacterial infections or non-documented infections, 129 (76%) recovered with the piperacillin and netilmicin combination treatment. All gram-positive bacterial infections failing first line therapy were cured after the addition of vancomycin. Piperacillin and netilmicin appeared very effective in this large monocentric prospective study. It does not seem necessary to include vancomycin in first line therapy of infections of the neutropenic patients in our institution; however, vancomycin must be added early in the case of suspected or documented staphylococcal infection failing empiric treatment.

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Piperacillin in Kombination mit Netilmicin zur Therapie bei granulozytopenischen Patienten mit Fieber

Zusammenfassung Die Wirksamkeit von Piperacillin (3×4 g/Tag) in Kombination mit Netilmicin (5 mg/kg/Tag) in der Therapie fieberhafter Infektionen bei neutropenischen Patienten wurde geprüft. Die Studie wurde mit 203 Patienten über einen Zeitraum von 30 Monaten geführt. Knochenmarkstransplantatempfänger wurden in die Studie nicht aufgenommen. In 101 Fällen (50%) konnte ein Erreger indentifiziert werden. In 33 Fällen wurden Pilze, Viren oder Parasiten nachgewiesen, in 68 Fällen, meist Septikämien, bakterielle Erreger. 129 der insgesamt 169 auswertbaren Patienten (76%), bei denen eine dokumentierte bakterielle Infektion oder Fieber unbekannter Ursache vorlag, sprachen auf die Behandlung mit Piperacillin plus Netilmicin an. Alle Infektionen durch grampositive Bakterien, die auf die Primärtherapie nicht angesprochen hatten, wurden durch eine Zusatztherapie mit Vancomycin geheilt. In dieser großen, prospektiven Studie an einem Zentrum erwies sich die Kombination von Piperacillin und Netilmicin als sehr wirksam. Bei Patienten unserer Klinik erschien die primäre Zusatztherapie mit Vancomycin bei neutropenischen Patienten nicht erforderlich. Wenn jedoch eine Staphylokokkeninfektion nachgewiesen wird oder der Verdacht darauf besteht und die empirische Therapie sich als unzureichend wirksam erwiesen hat, muß frühzeitig mit einer Vancomycin-Zusatztherapie begonnen werden.

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Supported by Lederle-Cyanamid France.     

Beta-lactam-resistant Enterobacter bacteremia in febrile neutropenic patients receiving monotherapy

Bacteremia with resistant Enterobacter species has been reported in febrile, neutropenic cancer patients receiving beta-lactam antibiotics. To assess the relationship between enterobacter bacteremia and ceftazidime monotherapy, medical records were reviewed and isolates were tested from 16 neutropenic and 35 nonneutropenic patients with Enterobacter bacteremia. Fifteen isolates from the neutropenic patients were resistant to extended spectrum cephalosporins; only 12 of 35 isolates from the nonneutropenic patients were resistant to Enterobacter species. The neutropenic patients also had more beta-lactam therapy, both immediately before bacteremia and in the preceding year, than did nonneutropenic patients. Prior beta-lactam antibiotic exposure may predispose neutropenic patients to develop resistant Enterobacter bacteremia.     

An evaluation of empirical antibiotic therapy in febrile neutropenic patients

A prospective study was undertaken to determine the effectiveness of an empirical antibiotic therapy regimen in 34 neutropenic patients undergoing bone marrow transplantation or remission-induction chemotherapy for leukaemia. Throughout the study period a total of 90 pyrexial episodes were monitored in which organisms designated to be pathogens were isolated from blood cultures on 38 occasions. The response rate to the combination of a ureidopenicillin with gentamicin fell sharply from 50% during patients' first pyrexial episodes to zero during the third and subsequent episodes. The preponderance of Gram-positive bacteria and the high overall resistance of bacterial isolates to these antibiotics have led us to reconsider our approach to empirical therapy and to include antibiotics with greater activity against Staphylococcus epidermidis. The emergence of fungi as a major cause of morbidity in patients with prolonged neutropenia underlines the necessity to introduce early empirical antifungal therapy in this group of patients.     

Short courses of antibiotics in selected febrile neutropenic patients.

To evaluate their policy of discontinuing broad spectrum antibiotics in patients with negative cultures who become afebrile but remain neutropenic, the authors retrospectively reviewed the charts of all pediatric patients diagnosed with cancer between 1980 and 1986. Two hundred seventy-one children had 385 admissions for infectious complications during the study period. In 39 of those episodes (9%), the patients had negative cultures, became afebrile, and were discharged with absolute neutrophil counts of less than 1000 cells/mm3 (mean 390 cells/mm3). They received relatively short courses of antibiotics with a median duration of 4 days. Only four of these patients became febrile during the followup period and there were no fatalities. Given the benign course of these patients, recommendations for prolonged antibiotic courses should be reconsidered.     

Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients

 A total of 101 cancer patients with 121 febrile neutropenia episodes were randomised to receive empirical treatment with i.v. meropenem (1 g/8 h) or ceftazidime (2 g/8 h). After 3 days, 89% of patients were on unmodified therapy in the meropenem group, compared with 83% in the ceftazidime group. Of the evaluable episodes (n=106), the success rate with unmodified empirical therapy until the end of the treatment course was slightly higher with meropenem than with ceftazidime (48% vs 38%, P=0.39). Furthermore, initial success with further infections was observed in 22% of episodes treated with meropenem and in 13% of episodes treated with ceftazidime. Glycopeptides were used as first modification in 28% and 39% of meropenem and ceftazidime recipients, respectively. Both treatments were well tolerated and there were no reports of drug-related nausea/vomiting or seizures. No significant differences in response rate or in tolerability were observed when analysing only the first febrile episodes. In conclusion, meropenem seems to be as efficacious and well tolerated as ceftazidime and may be associated with a lesser requirement for the addition of glycopeptides. Received: 15 April 1999 / Accepted: 9 June 1999     

Empiric therapy with aztreonam for febrile neutropenic patients with hematological malignancies

Combination of aztreonam/amikacin/ticarcillin (AAT) and latamoxef/amikacin/ticarcillin (LAT) were compared in a prospective randomized trial of empiric therapy for febrile neutropenic patients with hematological malignancies. Low dose amphotericin B was also added to each regimen from the beginning. Of 45 evaluable episodes, 23 were treated with AAT and 22 with LAT. The response rates were 61 percent for AAT and 50 percent for LAT, statistically not significant. There was one infection-related death among patients assigned to AAT therapy and also one among those assigned to LAT therapy. Dose escalation of amphotericin B seemed to be effective for those patients who did not improve with initial therapy.     

Empirical antibiotic therapy in febrile neutropenic patients with acute leukemia

One hundred and ninety-five episodes of fever during the neutropenic phase of chemotherapy in 49 patients with acute leukemia from 1984 to 1987 were analyzed with the following results: 1) Febrile episodes occurred in 80 percent of the neutropenic (less than 500/microliters) phase lasting more than 7 days after chemotherapy. 2) Febrile episodes consisted of 44 (22%) of established septicemia and 111 (57%) of suspected septicemia. 3) The pathogens causing septicemia were 8 GPC, 38 GNB (22 Pseudomonas species) and 6 fungi. Fungemia was confirmed on an average of 4.8 days after the onset of fever. The mortality of septic events was 10 out of 17 episodes (59%) when treated with antibiotics alone, while 8 out 27 (30%) with the combination of antibiotics plus antifungal drugs. 4) The mortality of suspected sepsis was only 2 out of 111 episodes. Eighty-three (75%) of these 111 episodes responded to antibiotics alone, while 26 (23%) cases needed antibiotics plus antifungal drugs. Our results suggest that in febrile neutropenic patient empiric broad-spectrum antibiotic therapy should be initiated which is especially effective for Pseudomonas species, but if fever persists despite more than 4 or 5 days of antibiotic therapy, additional antifungal therapy should be considered.     

Using teicoplanin for empiric therapy of febrile neutropenic patients with haematological malignancies

S ummary The cumulative experience with teicoplanin in treating febrile neutropenic patients included in three different comparative clinical trials conducted at a single institution during a 3-year period, is presented. 1 52 febrile episodes in 129 neutropenic patients were treated with iv. teicoplanin (6 mg/kg/d) combined with amikacin (15 mg/kg/d) plus ceftazidime (90 mg/kg/d). The study population comprised 75 patients with acute leukaemia and 77 marrow recipients: 53(% (81/152) had a central venous catheter in place and 68%) (103/152) had severe neutropenia (< 100/mm³) at the beginning of the febrile episode.
The overall response rate of the evaluiable febrile episodes was excellent: 88% (107/122) improved. Bacteraemias due to Gram-positive cocci accounted for 75% of the total (42/56) and pathogens in the blood isolates were mostly staphylo-cocci (coagulase-negative 14, coagulase-positive 13) and streptococci (131. The response rate of Gram-positive bacteraemias was good: 88% (37/42) improved and 75% (9/12) of Gram-positive bacteraemias having teicoplanin as the only antibiotic with in vitro activity against the infective strains were cured. Death due to infection accounted for 7% of total febrile episodes (11/152). Side effects were documented in 14(%, of the episodes. In a setting of high prevalence of Grampositive infections caused by strains with a high rate of resistance to aminoglycoside and betalactam antibiotics, there may be an advantage in including teicoplanin in the initial empiric antibiotic regimen for febrile neutropenic cancer patients.     

Moxalactam plus ticarcillin or tobramycin for treatment of febrile episodes in neutropenic cancer patients

Moxalactam disodium in combination with ticarcillin disodium or tobramycin sulfate was used to treat 445 episodes of suspected or confirmed infection in patients with cancer. The majority had leukemia and neutropenia. The rate of cures during the 231 confirmed infections was 65% for moxalactam and ticarcillin and 64% for moxalactam and tobramycin. Both regimens were comparable against aerobic gram-negative and polymicrobial infections. In gram-positive infections, the response rate for moxalactam and ticarcillin was 73% and for moxalactam and tobramycin, 53%. Only three of nine enterococcal infections responded to treatment. Thirteen percent of all organisms recovered were resistant to moxalactam. Side effects occurred infrequently; the most important was coagulopathy due to moxalactam. Nephrotoxic effects occurred in six patients receiving moxalactam and tobramycin and in none of those receiving moxalactam and ticarcillin. In 39 patients, a superinfection was confirmed. Fourteen were fungal, three were due to enterococcus, and one due to Klebsiella species. Eleven of the 14 fungal episodes occurred in the moxalactam-ticarcillin group. Moxalactam with ticarcillin and moxalactam with tobramycin are equally active for the initial treatment of presumed infection in patients with neutropenia.     

Ceftazidime monotherapy for empiric treatment of febrile neutropenic patients: a meta-analysis.

Whether ceftazidime monotherapy is equal in efficacy to combination regimens (Comb) for empiric treatment of febrile neutropenic patients was tested using meta-analysis. Published studies and abstracts of ceftazidime trials were identified, their quality assessed, the efficacy data abstracted and pooled, and effects of patient and study characteristics examined. The pooled odds ratio (OR) of failure of ceftazidime for febrile episodes was 1.27 (95% confidence interval [CI]: 0.79-2.03; n = 1077) and for bacteremic episodes was 0.72 (CI, 0.33-1.58; n = 248; OR less than 1.0 favors ceftazidime). Results were not significantly affected by type of antibiotic in Comb, age, neutropenia (less than 500/mm3), study quality, or combining abstracts. Results indicate that Comb does not offer a significant advantage over ceftazidime. A subgroup of profoundly neutropenic (less than 100/mm3) patients could not be assessed, raising the possibility that in this important subgroup monotherapy and Comb may not be equivalent. Use of ceftazidime empirically may require modification based on microbiologic results and clinical course.     

Empirical monotherapy with meropenem versus imipenem/cilastatin for febrile episodes in neutropenic patients

Summary In a nonblind, randomised, parallel-group study, initial empirical monotherapy with meropenem 1 g intravenously every 8 h was compared to an identical dosage of imipenem/cilastatin for the treatment of 66 febrile episodes in 61 adult neutropenic patients. 25/31 episodes treated with meropenem and 24/30 imipenem/cilastatin-treated episodes were still receiving unmodified therapy at 72 h (primary endpoint); this difference was not statistically significant. By the end of the treatment courses, 18/31 meropenem-treated episodes had responded clinically (cured or improved) compared with 18/30 episodes treated with imipenem/cilastatin. Another ten episodes initially treated with meropenem and six episodes treated with imipenem/cilastatin were cured after an additional antimicrobial agent had been administered (cured with modification). Satisfactory bacteriological responses (eradication plus presumed eradication) at the end of unmodified therapy was 9/11 in the meropenem group and 14/16 in the comparator group. Both regimes were well tolerated; however, there were more reports of nausea and/or vomiting in the imipenem/cilastatin group (7/33 vs. 2/33 in the meropenem group). The carbapenems meropenem and imipenem/cilastatin appear to be suitable agents for empirical monotherapy of febrile episodes in neutropenic patients. Meropenem may be better tolerated than imipenem/cilastatin, allowing optimal dosing in this patient population.

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Empirische Monotherapie mit Meropenem oder Imipenem/Cilastatin für Fieber bei neutropenischen Patienten

Zusammenfassung In einer offenen, randomisierten Vergleichsstudie wurde die initiale empirische Monotherapie mit Meropenem in einer Dosierung von 3 × 1g täglich verglichen mit Imipenem/Cilastatin in der gleichen Dosierung bei 66 Fieberepisoden von 61 erwachsenen neutropenischen Patienten. 72 Stunden nach Therapiebeginn erhielten noch 25/31 Patienten aus der Meropenem-Gruppe und 24/30 Patienten aus der Behandlungsgruppe mit Imipenem/Cilastatin die usprünglich zugewiesene Initialtherapie (Hauptzielkriterium). Bei Therapieende waren in der Meropenem-Gruppe 18/31 Episoden geheilt oder gebessert gegenüber 18/30 in der Gruppe mit Imipenem/Cilastatin. Weitere 10 Infektionsepisoden, die initial mit Meropenem behandelt wurden, und sechs Infektionsepisoden aus der Vergleichsgruppe konnten erfolgreich behandelt werden, nachdem eine zusätzliche antimikrobielle Substanz verabreicht worden war (Heilung nach Therapiemodifikation). Das zufriedenstellende bakteriologische Ansprechen (Keimelimination sowie vermutete Keimelimination) mit der Initialtherapie Meropenem betrug 9/11 und 14/16 mit Imipenem/Cilastatin. Beide Antibiotika wurden gut vertragen; es wurden jedoch unter Imipenem/Cilastatin mehr Fälle von Übelkeit und/oder Erbrechen registriert (7/33 vs 2/33 unter Meropenem). Die Carbapenem-Antibiotika Meropenem und Imipenem/Cilastatin scheinen geeignet für die empirische Monotherapie bei Fieberepisoden neutropenischer Patienten zu sein. Meropenem erlaubt durch seine offensichtlich bessere Verträglichkeit im Vergleich zu Impienem/Cilastatin auch eine optimale Dosierung bei diesem Patientengut.

     

Efficacy and safety of intravenous itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematological malignancies in Japan

Recently, empirical antifungal therapy with intravenous itraconazole (ITCZ) for neutropenic patients with antibiotics-resistant fever has been approved by Japanese Ministry of Health, Labour and Welfare on the bases of previous multicenter trials of foreign countries. In this study, we conducted a single-arm, multicenter, prospective study in order to evaluate the efficacy of empirical ITCZ injection on Japanese patients. Sixty-eight patients with hematological diseases who underwent anticancer chemotherapy or stem cell transplantation were enrolled. In this study, we found that the overall clinical response rate to ITCZ injection was 67.6% and success rate of achieving composite endpoints including survival, defervescence during neutropenia, no breakthrough fungal infections, and no premature discontinuation of drug was 50.0%. Mild adverse reactions were observed in 6 patients (8.8%). Further analysis revealed that possible/probable deep fungal infection according to the 2002 and 2008 criteria defined by EORTC/MSG were found in 19.1 and 7.5% of the patients, respectively. Interestingly, response rate to ITCZ injection of possible/probable cases according to the 2002 and 2008 criteria was 61.5% (8/13) and 100% (5/5), respectively. These results not only proved the good efficacy and safety of empirical ITCZ injection for Japanese patients, but also indicated a utility of the drug on future “presumptive” approach. For the Osaka Hematology Consortium.