Gram-positive infections in neutropenic patients: glycopeptide antibiotic choice.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to F Menichetti.
Explore the source record for details and available documents.
The increasing prevalence of Gram-positive infections in neutropenic cancer patients seems to be related to the use of central venous catheters, chemotherapy-induced oral and gastrointestinal mucositis, and the prophylactic use of fluoroquinolones. The need for anti-Gram-positive therapy in the neutropenic patient is supported by the increasing prevalence and the changing resistance of Gram-positive pathogens, as well as by the poor response of Gram-positive bacteraemia to aminoglycoside plus beta-lactam regimens. Combined therapy with either vancomycin or teicoplanin and other empirical antibiotics, has proved efficacious in adults and children with neutropenia, fever and Gram-positive infection. Vancomycin exerts greater antibacterial activity against strains of coagulase-negative staphylococci than teicoplanin and there is more data on its routine clinical use. In its favour, teicoplanin is less toxic and easier to administer. The time when a glycopeptide antibiotic should be introduced is still a matter of debate; support for both initial therapy and subsequent rescue therapy is found in the current literature. Large clinical trials are warranted to clarify further the role of anti-Gram-positive therapy in the neutropenic patient.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
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. 152 febrile episodes in 129 neutropenic patients were treated with i.v. 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 (less than 100/mm3) at the beginning of the febrile episode. The overall response rate of the evaluable 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 staphylococci (coagulase-negative 14, coagulase-positive 13) and streptococci (13). 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 Gram-positive infections caused by strains with a high rate of resistance to aminoglycoside and beta-lactam antibiotics, there may be an advantage in including teicoplanin in the initial empiric antibiotic regimen for febrile neutropenic cancer patients.
We conducted a prospective randomized clinical trial to compare the efficacy and tolerability of monotherapy with ceftriaxone (active ingredient of Rocephin) (CRO) versus imipenem/cilastatin (I/C) in febrile cancer patients with or without neutropenia. 120 febrile episodes were randomized and 89 (75%) were evaluable for efficacy analysis. The overall response rates to both regimens were good (86 and 79% improved in response to CRO and I/C, respectively). Overall mortality was low and similar in the two groups. Both regimens were well tolerated. Our preliminary data corroborate the efficacy of CRO or I/C as empirical monotherapy for febrile episodes in cancer patients. It will be up to future investigations to show whether one of these regimens is superior to the other.
The first case report of leukopenia with neutropenia due to the new glycopeptide antibiotic teicoplanin is described. The side effect occurred in a 73-year-old man hospitalized because of subacute bacterial endocarditis caused by Streptococcus faecalis. Leukopenia with neutropenia (white blood cells 2000/mm3, neutrophils 46%) developed after 20 days of teicoplanin therapy. After stopping teicoplanin white blood cell and neutrophil counts reverted to normal, but dropped again on rechallenge. A review of 1500 records of patients treated with teicoplanin alone or in combination with other drugs was also performed. Five cases were found in which leukopenia was possibly (four cases) or probably (one case) related to teicoplanin therapy. From these preliminary data the incidence of leukopenia related to teicoplanin seems to be low.
From 1984 to 1986, 1038 Gram positive cocci (865 Staphylococci and 173 Enterococci) have been tested for sensitivity to teicoplanin by the agar diffusion method: only one strain (Staphylococcus haemolyticus) resulted to have no zone of inhibition around the teicoplanin disk. All Staphylococcus haemolyticus strains showed higher MIC: 2.79 mcg/ml after 24h of incubation and 20.50 mcg/ml after 48h. The reduced teicoplanin sensitivity of Staphylococcus haemolyticus was not detected by the agar diffusion test.
To prevent bacterial infections in the neutropenic post-transplant period, norfloxacin 400mg twice daily was administered as oral prophylaxis to 44 marrow recipients isolated in laminar airflow rooms (LAFRs). Patients had a mean age of 30 years (8-50) and a male/female ratio of 29/15. The mean duration of prophylaxis was of 41 days (20-80), that of neutropenia (PMN less than 1000 x 10(6)/l) of 31 days (6-76) and that of severe neutropenia (PMN less than 100 x 10(6)/l) of 19 days (10-55). All but two patients developed one or more febrile episodes (total episodes: 71), 33 of which were documented infections. Eighteen bacteraemias occurred and all were caused by Gram-positive cocci: five by coagulase-negative staphylococci (three methicillin resistant), four by coagulase-positive (one methicillin resistant), seven by streptococci (four S. sanguis, one S. milleri, one group B, one group C), and two by enterococci. All streptococcal and enterococcal strains, but only one MR coagulase-positive staphylococcus, proved to be resistant to norfloxacin. Norfloxacin was well tolerated and no prophylactic course had to be interrupted because of side effects. In conclusion, norfloxacin adequately prevents infections caused by Gram-negative bacilli in bone marrow recipients isolated in LAFRs, but Gram-positive infections still remain a problem in these patients indicating the need for improving this prophylactic regimen.
Teicoplanin in combination with amikacin and ceftazidime was used as empirical therapy in treating 46 febrile episodes in 34 consecutive patients undergoing allogenic bone marrow transplantation. All but four of these febrile episodes occurred in neutropenic patients and 50% of them proved to be bacteraemias (23/46). Cure was achieved in 90% of Gram-positive bacteraemias (18/20) and in six of them teicoplanin was the only antibiotic with activity in vitro against the infecting strain. All (3/3) Gram-negative bacteraemias were cured. Central venous catheter removal was required in five patients (three tunnel infections, one exit-site infection and one thrombophlebitis). Two failures occurred among Gram-positive bacteraemias and in one case the patient died of infection. Four instances of side effects were documented but only one was severe (hearing loss).
Episodes of septicaemia caused by Gram-positive bacteria in five separate investigations of empirical antibiotic treatment for fever in patients with neoplastic disease have been analysed according to the antimicrobial agents administered and the outcome. The results suggest that the addition of an 'anti-staphylococcal agent', such as co-trimoxazole, vancomycin or teicoplanin, to the standard two-drug regimen (a beta-lactam antibiotic and an aminoglycoside) may be advantageous in improving the prognosis, particularly in Staphylococcus aureus septicaemia.
Imipenem/cilastatin as a single agent or in combination with amikacin was used as empirical treatment of severe hospital infections. Twenty-five patients were evaluable for efficacy and the overall response rate was 62% with imipenem/cilastatin alone and 80% with imipenem/cilastatin in combination with amikacin. The highest response rate was obtained in urinary tract infection (75%) and in pneumonia (70%) and the lowest response rate (50%) was observed in bacteremia of unknown origin and in skin and soft tissue infections. Eight failures were observed and seven of them occurred in patients treated with imipenem/cilastatin alone. Two deaths occurred, both in patients with bacteremia. Imipenem/cilastatin treatment was interrupted early in 3 patients because the pathogen developed resistance during therapy and in 2 other patients because of side effects. In our study imipenem/cilastatin proved to be efficacious and well tolerated. The addition of an aminoglycoside to imipenem/cilastatin might improve its efficacy and prevent pathogens from becoming resistant during therapy. Therefore this association would seem to be advisable for the therapy of bacteremic infections and for those caused by difficult pathogens.
Explore the source record for details and available documents.
Viridans streptococci septicemia was documented in ten cancer patients, 7 of whom were neutropenic (less than 1000/mmc). Pneumonia was presumed to be the source of bacteremia in six patients. Viridans streptococci isolated from sputum culture in an immunocompromised host must be regarded as the potential etiological agent, then further characterized and checked for antibiotic sensitivity.
Teicoplanin, 200-400 mg (3-6 mg/kg) daily iv or im, was used to treat 71 episodes of infection. The average duration of treatment was 22 days. The 64 evaluable episodes comprised 24 skin/soft tissue, 20 osteoarticular, ten urinary tract and one ventriculo-atrial shunt infections; one case of primary bacteraemia, three of endocarditis, two of pneumonia and three of pleural empyema. Fifty-five episodes were treated with teicoplanin monotherapy and nine with teicoplanin in association to other antibiotics. Overall 61% (39/64) of the evaluable infections were cured, 25% (16/64) improved and 14% (9/64) failed. Staphylococcus aureus was the most frequent pathogen, with 46 isolates. Infections by both methicillin-sensitive and resistant Staph. aureus strains showed favourable clinical and microbiological responses to teicoplanin. Side effects were observed in eight of the 64 episodes (12.5%). Bronchospasm was observed in two other cases at the beginning of therapy and the antibiotic administration was discontinued. Teicoplanin is an effective and well tolerated antibiotic for infections by Gram-positive bacteria, and it is effective against methicillin-resistant staphylococci.
Teicoplanin, a new glycopeptide antibiotic, is structurally related to ristocetin, an antibiotic known to induce human platelet agglutination and, thus, thrombocytopenia and thromboembolic side effects. The aim of this study was to evaluate the effects of teicoplanin on platelet function in vitro and ex vivo and on blood coagulation ex vivo. In the in vitro studies, spontaneous platelet aggregation; platelet aggregation induced by ADP, collagen, and ristocetin; and the release of beta-thromboglobulin from platelets were assessed. Platelets from healthy subjects were incubated with teicoplanin at final concentrations of 100, 1,500, 5,000, and 10,000 micrograms/ml. The maximal achievable concentration with therapeutic doses is 100 micrograms/ml. When compared with saline, teicoplanin at concentrations of 100 and 1,500 micrograms/ml had no effect on platelet function, but at concentrations of 5,000 and 10,000 micrograms/ml, it induced greater spontaneous platelet aggregation (P less than 0.01) and inhibited platelet aggregation induced by ADP, collagen, and ristocetin (P less than 0.01). Teicoplanin at concentrations of 100, 1,500, and 5,000 micrograms/ml did not induce the release of beta-thromboglobulin, in contrast to teicoplanin at a concentration of 10,000 micrograms/ml and ristocetin at a concentration of 1.5 mg/ml (P less than 0.01). In the ex vivo studies, platelet count, bleeding time, plasma beta-thromboglobulin, platelet aggregation induced by ADP, ristocetin, and epinephrine, activated partial thromboplastin time, prothrombin time, thrombin clotting time, and serum fibrinogen degradation products were evaluated at days 0, 3, and 6 and at 72 h after the end of therapy. All subjects completed the study without evidence of side effects. When compared with the pretreatment values, none of the values from these assays showed a significant change at any time during and after treatment. We concluded that platelet function and blood coagulation are not affected by therapeutic concentrations of teicoplanin and that in vitro platelet function is affected only by concentrations of teicoplanin far in excess of those that are clinically achievable.
The increasing prevalence of bacteremia caused by gram-positive bacteria in granulocytopenic acute leukemia patients prompted us to evaluate, in a prospective randomized trial, the role of teicoplanin, a new glycopeptide antibiotic, when it was added to amikacin plus ceftazidime, as an empiric therapy of fever in these patients. Of 47 evaluable episodes, 22 were treated with the teicoplanin regimen and 25 were treated with the combination of amikacin and ceftazidime. The overall response to therapy of patients treated with teicoplanin was slightly better (82% improvement) than that obtained with amikacin plus ceftazidime (52%). The response rate of patients with gram-positive bacteremias was 80% (4 of 5) to the regimen that included teicoplanin; 25% (1 of 4) of the patients treated with amikacin plus ceftazidime responded to treatment; and for patients with gram-negative bacteremias, the response rates were, respectively, 100% (4 of 4) and 70% (7 of 10). The better results obtained with amikacin-ceftazidime-teicoplanin treatment were most evident in patients with profound (less than 100/mm3) and persistent neutropenia (83 versus 30% improvement). Furthermore, a good response rate of patients with gram-positive bacteremias (seven of eight; 87% improvement) was achieved in a small group of bone marrow transplant patients who were all treated with amikacin-ceftazidime-teicoplanin. No severe side effects were documented in any patient. Teicoplanin, as a drug administered as a single daily dose, seems to be a safe and useful anti-gram-positive agent when used in combination with amikacin-ceftazidime as an empiric therapy of febrile episodes in granulocytopenic acute leukemia patients.