Meropenem versus imipenem-cilastatin for the treatment of hospitalized patients with complicated skin and skin structure infections: results of a multicenter, randomized, double-blind comparative study.

BACKGROUND: Meropenem, a broad-spectrum carbapenem with potent in vitro activity, is postulated to be an effective monotherapy for the treatment of complicated skin and skin structure infections (cSSSI). METHODS: This multicenter, international, double-blind, randomized, prospective study of hospitalized patients with cSSSI evaluated the efficacy, safety, and tolerability of meropenem (500 mg IV q8h) versus imipenem-cilastatin (500 mg IV q8h). The primary efficacy endpoint was clinical outcome at follow-up in the clinically evaluable (CE) and modified intent-to-treat populations (MITT; patients who met eligibility criteria and received at least one dose of study drug). The study aimed to demonstrate non-inferiority (delta of 10%, 95% confidence intervals) in clinical response in the CE population. Clinical responses for all pathogens at follow-up were assessed in the fully evaluable population (CE population with baseline pathogen and follow-up cultures). RESULTS: In total, 1,076 patients were enrolled. Of these, 692 patients comprised the MITT population (334 and 358 patients randomized to meropenem and imipenem-cilastatin, respectively) and 548 the CE population (261 and 287 patients randomized to meropenem and imipenem-cilastatin, respectively). Cure rates were 86.2% (meropenem) and 82.9% (imipenemcilastatin; 95% CI, -2.8, 9.3) in the CE population and 73.1% (meropenem) and 74.9% (imipenem-cilastatin; 95% CI, -8.4, 4.7) in the MITT population. The frequencies of adverse events and drug-related adverse events were similar between treatment groups. CONCLUSION: In one of the largest studies conducted to date of hospitalized patients with cSSSI, meropenem, 500 mg IV q8h had comparable safety and efficacy to imipenem-cilastatin, 500 mg IV q8h.

Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects.

Rituximab, a chimeric human immunoglobulin G(1) (IgG(1)) anti-CD20 monoclonal antibody has been shown to mediate cytotoxicity in malignant B cells via several mechanisms in vitro. These include direct antiproliferative and apoptotic effects, complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Glucocorticoids (GCs) are often administered in conjunction with rituximab in chemotherapeutic regimens or as premedication to reduce infusion-related symptoms. The effects of GCs on CDC and ADCC, and the direct apoptotic and antiproliferative effects of rituximab are unknown. Therefore, we evaluated these mechanisms in 9 B-cell non-Hodgkin lymphoma (B-NHL) cell lines using rituximab and GCs. Rituximab and dexamethasone induced synergistic growth inhibition in 6 B-NHL cell lines. Dexamethasone and rituximab induced significant G(1) arrest in 9 of 9 cell lines. The combination of rituximab and dexamethasone resulted in supra-additive increases in phosphatidylserine exposure and hypodiploid DNA content in 5 and 3 B-NHL cell lines, respectively. CDC and ADCC were neither impaired nor enhanced when dexamethasone and rituximab were administered concurrently. However, preincubation of both effector and tumor cells with dexamethasone reduced specific lysis in ADCC assays in 4 B-NHL cell lines. Preincubation of tumor cell lines with dexamethasone significantly increased cell sensitivity to CDC in 3 B-NHL cell lines. We conclude that the addition of dexamethasone to rituximab results in supra-additive cytotoxicity with respect to its direct antiproliferative and apoptotic effects, induces a cell-dependent increased sensitivity to rituximab-induced CDC, and has minimal negative impact on ADCC when used simultaneously with rituximab.

Rituximab: mechanism of action and resistance.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known. Currently, most data suggest that the predominant effector mechanism is antibody-dependent cell-mediated cytotoxicity, with a minor role of complement. With treatment, resistance to rituximab-mediated killing may emerge. Little is known regarding the molecular pathogenesis of this resistance. In rare cases, the CD20 antigen may be lost. Complement-resistance proteins may also increase, but it is not clear that this is the reason for loss of sensitivity. A better understanding of these mechanisms should allow combination therapy with agents capable of augmenting antibody-based killing.

Rituximab: Mechanism of action and resistance.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known. Currently, most data suggest that the predominant effector mechanism is antibody-dependent cell-mediated cytotoxicity, with a minor role of complement. With treatment, resistance to rituximab-mediated killing may emerge. Little is known regarding the molecular pathogenesis of this resistance. In rare cases, the CD20 antigen may be lost. Complement-resistance proteins may also increase, but it is not clear that this is the reason for loss of sensitivity. A better understanding of these mechanisms should allow combination therapy with agents capable of augmenting antibody-based killing. Semin Oncol 29 (suppl 2):2-9. Copyright © 2002 by W.B. Saunders Company.

Mechanism of action of rituximab.

Rituximab, the humanized chimeric anti-CD20 monoclonal antibody, represents a powerful tool for treating B-cell malignancies and is licensed for the treatment of relapsed or chemorefractory low-grade or follicular non-Hodgkin's lymphoma (NHL). It has a unique mode of action and can induce killing of CD20+ cells via multiple mechanisms. The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy. In vitro studies have made a significant contribution to the understanding of these mechanisms of action and have led to the development of innovative and effective treatment strategies to optimize patient response. The most significant of these strategies is the combination of rituximab and CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), which is proving a highly effective combination in the treatment of NHL. However, all patients do not respond equally well to rituximab, and in vitro studies have identified a possible mechanism of resistance involving the anti-complement inhibitors CD55 and CD59. Neutralizing antibodies to CD55 and CD59 can overcome resistance to rituximab-mediated complement-mediated cytotoxicity in vitro. This paper overviews our understanding of the mechanisms of action of rituximab and identifies how this knowledge could be applied in a clinical setting to maximize response in both sensitive and resistant patients.