A prospective, randomized comparison of ceftazidime and ciprofloxacin as initial empiric therapy in neutropenic patients with fever.

This study developed further clinical experience in using a single agent ("monotherapy") as empirical treatment for neutropenic patients with fever, and compared the safety and toxicity of two candidate agents, ceftazidime and ciprofloxacin. A prospective, randomized, single-center efficacy and safety comparison was conducted of intravenous ciprofloxacin, 200 mg every 12 hours, and ceftazidime, 2 g every eight hours, as initial empirical therapy in neutropenic patients with fever. Regimens were modified as necessary, guided by laboratory results and/or the clinical condition. Response was evaluated at 72 hours and at the end of the neutropenia. Toxicity was evaluated by regular clinical examination and laboratory investigations. A total of 43 patients with 51 febrile neutropenic episodes were enrolled into the study and randomly assigned to one of the two regimens. Five episodes were excluded from evaluation of efficacy because of protocol violations, leaving 46 evaluable episodes (21 ciprofloxacin, 25 ceftazidime). The two groups were well matched for risk factors for infection. There were no differences between the two groups in response rates either at 72 hours or at the end of neutropenia, although in the vast majority of patients some modification of the initial therapy was required. No patients died of uncontrolled bacterial infection. Superinfection with gram-positive cocci (often streptococci) was seen primarily in bone marrow transplant recipients who had been randomly assigned to receive ciprofloxacin. This study demonstrated that, in certain circumstances, a single antibiotic can be used successfully as initial empirical therapy in febrile neutropenic patients. In this study, ceftazidime and ciprofloxacin were generally of equal efficacy, but there appeared to be an increased incidence of streptococcal superinfection in bone marrow transplant recipients who received ciprofloxacin.

Lymphokines and the acute-phase response in clinical bone marrow transplantation.

This paper reviews the role of the acute phase response and of cytokines in clinical bone marrow transplantation. Data are discussed from the literature and from the authors experience which show that measurement of C-reactive protein is a rather non-specific marker of tissue injury, but that it is elevated in graft-versus-host disease, and especially in infection. Cytokines are clearly implicated in several aspects of transplantation, and tumour necrosis factor in particular may be important. Although there are some data which associate high TNF levels with severe graft-versus-host disease, this association may not hold true in individual patients.

In-vitro stimulation of TNF-alpha from human whole blood by cell-free supernatants of gram-positive bacteria.

Gram-positive bacteria are being recognized increasingly as the cause of shock-like syndromes, clinically indistinguishable from those seen in association with Gram-negative endotoxic shock. Much clinical and experimental data link tumour necrosis factor-alpha (TNF-alpha) with the pathogenesis of endotoxic shock, and a number of studies of individual Gram-positive species have also implicated TNF-alpha. We report here the first systematic study of the ability of cell-free supernatants of common Gram-positive bacteria to induce TNF-alpha from human peripheral blood monocytes in vitro. Almost all the 63 strains were able to induce TNF-alpha, although the levels were substantially lower than those obtained from supernatants of Gram-negative bacteria, used as controls. Streptococcus pneumoniae, S. pyogenes, viridans streptococci and coagulase-negative staphylococci were consistently more active than group B and D streptococci. TNF-alpha induction did not correlate with conventional markers of pathogenicity; amongst strains of Staphylococcus aureus, commensal and blood culture isolates did not induce significantly different amounts of TNF. We conclude that cell-free supernatants of most Gram-positive bacteria are capable of inducing TNF-alpha from human peripheral blood monocytes in vitro, but the significance of this finding remains to be determined.

Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative shock.

A monoclonal antibody to recombinant murine tumor necrosis factor-alpha (TNF alpha), TN3-19.12, was used to explore pathogenetic mechanisms and therapeutic strategies in gram-negative shock. In mice receiving an LD90 dose of Escherichia coli O111, TN3-19.12 prevented death if given 1.5 h before or 30 min after challenge. Less protection was conferred if the antibody was given 2.5 h after challenge. In control mice receiving an irrelevant antibody, L2-3D9, TNF alpha levels rose (less than or equal to 185.1 +/- 26.1 ng/ml) by 90 min and had returned to baseline by 5 h. Mice receiving TN3-19.12 did not have this response. TN3-19.12 was of limited benefit in mice receiving Pseudomonas aeruginosa but had no protective effect in cyclophosphamide-treated mice receiving Klebsiella pneumoniae. In L2-3D9-treated mice, TNF alpha levels were elevated to 61.8 +/- 27.9 and 49.7 +/- 5.1 ng/ml by 90 min in the two models, respectively. TNF alpha levels in TN3-19.12-treated mice in these two models were very low (3.9-5.5 ng/ml). TNF alpha is a mediator in gram-negative shock; antibody to TNF alpha can be of value in prophylaxis and treatment, but its clinical use remains to be established.

Sequential measurement of the murine acute-phase protein serum amyloid P component (SAP) as an indicator of graft-versus-host disease following allogeneic bone marrow transplantation in mice.

Murine models of bone marrow transplantation (BMT) are used commonly for studies of the pathogenesis and treatment of graft-versus-host disease (GVHD). We report here that the sequential measurement of the mouse acute-phase protein SAP can be used to provide a sensitive, quantitative index of the severity of GVHD. Thirty mice underwent allogeneic, and a further 30 syngeneic BMT. GVHD was assessed in vivo by clinical appearances and weight change, and post mortem by histology and calculation of splenic indices. Blood was obtained twice/week for SAP measurement and blood culture. In all mice an initial rise in SAP levels due to irradiation was followed by a return to baseline. Thereafter in syngeneic marrow recipients levels remained low. In contrast, after allogeneic BMT SAP levels rose progressively as mice developed GVHD, reaching a peak of 135 micrograms/ml prior to death, from a nadir at day 20 of 15 micrograms/ml. Mice with high splenic indices and histological evidence of severe GVHD had significantly higher SAP levels than mice with mild GVHD (P = 0.0002). Elevation in SAP levels occurred independently of bacteraemia. We conclude that in murine BMT sequential measurement of SAP provides an objective means of assessing GVHD in vivo.

Successful treatment of acute promyelocytic leukaemia during pregnancy.

A case is reported of a pregnant 16-year-old-woman diagnosed with Acute promyelocytic leukaemia (APL) at 25 weeks gestation and treated with all-trans retinoic acid (ATRA) (45 mg/m2) for 25 days in combination with chemotherapy. She achieved a complete cytogenetic and molecular remission. Clinical course was complicated, with an intracerebral bleed, respiratory failure requiring ventilation and prolonged pancytopenia following initial chemotherapy. A live female infant was born at 28 weeks gestation who survived to discharge with significant pulmonary complications. She remains oxygen dependent at 6 months of age. ATRA has been used from the 3rd week of gestation, but fetal malformations are common during the first trimester. In contrast it seems to be safe in the second and third trimesters with regard to teratogenesis but can cause other side-effects. Most successful outcomes in treatment of APL during pregnancy are seen after treatment with ATRA and delivery of the baby at as late a stage as possible. Pregnancies terminated before remission has been obtained or those treated in the first trimester have a poor maternal outcome.

Monoclonal antibody to endotoxin core protects mice from Escherichia coli sepsis by a mechanism independent of tumor necrosis factor and interleukin-6.

To study the role of cytokines as mediators of endotoxin-induced shock, the serum levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were compared in mice receiving either a monoclonal antibody to endotoxin core (clone 20), an irrelevant monoclonal antibody (A1), or culture media (DMEM/FCS) alone before lethal challenge with live Escherichia coli O111:B4. Clone 20 given 1.5 h before the bacterial challenge protected mice from death (mortality at 48 h 3% vs. 87%, P less than .001). The pattern of IL-6 release was indistinguishable in clone 20 recipients and controls: The area under the curve (AUC) for 5 h was 1.22 +/- 0.07 x 10(6), 1.03 +/- 0.17 x 10(6), and 1.22 +/- 0.07 x 10(6) units/ml for clone 20, A1, and DMEM/FCS, respectively. Similarly, the timing and extent of TNF release in the serum was virtually identical in clone 20 recipients that survived and control animals that died. AUC for 5 h was 30.8 +/- 4.0 x 10(3), 28.1 +/- 1.1 x 10(3), and 30.4 +/- 4.7 x 10(3) ng/ml in clone 20, A1, and DMEM/FCS recipients, respectively. Thus, TNF and IL-6 appear insufficient to cause death in this model of experimental gram-negative shock.

Successful high dose therapy for relapsed mediastinal large B cell lymphoma following surgical repair of anterior chest wall defect.

We describe a man with relapsed large B cell mediastinal lymphoma and associated infected large anterior chest wall defect who required high dose salvage therapy for his underlying disease. An initial mediastinotomy wound, associated with recurrent sepsis, had developed into an abscess, then fistula and eventually a large anterior chest wall defect. Safe use of salvage chemotherapy required reconstructive surgery consisting of a pedicled muscle flap. The subsequent high dose chemotherapy was carried out without complications and 15 months later the patient is alive and well.

A comparative study of imipenem versus piperacillin plus gentamicin in the initial management of febrile neutropenic patients with haematological malignancies.

Three-hundred and twelve episodes of fever in 234 neutropenic patients with haematological malignancies were treated empirically with either imipenem or a combination of piperacillin and gentamicin. There were no significant differences in the percentages of patients responding to therapy at either 72 h (59% and 56% of assessable episodes in the imipenem and combination groups respectively) or at the end of treatment (55% and 53% of assessable episodes in the imipenem and combination groups respectively). Patients in the piperacillin plus gentamicin group experienced significantly more renal tubular damage whereas those who received imipenem suffered more nausea or vomiting. We conclude that imipenem monotherapy represents an acceptable alternative to piperacillin plus gentamicin as empirical therapy of the febrile neutropenic patient.