Options and limitations of teicoplanin in febrile granulocytopenic patients

S ummary During the years 1985–89 three studies on the efficacy and safety of teicoplanin in the treatment of febrile granulocytopenic patients suffering from haematological malignancies were assessed. In the first prospective study, teicoplanin at a dose of 400 mg/d was added to the initial empiric therapy of 65 febrile granulocytopenic episodes. When teicoplanin was given because of proven or presumed Gram-positive infection, 67% of cases were treated successfully. Patients with skin and soft-tissue infections achieved a 78% response rate. The second study on 120 patients was designed as a prospective randomized trial to compare the efficacy and toxicity of ceftazidime with and without teicoplanin. Response was achieved in 25/51 (49%) cases from the ceftazidime and in 33/52 cases (63%) from the combination groups. Seven of 18 (39%) cases with initial bacteraemia in the monotherapy group compared with 10/20 (50%) cases in the combination group responded to the empiric regimen. A retrospective analysis was carried out on the efficacy of teicoplanin in 125 cases of proven Gram-positive Hickman line-associated bacteraemia. Teicoplanin proved to be effective in eradicating 80% of the Staphylococcus epidermidis. 72% of the Staph. aureus , 90% of the 'viridans' streptococci and 67% of the enterococci. Removal of the catheter was required in 13% of cases in order to control the infection, and only one patient died of a catheter-related septicaemia caused by Staph. aureus . The total success rate leaving the catheter in situ was 78%, and 92% if cases with catheter removal were included. Serum levels of teicoplanin were predictable giving a peak and trough concentration on the fourth day of 30.4 ± 5.0 mg/l and 9.8 ± 1.7 mg/l. Hearing loss of 20 dB at 8000 Hz was noted in one case and transient liver or kidney disturbances attributable to the drug were observed in 4% of cases.     

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.     

Teicoplanin in the treatment of Gram-positive bacteraemia in neutropenic patients

S ummary The increasing incidence of bacteraemia caused by Gram-positive bacteria in neutropenic patients prompted the authors to evaluate, in a prospective trial, the role of teicoplanin in the treatment of this infection. Over a 15-month period. 76 cases of bacteraemia (out of 265 evaluable episodes of fever) were observed at the Division of Haematology. University La Sapienza. Kome. Of the 76 cases studied, 46 (60%) were caused by Gram-positive bacteria and 28 (37%) were caused by Gram-negative bacilli. All febrile episodes were treated randomly and empirically with piperacillin plus amikacin with or without teicoplanin. Overall, 41 (54%) of the 76 cases of bacteraemia responded to the initial antibiotic regimen: with subsequent modifications the response rate rose to 96%.
In the treatment of Gram-positive bacteraemia. first-line administration of teicoplanin was found to be associated with early defervescence and with a significantly higher rate of success without modification of treatment (P < 0.01). Addition of teicoplanin as second-line therapy produced a favourable outcome in 12 (70%) out of 17 cases of bacteraemia unresponsive to the initial piperacillin + amikacin regimen. No cases of Gram-positive bacteraemia associated with septic shock or adult respiratory distress syndrome were observed in either treatment group. Only two late deaths were observed, and these occurred in patients with streptococcal septicaemia who were not receiving early teicoplanin.
The above data do not endorse the use of glycopeptide antibiotics in the early treatment of fever in neutropenic patients: rather, these compounds should be reserved for proven or presumed Gram-positive infections which do not respond to initial beta-lactam/aminoglycoside treatment.     

Ceftazidime plus teicoplanin versus ceftazidime plus amikacin as empiric therapy for fever in cancer patients with granulocytopenia

S ummary In a prospective randomized study, 100 episodes of fever (>38°C) and granulocytopenia (<1000/μ1) in cancer patients were empirically treated with ceftazidime (2 g every 8 h) plus teicoplanin (400 mg every 8 h on day 1: 400 mg every day thereafter) or ceftazidime (2 g every 8 h) plus amikacin (500 mg every 8 h).
Bacteraemia. clinically documented infection and possible infection were documented in seven. 11 and 19 patients treated with ceftazidime plus teicoplanin and in 11, four and 17 patients treated with ceftazidime plus amikacin. Overall, the response rate was similar in the two groups of patients as was the need for treatment modifications and the rate of death.
For documented Gram-positive bacteraemia, the response rate was 2/5 patients treated with ceftazidime plus teicoplanin and 2/7 with ceftazidime plus amikacin: for documented Gram-negative bacteraemia. the response rate was 1/2 and 3/4 patients respectively. No breakthrough bacteraemia was observed. Tolerance was excellent. although renal toxicity (elevation of serum creatinine) was observed in three patients treated with ceftazidime plus teicoplanin and in none allocated to ceftazidime plus amikacin.     

Amikacin plus piperacillin versus ceftazidime as initial therapy in granulocytopenic patients with presumed bacteremia

69 febrile granulocytopenic episodes without an initial focus of infection were assessed for empiric treatment either with high-dose amikacin plus piperacillin or ceftazidime. 90% of patients in each group survived the granulocytopenic episode; 15 (44 +/- 17%) episodes treated with the combination and 23 (66 +/- 16%) given ceftazidime responded without any modification of initial therapy and half defervesced within 72 h. Persistent fever was the most frequent reason for altering treatment which was done empirically in 90% of cases, but two-thirds of patients required further treatment modification. An infectious focus mainly involving the lung developed during granulocytopenia in 21 patients (30%), of which 17 occurred during antimicrobial therapy. Only 1 infection was shown to be due to bacteria, while 7 were due to fungi. Amikacin levels were similar to those expected following a normal dose (mean peak of 34.7 and mean trough of 12.6 mg/l). Therapy with the combination resulted in a higher serum creatinine (p less than 0.001) and a lower potassium level (p less than 0.001) in comparison with monotherapy. Potassium supplementation was required in 45 +/- 17% of patients given the combination compared with only 4 +/- 7% of those treated with ceftazidime. While both regimens appeared to be equally effective as initial therapy, the need for modification was high in both patient groups. Monotherapy being both simpler to administer and less toxic seems therefore to be the logical choice although the period of empiric therapy must be fully exploited in order to improve diagnosis and therefore antimicrobial management.     

Clinical index to predict bacteraemia caused by staphylococci

Abstract. Objectives. To define risk factors associated with bacteraemia caused by Staphylococcus aureus or coagulase-negative staphylococci; and to use them to define patients in need of empiric anti-staphylococcal antibiotic treatment. Design, Derivation set: observational, prospective study; validation set: retrospective analysis of a prospectively collected database. Setting. Derivation set: Beilinson Medical Centre, Petah Tiqva, Israel—a 900-bed university hospital. Validation set: St Thomas's Hospital, London, UK—an 800-bed teaching hospital. Subjects. All episodes of bacteraemia detected at Beilinson Medical Centre between March 1988 and September 1990 (derivation set, n = 1410), and at St Thomas's Hospital during 1987–1990 (validation set, n = 1040). Interventions. None. Main outcome measures. Percentage of staphylococcal bacteraemia in groups of patients defined by the models. Results. The following factors were associated with Staphylococcus aureus bacteraemia: focus of infection (whether high or low risk), haemodialysis, intravenous drug abuse and infection acquired in the orthopaedic ward. A logistic model was used to divide the derivation set into three groups with percentages of Staphylococcus aureus bacteraemia of 1.8%, 13.2% and 33.7% (P < 0.0001); and the validation group 2.5%, 18.2% and 53.2% (P < 0.0001). Factors associated with coagulase-negative staphylococcal bacteraemia were: central or peripheral intravenous catheter as the focus of infection, a preterm neonate, the presence of a central intravenous catheter, low temperature, and a low white blood cell count. A second model including those factors was used to divide the derivation set into three groups with percentages of coagulase-negative staphylococcal bacteraemia of 1.9%, 22.8%, and 43% (P < 0.0001). In the validation set, the percentages were 2.9%, 22.4% and 31.0% (P < 0.001). Conclusions. The present study defines groups at high risk for staphylococcal bloodstream infection, in which empiric treatment should include an anti-staphylococcal drug.     

Ceftazidime plus amikacin versus ceftazidime plus vancomycin as empiric therapy in febrile neutropenic children with cancer

Two antibiotic regimens, ceftazidime plus amikacin and ceftazidime plus vancomycin, were compared in a prospective, randomized clinical trial as empiric therapy in febrile granulocytopenic children with cancer. The rate of response was similar in the two groups (66% vs. 77%). The prevalence of secondary gram-negative bacteremia was higher--but not significantly higher--in the group receiving vancomycin. Adverse reactions also occurred more often in the latter group (35% vs. 4%). Mortality did not differ significantly in the two groups. Adjustment for independent predictors of response to treatment by means of multivariate analysis confirmed the lack of any remarkable difference between the responses to the two regimens. We conclude that the use of vancomycin instead of amikacin in combination with ceftazidime does not significantly improve the outcome of treatment of fever and infection in granulocytopenic children with cancer and that the use of vancomycin is associated with an increased frequency of both secondary infections due to gram-negative bacteria and adverse reactions.     

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

S ummary 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 piperacilin (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 (75%) 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.     

Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients

 Infections remain the major cause of morbidity and mortality among neutropenic cancer patients. The current study addresses the question whether monotherapy with the new broad-spectrum carbapenem meropenem exhibits efficacy comparable to that of the standard combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Seventy-one patients with hematological malignancies (55%) or solid tumors (45%), neutropenia <500/μl, and fever <38.5  °C were randomly assigned to either meropenem (1 g every 8 h) or ceftazidime (2 g every 8 h) and amikacin (15 mg/kg/day) intravenously. Meropenem (n=34) and ceftazidime/amikacin (n=37) were equivalent with respect to the clinical response at 72 h (62% versus 68%) (p<0.05) and at the end of unmodified therapy (59% versus 62%). Gram-positive bacteremia responded poorly in the meropenem and ceftazidime/amikacin group (29% versus 25%), whereas all gram-negative bacteremias responded except for one in the meropenem group caused by Pseudomonas aeruginosa. All patients survived to 72 h. One patient in each group died of gram-positive sepsis resistant to study medication. No significant side effects occurred in any regimen. This study suggests that meropenem monotherapy might be as effective as combination therapy with ceftazidime and amikacin for the empirical treatment of febrile neutropenic patients. Received: 13 June 1997 / Accepted in revised form: 5 December 1997     

Staphylococcus aureus Bacteremia in Patients with Hematological Malignancies and/or Agranulocytosis

ABSTRACT. A total of 6 253 cases of Staphylococcus aureus bacteremia, including 274 (4.4%) endocarditis cases, were registered in Denmark in the period 1975–1984. Patients with hematological malignancies and/or agranulocytosis accounted for 479 of the bacteremia cases. The incidence of endocarditis in this group of patients was only 0.4% as compared to 4.7% in other patients with staphylococcal bacteremia (p<0.01). The lower incidence of endocarditis complicating bacteremia in these patients may justify a shorter course of therapy than usually recommended for suspected endocarditis. Patients with hematological malignancies and other patients with agranulocytosis had a higher mortality (49 and 46%, respectively) than other patients with S. aureus bacteremia (33%). The highest mortality was found in patients with multiple myeloma (71%, p<0.01), the lowest in patients with acute lymphocytic leukemia (28%, p<0.01). The higher mortality in these patients may indicate that empiric antibiotic regimens in granulocytopenic patients should include a specific anti-staphylococcal agent.     

A multi-centre prospective study of febrile neutropenia in Norway: microbiological findings and antimicrobial susceptibility

The urgent need to treat presumptive bacterial or fungal infections in neutropenic patients has meant that initial therapy is empiric and based on the pathogens most likely to be responsible, and drug resistance. The traditional empirical treatment in Norway has been penicillin G and an aminoglycoside, and this combination has been criticized over recent y. We wished to analyse the microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in febrile neutropenic patients. This was a prospective multicentre study. During the study period of 2 y, a total of 282 episodes of fever involving 243 neutropenic patients was observed. In 34% of episodes bacteraemia was documented. Overall, 40% of the episodes were caused by Gram-positive organisms, 41% by Gram-negative organisms and 19% were polymicrobial. The most frequently isolated bacteria were Escherichia coli (25.6%), a- and non-haemolytic streptococci (15.6%), coagulase-negative staphylococci (12.4%) and Klebsiella spp. (7.4%). None of the Gram-negative isolates was resistant to gentamicin, meropenem, ceftazidime or ciprofloxacin. Only 5 coagulase-negative staphylococci isolates were resistant to both penicillin G and aminoglycoside. The overall mortality rate was 7%, and 1.2% due to confirmed bacteraemic infection.     

A randomized clinical trial of ceftriaxone and teicoplanin versus ceftazidime and teicoplanin as antibiotic therapy in febrile neutropenic cancer patients and bone marrow transplant recipients

Summary A prospective, randomized clinical trial comparing combination therapy with ceftriaxone and teicoplanin versus ceftazidime and teicoplanin in the treatment of febrile episodes in neutropenic cancer patients and bone marrow transplant recipients was performed. One hundred and two patients were randomized, but two patients were considered unevaluable for efficacy, and three patients were withdrawn due to incorrect randomization. Of the remaining 97 patients, infection resolved without modification of therapy in 31/49 (63%) patients treated with ceftriaxone/teicoplanin versus 27/48 (56%) patients treated with ceftazidime/teicoplanin (P=0.48). Of all 97 patients treated therapy was modified in 18/49 (36%) with ceftriaxone/teicoplanin and 21/48 (43%) with ceftazidime/teicoplanin. Nineteen patients treated with ceftriaxone/teicoplanin received netilmicin and 21 patients treated with ceftazidime/teicoplanin also received netilmicin according to the study design (escalation therapy). When netilmicin was added infection resolved in 78% of patients treated with ceftriaxone/teicoplanin versus 84% of those treated with ceftazidime/teicoplanin. It was concluded that combination therapy with ceftriaxone/teicoplanin is an alternative to combination therapy with ceftazidime/teicoplanin, and has the advantage of once daily administration.

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Antibiotische Therapie der febrilen Neutropenie von Tumor- und Knochenmarktransplantationspatienten. Eine randomisierte Studie mit Ceftriaxon und Teicoplanin im Vergleich mit Ceftazidim und Teicoplanin

Zusammenfassung In einer prospektiven, randomisierten klinischen Studie wurde die Kombinationstherapie mit Ceftriaxon und Teicoplanin gegen die Kombinationspartner Ceftazidim und Teicoplanin bei neutropenischen Patienten oder Patienten nach Knochenmarktransplantation verglichen. Insgesamt wurden 101 Patienten in die Studie eingebracht, davon waren 97 Patienten auswertbar. In der Ceftriaxon/Teicoplanin-Gruppe waren 63% der Patienten geheilt, gegenüber 56% der Patienten in der Ceftazidim/Teicoplanin-Gruppe. Dieses Ergebnis war ohne Modifikation der Studien-Medikamente erreicht worden. Bei 18 von 49 Patienten in der Ceftriaxon/Teicoplanin-Gruppe und 21 von 48 Patienten in der Ceftazidim/Teicoplanin-Gruppe wurde von der Studienmedikation abgegangen und zusätzlich Netilmicin (Eskalationstherapie) gegeben. Durch die zusätzliche Gabe von Netilmicin waren 78% der Patienten in der Ceftriaxon/Teicoplanin-Gruppe und 84% in der Ceftazidim/Teicoplanin-Gruppe geheilt. Diese Daten deuten darauf hin, daß die Kombinationstherapie mit Ceftriaxon/Teicoplanin eine Alternative zur Kombinationstherapie mit Ceftazidim und Teicoplanin darstellt, zumal die Gabe von Ceftriaxon und Teicoplanin den Vorteil hat, daß diese Medikamente nur einmal pro Tag gegeben werden müssen.

     

Empiric therapy with amphotericin B in febrile granulocytopenic patients

The early diagnosis of invasive fungal infection in granulocytopenic patients remains unreliable. Granulocytopenic patients who are persistently or recurrently febrile despite therapy with appropriate antibacterial agents are at high risk for the development of such infection. Two randomized clinical trials demonstrated that the empiric administration of amphotericin B to persistently or recurrently febrile granulocytopenic patients decreased the frequency, morbidity, and mortality of invasive fungal infection; these effects were especially marked in profoundly granulocytopenic patients who were not receiving antifungal prophylaxis. Current studies continue to indicate that prompt empiric administration of amphotericin B to persistently or recurrently febrile granulocytopenic patients ensures earlier treatment of deep mycoses. The roles of newer antifungal triazole compounds and of liposomal and lipid complexes of amphotericin B in empiric antifungal therapy must be investigated further in thoughtfully designed, randomized clinical trials.     

Staphylococcal bacteraemia: the hospital or the home? A review of Staphylococcus aureus bacteraemia at Concord Hospital in 1993

Aims: To examine the risk factors for, and the complications and mortality of, Staphylococcus aureus bacteraemia. Methods: A retrospective case review of patients with S. aureus bacteraemia in 1993 diagnosed at the Concord Repatriation General Hospital, Sydney. Results: Of 104 cases reviewed, 32 were due to methicillin resistant S. aureus (MRSA), 73 were due to methicillin sensitive S. aureus (MSSA) and one was a dual infection. Twenty-eight of the bacteraemias were community-acquired, including one case of MRSA, and 76 were hospital-acquired; 38% had an implanted prosthetic device or graft. The average age (68 years), incidence of underlying diseases and hospitalisation in the past month (26%) did not differ between MRSA and MSSA groups. MRSA was more likely in patients with recent broad-spectrum antibiotic use (53%vs 0, p<.01). Vascular access was the commonest source of sepsis (61 %) but in community-acquired cases the source was unknown in 50%. Use of central line access was more predictive of MRSA infection (75%vs 49%, p=.018). In hospital-acquired infection, MRSA sepsis occurred later in the course of the admission (26 days vs eight days, p<.01). Directly attributable mortality was highest in MRSA and community-acquired MSSA infection (9% and 11%) compared with hospital-acquired MSSA infection (1%). Conclusions: Nosocomial S. aureus bacteraemia, particularly MRSA, is a major source of preventable morbidity, which could be addressed by improved infection control of MRSA, antibiotic use and attention to central line catheter use.     

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.     

Ceftazidime with or without amikacin for the empiric treatment of localized infections in febrile,granulocytopenic patients

Summary In a prospective randomized study, 90 granulocytopenic febrile patients presenting with a localized infection were treated empirically with ceftazidime alone or in combination with amikacin (1.5 g/day). Two thirds had received selective oral antimicrobial prophylaxis before therapy. The treatment groups were comparable in terms of the depth and duration of granulocytopenia as well the distribution of the infection categories and rate of bacteremia. There was no difference with respect to the final response: 53% for the monotherapy group versus 48% for the combination group, and both regimens appeared to be equally safe. The duration of fever, clinical symptoms, antibiotic therapy, and granulocytopenia were comparable for both treatment groups, and approximately 90% of patients survived the infection. Only one patient given monotherapy required amikacin. It is concluded that aminoglycosides are not necessary for the empiric treatment of infectious complications in granulocytopenic patients if antibacterial prophylaxis has been given before-hand.J. P. Donnelly is supported by Glaxo Group Research, London, United Kingdom     

Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia.

Sixty-four consecutive febrile episodes in 50 consecutive patients with malignancy and neutropenia were empirically treated with a combination of ceftazidime and amikacin. Of 52 analysable episodes, the response rate was 59.6% overall and 26.3% of episodes with microbiologically documented infections with septicaemia. Infection-related death occurred in 10 patients (19.2% of episodes). The response rates were similar in patients with acute leukaemia or other malignancies. Poor response is attributed to increased frequency of infections with Gram-positive and fungal organisms. A modified empiric regimen including cover for Gram-positive and fungal organisms is suggested in similar patient populations.     

Clinical significance of Staphylococcus aureus infection in patients with chronic liver diseases

Background: Staphylococcus aureus increasingly is recognized as an important pathogen in patients with chronic liver diseases. The purpose of this study was to evaluate clinical features and the outcome of S. aureus infections in patients with chronic liver diseases. Methods: From the database of a surveillance study for S. aureus infections, the data regarding S. aureus infections in patients with chronic liver diseases were analysed and compared with those in patients with other diseases. Results: We identified 298 patients who had chronic liver diseases; 151 (50.7%) patients had cirrhosis, 76 (25.5%) had chronic hepatitis and the remaining 71 (23.8%) had other diseases. The most common type of S. aureus infection in patients with chronic liver diseases was primary bacteraemia (n=68, 22.8%) and 92 (30.9%) patients had concomitant bacteraemia. When compared with other disease group, bacteraemia and bone infection were more frequent in the liver disease group (P<0.05). The 30‐day mortality rate of the liver disease group was significantly higher than that of the other disease group (29.4 vs. 16.7%, P<0.001). A multivariate analysis showed that chronic liver disease was a significant factor associated with mortality, along with old age, immunosuppressive treatment, intubated state, indwelling urinary catheter, pneumonia and concomitant bacteraemia. Conclusions: Bacteraemia was the most common type of S. aureus infection in patients with underlying liver diseases, predicting higher mortality rates. The mortality rate of patients with liver diseases was significantly higher than that of patients with other diseases when S. aureus infection developed.     

A clinical trial on efficacy and safety of teicoplanin in combination with beta-lactams and aminoglycosides in the treatment of severe sepsis of patients undergoing allogeneic/autologous bone marrow transplantation

S ummary Early institution of empiric therapy with a broad-spectrum antibiotic has markedly reduced the morbidity and mortality from infections complicating severe or prolonged cytopenia in patients receiving either an allogeneic or autologous hone marrow transplant. Ceftazidime in combination with an aminoglycoside, i.e. netilmicin, has been established as a combination schedule offering low or even avoiding therapy-related toxicity.
We evaluated teicoplanin for suspected Gram-positive infections after inadequate response to initial beta-lactam and aminoglycoside combination therapy. All 11 patients so far included in this study received either an allogeneic (five patients) or an autologous (six patients) bone marrow transplant for acute myeloid leukaemia (AML). non-Hodgkin lymphoma (NHL. high grade) or other malignant diseases. All patients developing a primary septicaemia of unknown origin (10 patients) or a catheter related septicaemia (one patient) were treated with 400 mg teicoplanin, administered i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g. i.v., t.i.d., netilmicin 400 mg once daily). All 11 patients responded to therapy. 10 patients were clinically cured, one patient improved under therapy. The therapeutic regimen was well tolerated and adverse drug reactions did not occur. We have not observed any delayed take or prolonged neutropenia or thrombocytopenia with this therapeutic regimen when compared to other bone marrow transplant patients who did not receive this antimicrobial therapy.
Our preliminary results suggest that teicoplanin is a potentially effective and well-tolerated antimicrobial agent in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides.     

Moxalactam and piperacillin: A study of in vitro characteristics and pharmacokinetics in cancer patients

Summary We evaluated the microbiologic characteristics including MIC determinations, synergy plate assays and serum bactericidal activity for two regimens being examined as empiric antibiotic therapy for febrile granulocytopenic cancer patients. The regimens consisted of moxalactam (4 g i.v. q12h) plus piperacillin (75 mg/kg i.v. q6h) or moxalactam (as above) plus amikacin (levels adjusted to one hour post-infusion levels of 25 mg/l and troughs of 6–8 mg/l). Detailed pharmacokinetics were ascertained for the beta lactams. All drugs were active against a panel of 11 strains each ofEscherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, andStaphylococcus aureus. The pharmacokinetic profile showed serum levels sufficient to provide good antimicrobial activity throughout the dosing interval. Both regimens displayed synergistic or partially synergistic activity in the main for the test organisms; moxalactam plus piperacillin produced good results againstS. aureus andP. aeruginosa. In the serum bactericidal assays, the moxalactam-piperacillin combination produced significantly higher mean titers at both peak and trough when compared to the moxalactam-amikacin regimen. This may be because moxalactam acts as a beta lactamase inhibitor for both staphylococcal beta lactamase, as well as the Sabath-Abraham Id type beta lactamase carried byP. aeruginosa (among others). Moxalactam-piperacillin deserves extensive evaluation as empiric therapy for the febrile neutropenic cancer patients.

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Moxalactam und Piperacillin: In vitro-Charakteristika und Pharmakokinetik bei Karzinompatienten

Zusammenfassung Wir untersuchten die mikrobiologischen Charakteristika mit MHK-Bestimmungen, Synergismus-Plattentests und Serumbakterizidie von zwei Therapieregimen, die für die empirische Antibiotikatherapie bei granulozytopenischen Krebspatienten mit Fieber geprüft wurden. Die Therapieschemata bestanden aus Moxalactam (4 g i.v. alle 12 Stunden) plus Piperacillin (75 mg/kg i.v. alle 6 Stunden) oder Moxalactam (wie oben) plus Amikacin (Anpassung der Serumspiegel auf 25 mg/l eine Stunde nach der Infusion und Talspiegel 6–8 mg/l). Für die -Lactam-Antibiotika wurden detaillierte pharmakokinetische Bestimmungen durchgeführt. Alle Medikamente waren gegen eine Gruppe von jeweils 11 Stämmen vonEscherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa undStaphylococcus aureus wirksam. Das pharmakokinetische Profil zeigte Serumspiegel, die für eine gute antimikrobielle Aktivität während des gesamten Dosierungsintervalls ausreichten. Beide Therapieschemata wiesen synergistische oder teilweise synergistische Aktivität für die wesentlichen Testorganismen auf. Moxalactam plus Piperacillin zeigte auch gute Ergebnisse in der Aktivität gegenS. aureus undP. aeruginosa. Im Serum-Bakterizidie-Test zeigte die Kombination Moxalactam-Piperacillin im Mittel signifikant höhere Titer zum Zeitpunkt der Spitzen- und Talspiegel als die Kombination Moxalactam-Amikacin. Möglicherweise ist dies darauf zurückzuführen, daß Moxalactam sowohl die Staphylokokken--Lactamase hemmt als auch die -Lactamase vom Sabath-Abraham-Typ Id, die (unter anderen)P. aeruginosa trägt. Umfangreiche Studien zur Kombination Moxalactam-Piperacillin für die empirische Therapie bei neutropenischen Karzinompatienten mit Fieber sind gerechtfertigt.