ABSTRACT
BACKGROUND: The chemotherapeutic agent 5-fluorouracil (5-FU) is catabolized by dihydropyrimidine dehydrogenase (DPD), the deficiency of which may lead to severe toxicity or death. Since 2019, DPD deficiency testing, based on uracilemia, is mandatory in France and recommended in Europe before initiating fluoropyrimidine-based regimens. However, it has been recently shown that renal impairment may impact uracil concentration and thus DPD phenotyping. PATIENTS AND METHODS: The impact of renal function on uracilemia and DPD phenotype was studied on 3039 samples obtained from three French centers. We also explored the influence of dialysis and measured glomerular filtration rate (mGFR) on both parameters. Finally, using patients as their own controls, we assessed as to what extent modifications in renal function impacted uracilemia and DPD phenotyping. RESULTS: We observed that uracilemia and DPD-deficient phenotypes increased concomitantly to the severity of renal impairment based on the estimated GFR, independently and more critically than hepatic function. This observation was confirmed with the mGFR. The risk of being classified 'DPD deficient' based on uracilemia was statistically higher in patients with renal impairment or dialyzed if uracilemia was measured before dialysis but not after. Indeed, the rate of DPD deficiency decreased from 86.4% before dialysis to 13.7% after. Moreover, for patients with transient renal impairment, the rate of DPD deficiency dropped dramatically from 83.3% to 16.7% when patients restored their renal function, especially in patients with an uracilemia close to 16 ng/ml. CONCLUSIONS: DPD deficiency testing using uracilemia could be misleading in patients with renal impairment. When possible, uracilemia should be reassessed in case of transient renal impairment. For patients under dialysis, testing of DPD deficiency should be carried out on samples taken after dialysis. Hence, 5-FU therapeutic drug monitoring would be particularly helpful to guide dose adjustments in patients with elevated uracil and renal impairment.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Dihydropyrimidine Dehydrogenase Deficiency/complications , Dihydropyrimidine Dehydrogenase Deficiency/chemically induced , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Antimetabolites, Antineoplastic/adverse effects , Fluorouracil/therapeutic use , Uracil/therapeutic useABSTRACT
OBJECTIVES: This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter. PATIENTS AND METHODS: This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included. RESULTS: Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy. CONCLUSIONS: This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L.
Subject(s)
Antifungal Agents , Fluconazole , Adult , Humans , Adolescent , Fluconazole/therapeutic use , Fluconazole/pharmacokinetics , Antifungal Agents/therapeutic use , Cohort Studies , Critical IllnessABSTRACT
The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m±SD=-0.015±0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m±SD=-0.036±0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS.
Subject(s)
Drug Monitoring/methods , Immunosuppressive Agents/pharmacokinetics , Mycophenolic Acid/analogs & derivatives , Adolescent , Bayes Theorem , Child , Humans , Immunosuppressive Agents/therapeutic use , Models, Biological , Mycophenolic Acid/pharmacokinetics , Mycophenolic Acid/therapeutic use , Nephrotic Syndrome/congenital , Nephrotic Syndrome/drug therapyABSTRACT
Gram-negative vaccines can elicit the production of tumor necrosis factor (TNF) in mice primed by muramyl dipeptide (MDP) or by its lipophilic derivative MDP-dipalmitoyl glycerol (MDP-GDP). In mice pretreated with MDP and particularly with MDP-GDP, Bordetella pertussis vaccine was shown to be more effective than typhoid vaccine. The time course of TNF production in the blood did not indicate any difference between the effect of MDP or of MDP-GDP. In both cases the cytotoxic activity reached maximal levels by 2 h after injection of the bacterial preparations and returned to normal values between 3 and 5 h after the challenge. In nude mice, high titers of circulating TNF were also produced by combined treatment with MDP-GDP and bacterial vaccine. Moreover, in tumor-bearing mice the association of MDP or of MDP-GDP to a bacterial vaccine induced a strong hemorrhagic necrosis, whereas each treatment alone was inactive. It was also found that mice were less sick when they were primed with MDP-GDP than with MDP, and when TNF was elicited by B. pertussis instead of lipopolysaccharide. Moreover, nude mice appeared more resistant to shock and to hemoconcentration than normal mice.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Bacterial Vaccines/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Animals , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Pertussis Vaccine/pharmacology , Time Factors , Triglycerides/pharmacology , Typhoid-Paratyphoid Vaccines/pharmacologyABSTRACT
Lipopolysaccharide-induced necrosis of grafted tumors was potentiated by several hydrophilic and lipophilic muramyl dipeptide (MDP) derivatives administered a few hours prior to small amounts of lipopolysaccharide (LPS) in spite of low titers of induced circulating tumor necrosis factor (TNF). However, pretreatment with MDP derivatives did increase the level of TNF in the blood of mice challenged by a greater dose of LPS. The TNF amount in 2 h postendotoxin mouse serum reached a peak when the glycopeptide had been given 6 h before the challenge, being approximately 100-fold above that obtained in unprimed mice. The cytotoxic activity in mouse serum was inhibited by rabbit antibodies raised against recombinant mouse TNF. Although there exists a toxic synergism between BCG or MDP and endotoxin, the effect of certain MDP derivatives was not related to an increased susceptibility to the toxicity of LPS.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Lipopolysaccharides/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Acetylmuramyl-Alanyl-Isoglutamine/toxicity , Animals , Drug Synergism , Female , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Tumor Necrosis Factor-alpha/toxicityABSTRACT
Innate and acquired resistance to Klebsiella pneumoniae infection were investigated in high (HI) and low (LI) antibody responder lines of mice. The two lines were very susceptible to infection since even small inoculum doses of a virulent strain provoked a 100% mortality within a few days. However the mean survival time was significantly longer in LI than in HI. (HI X LI) F1 hybrids were more resistant than both parental lines. Immunization with heat killed K. pneumoniae was able to confer full protection on the mice in the two lines. However there was a large difference in the number of killed bacteria required to induce the protective effect in HI and in LI mice. The dose-effect relationship for protection correlated with that of antibody production. The protective role of antibodies was confirmed by the survival of HI and LI mice, when antibodies were passively given prior to lethal challenge. The results are in agreement with the fact already demonstrated, that the defect of LI mice in antibody responsiveness is a quantitative one. Therefore a satisfactory immune protection against K. pneumoniae could be obtained in LI mice by adapting the vaccination procedure.
Subject(s)
Antibodies, Bacterial/genetics , Bacterial Vaccines/immunology , Klebsiella Infections/immunology , Animals , Dose-Response Relationship, Immunologic , Female , Immunity, Innate , Immunization, Passive , Klebsiella Infections/prevention & control , Klebsiella pneumoniae , Male , MiceABSTRACT
A selective inhibition of LPS-induced tumor necrosis factor-alpha (TNF) response in mice was caused by an injection of recombinant human interleukin-1 (IL-1). The decrease in serum TNF level reached 70 to 80 percent of the controls receiving LPS alone when IL-1 was given simultaneously or prior to the challenge. At the same time serum IL-6 release was more elevated. Ex vivo assays have shown that macrophages from IL-1 treated animals did not respond to LPS when stimulated immediately after harvesting but recovered their normal responsiveness after being cultured for 2 hours and then washed. In vitro with or without addition of IL-1, mouse elicited macrophages responded equally to LPS in releasing TNF. In the absence of a direct and lasting effect on TNF-producing cells, the host reaction responsible for the inhibitory effect of IL-1 could be related to the overproduction of corticosterone that occurred after IL-1 injection, since it was not observed in adrenalectomized animals. Indeed the blockade of corticoid secretion by indomethacin prevented the inhibition of TNF production induced by IL-1 administration before LPS challenge. TNF administration did not result in elevation of corticosterone level and in contrast to IL-1 enhanced the TNF response to LPS injection. In vitro and ex vivo assays have shown this enhanced response to LPS was linked to a direct and prolonged effect of TNF on TNF-producing cells. Muramyl dipeptide (MDP) which was used as a known priming agent for enhanced cytokine release had a similar effect on TNF-producing cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Down-Regulation/drug effects , Interleukin-1/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Adrenal Glands/metabolism , Adrenalectomy , Animals , Corticosterone/blood , Dexamethasone/pharmacology , Female , Germ-Free Life , Indomethacin/pharmacology , Interleukin-6/biosynthesis , Lipopolysaccharides/immunology , Macrophages/drug effects , Macrophages/metabolism , Mice , Recombinant Proteins/pharmacology , Time Factors , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
AIMS: To evaluate the rapid identification of Candida glabrata using a one minute trehalase and maltase test in four clinical laboratories. METHOD: The test was evaluated with 944 freshly isolated yeasts comprising 572 C glabrata and 372 non-C glabrata strains. These strains were isolated on one of three differential media-Candida ID, CHROMagar Candida, or Albicans ID2 medium-and all strains were fully identified using standard methods. RESULTS: The trehalase and maltase test allowed the overall identification of 550 of 572 C glabrata strains (sensitivity, 96.2%) and only 11 of 372 isolates of other yeast species yielded a false positive result (specificity, 96.8 %). Sensitivity and specificity were consistent from one laboratory to another. Using Candida ID medium, the rapid trehalase and maltase test showed a sensitivity of 95% and specificity of 96.2%. Using CHROMagar Candida, sensitivity and specificity were 95.6% and 98.1%, respectively. Using Albicans ID2 medium (tested by two laboratories), the sensitivity was 100% and 98.5% and specificity was 98.1% and 98.2%. In 60% of cases, the test could be performed directly from the primary isolation medium, thus reducing the time for identification. CONCLUSION: The rapid trehalase and maltase test was highly reliable for the presumptive identification of C glabrata on primary isolation using three different chromogenic media. Direct recognition of C albicans by means of their characteristic colour on chromogenic media coupled with one minute trehalase maltase testing performed only on suspect colonies of C glabrata allowed for rapid presumptive identification of the two yeast species most commonly encountered in clinical samples.
Subject(s)
Candida glabrata/isolation & purification , Trehalase/metabolism , alpha-Glucosidases/metabolism , Candida glabrata/metabolism , Mycology/methods , Reagent Kits, Diagnostic , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
As valpromide is a prodrug of valproic acid (valproate), the clinical presentation of overdoses with either valpromide or valproate sodium is generally considered similar. Whereas plasma peak levels and signs of central nervous system depression occur within a few hours after the acute ingestion of regular-release forms of valproate sodium, delayed toxicity and time to peak levels following valpromide ingestion can be seen as shown by the three reported cases. They were initially considered as mild because patients presented with no or only moderate symptoms and serum valproate levels were below or at therapeutic levels on admission more than 3 hours post-ingestion in two of the three patients. Serum valproate levels were not monitored until marked deterioration more than 10 hours after ingestion. At the time of deterioration, serum valproate was at toxic level in the three reported cases. Therefore, large intake of valpromide should be closely monitored because no or moderate symptoms together with low plasma levels in the first few hours after ingestion do not exclude a subsequent severe intoxication. Despite the usual favourable outcome and the poor correlation between plasma levels and toxic symptoms, patients should not be discharged until plasma levels are documented to remain at low levels for at least 10 hours after the ingestion of valpromide and the patient asymptomatic.
Subject(s)
Anticonvulsants/poisoning , Prodrugs/poisoning , Valproic Acid/analogs & derivatives , Valproic Acid/poisoning , Adult , Anticonvulsants/blood , Coma/chemically induced , Dyspnea/chemically induced , Female , Hepatic Encephalopathy/chemically induced , Humans , Male , Time Factors , Valproic Acid/bloodABSTRACT
Following administration of anti-digoxin Fab fragments, monitoring unbound digoxin concentrations may help ensure appropriate dosing, and prevent recrudescent toxicity. Ultrafiltration by using Centrifree system and measurement of digoxin in the ultrafiltrate is considered as reference technique. However, ultrafiltration method is cumbersome, costly, and some immunoassays are affected by matrix differences. Another approach is to analyse the serum directly by digoxin immunoassays without ultrafiltering it. The validity of results obtained depends on the architecture of the immunoassay and the amount of Fab in the sample. The old radioimmunoassays and usually the other competitive immunoassays give inaccurate results. The fluorescence polarization immunoassay (FPIA) slightly underestimates the total digoxin concentrations. Total digoxin levels obtained at 24 hours and 48 hours after treatment permit measurement of the half-life of digoxin Fab complexes and can be used to estimate when the patient can be redigitalized, if necessary. The sequential immunoassays usually overestimate the free digoxin concentrations. The differences observed are >25% and cannot be explained solely by albumin binding (normal range, 20% +/- 5%). To date, ultrafiltration remains the best strategy for accurate determination of digoxin concentrations in the presence of antidigoxin Fab fragments.
Subject(s)
Digoxin/blood , Digoxin/immunology , Drug Monitoring/methods , Immunoglobulin Fab Fragments/therapeutic use , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , UltrafiltrationSubject(s)
Carcinoma, Ehrlich Tumor/prevention & control , Cell Wall/immunology , Immunization , Leukemia, Lymphoid/prevention & control , Mycobacterium/immunology , Animals , BCG Vaccine , Endotoxins/adverse effects , Female , Hepatomegaly/prevention & control , Histamine/adverse effects , Hypersensitivity/etiology , Immunization/adverse effects , Leukemia, Experimental/prevention & control , Mice , Mice, Inbred Strains , Splenomegaly/prevention & controlSubject(s)
Acetylmuramyl-Alanyl-Isoglutamine/chemical synthesis , Adjuvants, Immunologic/chemical synthesis , Glycopeptides/chemical synthesis , Pyrogens/chemical synthesis , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Adjuvants, Immunologic/pharmacology , Animals , Female , Mice , Rabbits , Structure-Activity RelationshipSubject(s)
Antigens/metabolism , Endotoxins/toxicity , Polysaccharides, Bacterial/metabolism , Polysaccharides, Bacterial/toxicity , Salmonella/immunology , Salmonella/metabolism , Acetates/metabolism , Adrenalectomy , Alkalies/metabolism , Animals , Chromatography, Gel , Chromium Isotopes/analysis , Immunodiffusion , MiceSubject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Bacterial Infections/prevention & control , Animals , Bacterial Infections/immunology , Cytokines/immunology , Immunocompromised Host , Immunologic Factors/pharmacology , Mice , Trehalose/analogs & derivatives , Trehalose/pharmacology , Triglycerides/pharmacologyABSTRACT
UNLABELLED: After consumption of mushrooms containing amatoxins (Amanita, Lepiota, and Galerina species), symptoms usually develop after a long delay (>6 h). Initial symptoms start as severe gastroenteritis, progressing to liver failure and possibly death as a result of hepatic coma. Since the survival rate of poisoned patients is claimed to depend on the time of beginning of efficient treatment, fast and reliable assays for amatoxins in biological fluids are essential. Described analytical methods for amatoxins include high performance liquid chromatography and radioimmunoassay (RIA). Recently, a new enzyme-linked immunosorbent assay (Bühlmann Amanitin ELISA kit) has been introduced as an alternative method to RIA. This ELISA-based assay offers several advantages: no complex extraction procedure is required (vs. HPLC) and no safety precautions concerning radioactivity have to be taken (vs. RIA). From August 2004 to October 2005, a pilot study was performed to test the practicability and the clinical utility of this method in emergency situations. RESULTS: ten urines, 9 serums and 1 faeces from 10 patients suffering from acute gastroenteritis after mushroom ingestions (7 contaminated meals) were analyzed. Definitive diagnosis of amatoxin poisoning was made in 4 cases (3 contaminated meals) on the basis of the anamnesis, laboratory results, and clinical course. A patient developed a severe amatoxin poisoning with urinary amanitins level < 1.5 microg/L (urines were collected more than 72 h after mushroom ingestion). Two patients were paucisymptomatic with urinary amanitins levels >10 microg/L (urines were collected before the 36th hour). CONCLUSION: Urine is the sample of choice for the determination of amatoxins. The most critical factor to invalidate the usefulness of this analysis is time. After 36 h, the sensitivity is unreliable.
Subject(s)
Amanitins/urine , Enzyme-Linked Immunosorbent Assay , Mushroom Poisoning/urine , Phalloidine/poisoning , Female , Humans , Male , SyndromeABSTRACT
Two synthetic glycopeptides (MurNAc-L-Ala-D-isoGln and MurNAc-L-Ala-D-Glu), having adjuvant activity, were shown to enhance non-specific resistance to infection against K. pneumoniae. These compounds were active by various routes including oral administration and even if administered after the challenge. Two steroisomers lacking adjuvant activity did not protect the infected Mice.
Subject(s)
Adjuvants, Immunologic , Glycopeptides/therapeutic use , Klebsiella Infections/prevention & control , Administration, Oral , Animals , Glycopeptides/administration & dosage , Klebsiella pneumoniae , Mice , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In a previous study, we demonstrated that lipopolysaccharide (LPS) and other bacterial immunostimulants, in contrast to their activity in a closely related high-responder subline, failed to elicit nonspecific resistance in LPS low-responder mice against Klebsiella pneumoniae infection. To investigate the type of inheritance controlling the LPS-induced nonspecific resistance to infection, the present study was performed in low- and high-responder C3H sublines and in F1 and F2 hybrids. In addition, F1 mice were backcrossed to each parental type. Inheritance of susceptibility to endotoxin was also tested in both sublines and their hybrids and backcross progeny. For these latter assays, mice were previously adrenalectomized because removal of this gland considerably enhances their sensitivity. Our present findings are consistent with the hypothesis that LPS enhances nonspecific resistance to infection and that susceptibility to endotoxin shock in the absence of corticoids may be determined by a single autosomal dominant gene.
Subject(s)
Klebsiella Infections/genetics , Lipopolysaccharides , Shock, Septic/complications , Adrenalectomy , Animals , Blood Bactericidal Activity , Corynebacterium/immunology , Hybridization, Genetic , Klebsiella Infections/complications , Klebsiella Infections/prevention & control , Lethal Dose 50 , Mice , Mice, Inbred C3H , Mice, Inbred C57BLABSTRACT
N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide) and certain derivatives that are structural analogs of part of the bacterial peptidoglycan monomer have been shown to be adjuvant active and to enhance the nonspecific immunity of adult mice infected by Klebsiella pneumoniae. In the present study muramyl dipeptide and two other synthetic analogs were found to be active in newborn mice. This activity could be demonstrated after administration by subcutaneous or even by oral route. In contrast to what was observed after treatment by lipopolysaccharide, 8-day-old mice were definitively protected against bacterial challenge by these glycopeptides. Therefore such molecules could have a great value in view of studying and correcting the neonate's unresponsiveness.
Subject(s)
Adjuvants, Immunologic , Animals, Newborn/immunology , Glycopeptides/immunology , Immunity, Innate , Klebsiella Infections/immunology , Adjuvants, Immunologic/therapeutic use , Adrenalectomy , Animals , Glycopeptides/administration & dosage , Klebsiella Infections/prevention & control , Klebsiella pneumoniae/immunology , Lipopolysaccharides/immunology , Mice , Muramic Acids/immunology , PhagocytosisABSTRACT
N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP), is a synthetic immunoadjuvant analogue of a bacterial peptidoglycan subunit that has a definite pyrogenic effect in the rabbit. Some adjuvant-active derivatives such as murabutide [MDP(Gln)-OnBu] or murametide [MDP(Gln)-OMe] are not pyrogenic. Murabutide did not stimulate human or rabbit cells to release endogenous pyrogen (EP), but murametide induced EP production at the same dosage levels as MDP. Moreover, plasma from rabbits treated with murametide transferred into untreated recipients elicited a febrile response typical of EP fever and comparable with that induced by plasma from MDP-treated animals. Murametide not only inhibited the central effect of EP that is generated but also the effect of an extra dose of EP administered later by the intravenous route. Moreover, pretreatment of rabbits with murametide decreased fever responses induced by certain high-molecular-weight exogenous pyrogens as mediated through the production of EP.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Adjuvants, Immunologic/pharmacology , Fever/chemically induced , Interleukin-1 , Pyrogens/pharmacology , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Animals , Fever/drug therapy , Humans , Male , Proteins/metabolism , RabbitsABSTRACT
Lipopolysaccharides (LPS) of gram-negative bacilli are known to protect mice against unrelated bacterial infections and to be nonspecific mitogens of murine bone marrow-derived (B-) lymphocytes. For assessment of the role of these cells in the mechanism of LPS-induced resistance to infection with Klebsielia, various nontoxic mitogens were assayed. In contrast to LPS or lipid A, the nontoxic mitogens did not protect mice. Experiments were also performed with LPS in nude mice and in mice treated with immunosuppressants. Stimulation by LPS was decreased after administration of hydrocortisone or cyclophosphamide under conditions that inhibited the in vitro activation of lymphocytes by mitogens. Moreover, nude mice and mice treated with 6-mercaptopurine were more resistant to Klebsiella than were control mice.