Treatment Of Febrile Neutropenic Patients Research Articles

Ceftazidime Monotherapy for Empiric Treatment of Febrile Neutropenic Patients: A Metaanalysis

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.

Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases

100 febrile patients with chemotherapy-induced neutropenia (less than 0.5 x 10(9)/l) were empirically treated by ceftriaxone (2 g daily in adults, 50 mg/kg daily in children, as a once daily injection) and amikacin (15-20 mg/kg daily). The mean age was 41 years (range 8-72). 51 patients had acute leukemia, 29 non-Hodgkin's lymphoma, 12 Hodgkin's disease, 8 other disorders. 23 febrile episodes were bacteriologically documented (gram-positive: 13 patients; gram-negative: 8 patients; Candida: 2 patients) including 13 cases of bacteremia; 10 were clinically documented, and 67 remained of undetermined origin. Apyrexia was obtained in 39 patients by ceftriaxone plus amikacin alone (success), in 36 patients after the addition of vancomycin and/or amphotericin B (improvement), whereas in the remaining 25 patients it was necessary to substitute the study drug. The failure rate was correlated to the duration of neutropenia: 0/13 when neutropenia less than 6 days; 3/41 (7%) when 6-10 days; 22/46 (48%) when greater than 10 days. Only 2/20 (10%) of patients with neutropenia greater than 20 days were treated with ceftriaxone plus amikacin alone. 9 of the 23 bacteriologically documented episodes were successes (including 6 of the 11 cases due to Staphylococcus), 7 were improvements and 7 were failures (including the 3 cases due to Pseudomonas). No side effects were seen. Ceftriaxone plus amikacin is an effective firstline antibiotic combination in the treatment of febrile neutropenic patients.

A randomized study of teicoplanin plus ciprofloxacin versus gentamicin plus piperacillin for the empirical treatment of fever in neutropenic patients

We compared the combination of teicoplanin plus ciprofloxacin with gentamicin plus piperacillin for the empirical treatment of fever in 80 neutropenic patients. A favourable clinical response rate was achieved in 28/38 (74%) patients receiving teicoplanin plus ciprofloxacin and in 17/35 (49%) of those receiving gentamicin plus piperacillin (P = 0.05). Microbiologically documented infections accounted for 55% of febrile events. When these episodes were analysed separately, response to teicoplanin plus ciprofloxacin remained unchanged at 74% whereas only 35% patients responded to gentamicin and pieracilin (P = 0.034). Gram-positive organisms accounted for 78% bacterial isolates with Staphylococcus epidermidis the most common pathogen. Ten out of 12 (83%) Staph. epidermidis infections resolved when treated with teicoplanin and ciprofloxacin as compared with a response rate of only two out of eight (25%) with gentamicin and piperacillin (P = 0.032). The combination of teicoplanin and ciprofloxacin was associated with no severe drug-related adverse events; by contrast, two patients receiving gentamicin plus piperacilin were withdrawn owing to adverse drug reactions, one with acute renal failure and one following a severe allergic reaction to piperacillin. We conclude that teicoplanin with ciprofloxacin is more effective than gentamicin plus piperacillin for the empirical treatment of febrile neutropenic patients. The high incidence of Gram-positive infection in our unit probably justifies the use of a specific anti-Gram-positive agent in the first-line antibiotic regimen.

Role of glycopeptide antibiotics in the treatment of febrile neutropenic patients

The exact timing of the introduction of the glycopeptide antibiotics teicoplanin and vancomycin in the management of the febrile neutropenic patient continues to be controversial. However, there are certain firm criteria now emerging. Bacteraemia can be eradicated with a success rate approaching 100% in cases where the organism can be identified and shown to be sensitive. Approximately 65% of cases of soft-tissue infection, usually occurring with the use of a Hickman or equivalent indwelling catheter, are associated with the presence on culture of Gram-positive organisms of presumed skin origin. Such infection is an indication for the early use of antibiotics with proven activity against coagulase-negative staphylococci and diptheroids. Resolution of fever in up to 50% of cases may result from using 'planned progressive therapy': the introduction of specific Gram-positive cover in patients who have failed to respond at 48-72 h to regimens such as a ureidopenicillin or a third-generation cephalosporin with or without an aminoglycoside. This approach reduces the number of patients who go on to receive empirical amphotericin B intravenously for presumed fungal infection. Using teicoplanin or vancomycin as first-line agents in the empirical treatment of first fever in febrile neutropenic patients is perhaps more controversial. Recent developments which include using quinolone-based prophylaxis more widely and introducing cytokines to reduce the period of neutropenia may increase the likelihood that a neutropenic patient's febrile episode will be due to a Gram-positive organism. The dilemma of choosing broad-spectrum monotherapy or targeted combination therapy in the situation remains unresolved. Current studies, however, should help to clarify this situation. Finally, other current studies of teicoplanin and vancomycin as prophylactic agents administered either orally or systemically, may provide additional indications for their use in the neutropenic patient.

Ceftazidime monotherapy is as effective as ceftazidime combined with gentamicin in the treatment of febrile neutropenic patients

To evaluate the efficacy of ceftazidime monotherapy in the empirical treatment of febrile neutropenic patients, a randomized trial was performed of ceftazidime (C) vs. ceftazidime and gentamicin (C + G) with the addition of teicoplanin (T) for those patients with a long intravenous line-associated infection. Success without modification at the end of treatment was seen in 32·7% (C), 28·3% (C + G), 52·4% (C + T) and 65·2% (C + G + T). Monotherapy with ceftazidime is as effective as when used in combination with an aminoglycoside in neutropenia.

Aztreonam in the prevention and treatment of infection in neutropenic cancer patients

The treatment of bacterial infections in neutropenic cancer patients presents a serious challenge to physicians. Although gram-positive infections have become more common in recent years, most infections in this population are caused by gram-negative bacilli. No single regimen has been found to be optimal, and most commonly used regimens are associated with significant disadvantages. Extensive investigation is therefore under way to evaluate the potential of several promising newer antimicrobial agents. Aztreonam, for example, is active against most gram-negative pathogenic bacteria and has been evaluated in several clinical trials in neutropenic patients. As the only agent with gram-negative activity or in combination either with aminoglycosides or with other beta-lactam antibiotics, aztreonam proved useful in the treatment of gram-negative infections in this population. Combination with an aminoglycoside, however, was not found to improve efficacy over aztreonam alone. In fact, since aminoglycosides may potentiate ototoxicity and nephrotoxicity, it may be more appropriate to replace the aminoglycoside component of a combination regimen with aztreonam, as indicated by data from a study of aztreonam plus cefoperazone. Aztreonam selectively inhibits the aerobic gram-negative intestinal flora with only minimal disruption of anaerobic flora, and may be useful for infection prevention, but the importance of anaerobic preservation is not clear. It was concluded that aztreonam appears to be a useful agent for the treatment of febrile neutropenic patients, but further study is recommended.

Randomized multicentre study of ciprofloxacin and azlocillin versus gentamicin and azlocillin in the treatment of febrile neutropenic patients

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.

Assessment of the interaction between ciprofloxacin and teicoplanin in vitro and in neutropenic patients

The interactions of ciprofloxacin and teicoplanin were investigated against methicillin-sensitive and methicillin-resistant Staphylococcus aureus and Staph. epidermidis isolated during a clinical trial of the efficacy of this combination. In-vitro studies of the combination of ciprofloxacin and teicoplanin found no evidence of any antagonism between these two drugs in terms of inhibition of bacterial multiplication, as determined by Fractional Inhibitory Concentration Indices, and lethality. Clinical use of teicoplanin plus ciprofloxacin as empirical therapy in 29 febrile neutropenic patients revealed an overall response rate of 75%. Response rate for staphylococcal infections, which accounted for 53% of isolated pathogens, was 80%. No serious adverse drug reactions were seen. Our results show that both in vitro, and in the treatment of febrile neutropenic patients, teicoplanin plus ciprofloxacin is an effective anti-staphylococcal combination.

Intravenous ciprofloxacin as empirical treatment of febrile neutropenic patients

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.

Preliminary evaluation of ciprofloxacin, a new 4-quinolone antibiotic, in the treatment of febrile neutropenic patients.

Twenty-four episodes of fever in neutropenic patients with haematological malignancy were treated with ciprofloxacin. In 13 episodes ciprofloxacin was used after failure of first-line antibiotic therapy, and in 11 episodes because of a history of allergy to the proposed first line antibiotics. Improvement or temporary improvement was seen in 64% of patients with evaluable infection. Fifty per cent of patients with bacteraemia improved. Resistance to ciprofloxacin developed in strains of staphylococci and streptococci, but Gram-negative organisms were generally extremely sensitive to the antibiotic. One patient developed a severe photosensitivity rash but there were no other adverse reactions. Preliminary pharmacokinetic data were obtained following intravenous infusion of 400 mg of ciprofloxacin in five patients. The mean plasma half-life was 3.6 +/- 1.0 h and the mean plasma clearance was 8.42 +/- 2.5 ml/min/kg.

In vitro models for the study of combination antibiotic therapy in neutropenic patients

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, meziocillin, 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 predictive of clinical outcome than are traditional static in vitro methods used to study antibiotic combinations.

Comparative review of combination therapy: two beta-lactams versus beta-lactam plus aminoglycoside

Febrile neutropenic patients are usually treated with a combination of a beta-lactam and an aminoglycoside. Since Pseudomonas aeruginosa is an important pathogen in these patients, the empiric use of possibly synergistic combinations against that organism has been traditionally recommended. The recent appearance of betalactams more active against P. aeruginosa and the well-known nephrotoxicity of aminoglycosides have led some to advocate the use of beta-lactam combinations for empiric treatment of fever in neutropenic cancer patients. This article reviews the available literature on the controlled use of combinations of beta-lactams in the treatment of febrile neutropenic patients as compared with that of combinations of beta-lactams and aminoglycosides. The review includes comparison of overall response, response in patients with septicemia or other infections, response associated with different pathogens, the effect of profound neutropenia, and an evaluation of the toxicities encountered. Overall, these results show that response rates with a combination of two beta-lactams are similar to those obtained with the combinations of a beta-lactam and an aminoglycoside for infections in patients with serious underlying disease and compromised mechanisms of defense. They also suggest that the steady emergence of resistance of pathogens to betalactams has often been overcome by the use of newer drugs in regard to infections caused by the Enterobacteriaceae but much less effectively in regard to P. aeruginosa. There are still important theoretic reasons for preferring an aminoglycoside-containing combination as empiric therapy in febrile neutropenic patients, and our overall conclusion is that it would be appropriate to conduct a large-scale trial comparing beta-lactam combinations with the traditional beta-lactam plus aminoglycoside regimens in that setting.

Aspects of clinical trials with ceftazidime worldwide

Overall results from worldwide clinical studies of ceftazidime in open and comparative trials conducted over a four-year period in North America, Europe, and elsewhere are presented. Data from 3,570 patients treated with ceftazidime in open studies and from 1,340 patients receiving ceftazidime and 1,180 patients receiving other antibiotics In comparative studies are discussed. The comparative antibiotics consisted of aminoglycosides alone in 14.2 percent of patients, aminoglycosides combined with one or two beta-lactams in 43 percent, beta-lactams alone in 34 percent, and other antibiotic combinations in 8.8 percent. In comparative studies, bacterial clearance rates were 80.6 percent for ceftazidime and 72.5 percent for other antibiotics. Clinically, 92.6 percent of the infected sites in ceftazidime-treated patients in open studies were cured or improved, and 91.1 percent were cured or improved in comparative studies; 84.8 percent of the infected sites were cured or improved in patients treated with other antibiotics. Data indicate that ceftazidime monotherapy is as effective as combination antibiotic therapy in the empiric treatment of febrile non-neutropenic patients. The role of ceftazidime monotherapy in the treatment of febrile neutropenic patients is not yet firmly established. Superinfections were reported in 2.6 percent of the patients treated with ceftazidime alone in open trials, in 4.2 percent of the patients treated with ceftazidime alone in comparative trials, and in 8.5 percent of the patients treated with other antibiotics. During treatment, the sensitivity of bacteria to ceftazidime decreased in 2.5 percent of the pathogens isolated. Adverse events occurred in 10.2 percent of patients treated with ceftazidime in open studies, in 8.4 percent of those treated with ceftazidime in comparative studies, and in 8.8 percent of those treated with other antibiotics. The adverse events In both ceftazidime- and control-treated patients were thought by the investigators to be drug-related in about 40 percent of cases, not drug-related in 20 percent of cases, and of unknown etiology in the remaining cases.