Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections.

OBJECTIVES: Oral combination of clindamycin and rifampicin is relevant for the treatment of staphylococcal osteoarticular infection (SOAIs). However, rifampicin induces CYP3A4, suggesting a pharmacokinetic interaction with clindamycin with unknown pharmacokinetic/pharmacodynamic (PK/PD) consequences. This study aimed to quantify clindamycin PK/PD markers before and during rifampicin co-administration in SOAI. METHODS: Patients with SOAI were included. After initial intravenous antistaphylococcal treatment, oral therapy was started with clindamycin (600 or 750 mg t.i.d.), followed by addition of rifampicin 36 h later. Population PK analysis was performed using the SAEM algorithm. PK/PD markers were compared with and without rifampicin co-administration, each patient being his own control. RESULTS: In 19 patients, clindamycin median (range) trough concentrations were 2.7 (0.3-8.9) mg/L and <0.05 (<0.05-0.3) mg/L before and during rifampicin administration, respectively. Rifampicin co-administration increased clindamycin clearance by a factor 16 and reduced the AUC0-8h/MIC by a factor 15 (P < 0.005). Clindamycin plasma concentrations were simulated for 1000 individuals, without and with rifampicin. Against a susceptible Staphylococcus aureus strain (clindamycin MIC 0.0625 mg/L), >80% of individuals would reach all proposed PK/PD targets without co-administration of rifampicin, even with low clindamycin dose. For the same strain, when rifampicin was co-administered, the probability to reach clindamycin PK/PD targets dropped to 1% for %fT>MIC = 100% and to 6% for AUC0-24h/MIC > 60, even with high clindamycin dose. CONCLUSION: Rifampicin co-administration with clindamycin has a high impact on clindamycin exposure and PK/PD targets in SOAI, which could result in clinical failure even for fully susceptible strains.

Population pharmacokinetics and pharmacodynamics of imipenem in neutropenic adult patients.

OBJECTIVE: Imipenem is recommended in patients with chemotherapy-induced febrile neutropenia. Although alterations of antibiotic pharmacokinetic parameters have been reported in such patients, little data is available on imipenem. METHODS: Prospective, single-center, non-interventional pharmacokinetic cohort study in adults with chemotherapy-induced febrile neutropenia. Critically ill patients were excluded. Imipenem was administered as a 30-min infusion of 1000 mg/8h. Total imipenem plasma concentrations were assayed by high-performance liquid chromatography during neutropenia and just after neutrophil recovery. We estimated population pharmacokinetic parameters of imipenem by non-linear mixed-effect modelling using the SAEM algorithm. RESULTS: Sixteen patients were included in the study, including nine women (56.3%), median age 37 years (range, 18.3; 78.3). Eight patients had an hematological malignancy (50.0%) and seven had a solid tumor (43.8%). Imipenem pharmacokinetics were best described by a one-compartment model with first-order elimination. Mean values for imipenem were: clearance 14.3L/h and 10.9L/h and volume of distribution 20.7L and 14.5 L during neutropenia and after recovery, respectively. Imipenem plasma area under the curve at steady state was reduced by 23% during neutropenia. However, all patients achieved a pharmacodynamic target of %fT>MIC ≥ 40% with a regimen of 1000 mg/8 h or 500 mg/6 h, for MICs up to 2 mg/L. The pharmacodynamics profile for a target of %fT > MIC = 100% was however less favorable with 500 mg/6 h or 1000 mg/8 h either during or after neutropenia. CONCLUSION: Pharmacokinetic/pharmacodynamic goals for imipenem were similar in patients during and after neutropenia, despite reduced plasma exposure.

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav.

BACKGROUND: Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. MATERIALS AND METHODS: Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC-tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. RESULTS: Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). CONCLUSIONS: Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

Need for integrative thinking to fight against emerging infectious diseases. Proceedings of the 5th seminar on emerging infectious diseases, March 22, 2016 - current trends and proposals.

We present here the proceedings of the 5th seminar on emerging infectious diseases, held in Paris on March 22nd, 2016, with seven priority proposals that can be outlined as follows: encourage research on the prediction, screening and early detection of new risks of infection; develop research and surveillance concerning transmission of pathogens between animals and humans, with their reinforcement in particular in intertropical areas ("hot-spots") via public support; pursue aid development and support in these areas of prevention and training for local health personnel, and foster risk awareness in the population; ensure adapted patient care in order to promote adherence to treatment and to epidemic propagation reduction measures; develop greater awareness and better education among politicians and healthcare providers, in order to ensure more adapted response to new types of crises; modify the logic of governance, drawing from all available modes of communication and incorporating new information-sharing tools; develop economic research on the fight against emerging infectious diseases, taking into account specific driving factors in order to create a balance between preventive and curative approaches.

Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review.

BACKGROUND: Anti-staphylococcal penicillins (ASPs) are recommended as first-line agents in methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. Concerns about their safety profile have contributed to the increased use of cefazolin. The comparative clinical effectiveness and safety profile of cefazolin versus ASPs for such infections remain unclear. Furthermore, uncertainty persists concerning the use of cefazolin due to controversies over its efficacy in deep MSSA infections and its possible negative ecological impact. AIMS: The aim of this narrative review was to gather and balance available data on the efficacy and safety of cefazolin versus ASPs in the treatment of MSSA bacteraemia and to discuss the potential negative ecological impact of cefazolin. SOURCES: PubMed and EMBASE electronic databases were searched up to May 2017 to retrieve available studies on the topic. CONTENTS: Although described in vitro and in experimental studies, the clinical relevance of the inoculum effect during cefazolin treatment of deep MSSA infections remains unclear. It appears that there is no significant difference in rate of relapse or mortality between ASPs and cefazolin for the treatment of MSSA bacteraemia but these results should be cautiously interpreted because of the several limitations of the available studies. Compared with cefazolin, there is more frequent discontinuation for adverse effects with ASP use, especially because of cutaneous and renal events. No study has evidenced any change in the gut microbiota after the use of cefazolin. IMPLICATIONS: Based on currently available studies, there are no data that enable a choice to be made of one antibiotic over the other except in patients with allergy or renal impairment. This review points out the need for future prospective studies and randomized controlled trials to better address these questions.

Complications following intravesical bacillus Calmette-Guerin treatment for bladder cancer: a case series of 22 patients.

BACKGROUND: Intravesical bacillus Calmette-Guerin (BCG) therapy is an effective and widely used treatment for superficial bladder carcinoma. Local complications are frequent whereas systemic complications are rare but can be serious, and their management is not well known. METHODS: We describe retrospectively the records of 22 patients treated in 3 infectious disease departments, for complications related to intravesical BCG therapy as treatment of bladder cancer. RESULTS: All the patients were male, with a median age of 68 years (range 56-88). Complications occurred after a median of 5 instillations (range 1-11) and were observed within 24 h following BCG instillation for 14 patients. Common symptoms were fever (n = 20), impaired general condition (n = 14), and shortness of breath (n = 7). Six patients had a systemic septic reaction leading to transfer into the intensive care unit for five of them. Lung infiltration was the most frequent presentation (n = 11). Mycobacterium bovis was isolated from only two patients, but histology showed the presence of a granuloma in nine patients. Antimycobacterial treatment was initialized in 17 patients; the outcome was favorable in 16 patients, with a median length of symptoms resolution of 22.5 days (range 5-425 days). Eleven patients received corticosteroids in addition to specific treatment and had a more rapid improvement. One patient died with disseminated BCGitis proved by biopsy. CONCLUSIONS: Complications following intravesical BCG therapy are rare but can be severe and fatal. Histology seems to be the method that contributes most in confirmation of the diagnosis. Antimycobacterial therapy is effective, and probably more efficient when combined with corticosteroids, but the regimen and duration of the treatment are not standardized.

[An update on measles]. / Actualité de la rougeole.

Measles is a highly contagious infectious disease, which needs more than 95% worldwide vaccination coverage of 2 doses to be eradicated. Despite an important involvement of the WHO for massive immunization, goals have not bean reached, and outbreaks can occur at any time in many countries, including Western Europe. In France, 22,000 cases were identified between 2009 and 2011, mainly in infants and young adults, which are not or not enough vaccinated (one dose). In 2012, even though the number of cases has drastically decreased, the outbreak is still going on, especially in South of France. That is why every clinician needs to be concerned about the clinical manifestations of the disease, and its complications. Besides a febrile rash, measles is often responsible of pneumonia and biologic hepatitis in adults. Hepatitis does not seem frequent in children. Clinicians need to be aware of specific complications, like encephalitis in case of cellular immunodepression, high risk of pneumonia in pregnant women. In patients previously vaccinated, incidence of complications is the same but patients are not contagious. Even if measles diagnosis is clinical, blood confirmation by serology is recommended in France when possible. Outcome is mainly favourable, but measles is not well-tolerated with high levels of hospitalisation even without any complication. Vaccination is the only way to protect against it.

Impact of imipenem and amikacin pharmacokinetic/pharmacodynamic parameters on microbiological outcome of Gram-negative bacilli ventilator-associated pneumonia.

OBJECTIVES: Despite recent advances, antibiotic therapy of ventilator-associated pneumonia (VAP) in ICU patients is still challenging. We assessed the impact of imipenem and amikacin pharmacokinetic and pharmacodynamic parameters on microbiological outcome in these patients. PATIENTS AND METHODS: Patients with Gram-negative bacilli (GNB) VAP were prospectively included. Blood samples for pharmacokinetic analysis were collected after empirical administration of a combination of imipenem three times daily and one single dose of amikacin. MICs were estimated for each GNB obtained from respiratory samples. Microbiological success was defined as a ≥10(3) cfu/mL decrease in bacterial count in quantitative cultures between baseline and the third day of treatment. RESULTS: Thirty-nine patients [median (min-max) age = 60 years (28-84) and median SAPS2 at inclusion = 40 (19-73)] were included. Median MICs of imipenem and amikacin were 0.25 mg/L (0.094-16) and 2 mg/L (1-32), respectively. Median times over MIC and over 5× MIC for imipenem were 100% (8-100) and 74% (3-100), respectively. The median C1/MIC ratio for amikacin was 23 (1-76); 34 patients (87%) achieved a C1/MIC ≥10. Microbiological success occurred in 29 patients (74%). No imipenem pharmacodynamic parameter was significantly associated with the microbiological success. For amikacin, C1/MIC was significantly higher in the microbiological success group: 26 (1-76) versus 11 (3-26) (P = 0.004). CONCLUSIONS: In ICU patients with VAP, classic imipenem pharmacodynamic targets are easily reached with usual dosing regimens. In this context, for amikacin, a higher C1/MIC ratio than previously described might be necessary.

Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia.

AIMS: Modifications of antimicrobials' pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We characterized amikacin pharmacokinetic variability in critically ill patients with ventilator-associated pneumonia (VAP) and evaluated several dosing regimens. METHODS: We conducted a prospective multicenter study in critically ill patients with presumptive diagnosis of Gram-negative bacilli (GNB) VAP. Patients empirically received imipenem and a single-dose of amikacin, which was administered as a 30-min infusion (20 mg/kg). Concentrations were measured 0.5, 1, 8, 16, and 24 h after beginning of infusion. Pharmacokinetic parameters were estimated using a population approach. Main pharmacodynamic target was a ratio ≥ 10 between the concentration achieved 1 h after beginning of infusion (C 1h) and the minimal inhibitory concentration of the liable bacteria (MIC). We simulated individual C 1h for several dosing regimens by Monte Carlo method and computed C 1h/MIC ratios for MICs from 0.5 to 64 mg/L. RESULTS: Sixty patients (47 males), median (range) age, and body weight, 61.5 years (28-84) and 78 kg (45-126), respectively, were included. Amikacin median C 1h was 45 mg/L (22-87). Mean value (between-patients variability) for CL, V1, Q, and V2 were 4.3 L/h (31 %), 15.9 L (22 %), 12.1 L/h (27 %), and 21.4 L (47 %), respectively. CL increased with CrCL (p<0.001) and V1 with body weight (p<0.001) and PaO2/FIO2 ratio (p<0.001). With a 25 mg/kg regimen, the pharmacodynamic target was achieved in 20 and 96 % for a MICs of 8 and 4 mg/L, respectively. CONCLUSION: Amikacin clearance was decreased and its volume of distribution was increased as previously reported. A ≥ 25 mg/kg single-dose is needed for empirical treatment of GNB-VAP.

Escherichia coli bacteraemia in pregnant women is life-threatening for foetuses.

In order to improve knowledge on Escherichia coli bacteraemia during pregnancy, we studied clinical data and performed molecular characterization of strains for 29 E. coli bacteraemia occurring in pregnant women. Bacteraemia mostly occurred in the third trimester of pregnancy (45%) and was community-acquired (79%). Portals of entry were urinary (55%) and genital (45%). E. coli strains belonged mainly to phylogroups B2 (72%) and D (17%). Four clonal lineages (i.e. sequence type complex (STc) 73, STc95, STc12 and STc69) represented 65% of the strains. The strains exhibited a high number of virulence factor coding genes (10 (3-16)). Six foetuses died (27%), five of them due to bacteraemia of genital origin (83%). Foetal deaths occurred despite adequate antibiotic regimens. Strains associated with foetal mortality had fewer virulence factors (8 (6-10)) than strains involved in no foetal mortality (11 (4-12)) (p 0.02). When comparing E. coli strains involved in bacteraemia with a urinary portal of entry in non-immunocompromised pregnant vs. non-immunocompromised non-pregnant women from the COLIBAFI study, there was no significant difference of phylogroups and virulence factor coding genes. These results show that E. coli bacteraemia in pregnant women involve few highly virulent clones but that severity, represented by foetal death, is mainly related to bacteraemia of genital origin.

Quinolones versus macrolides in the treatment of legionellosis: a systematic review and meta-analysis.

BACKGROUND: Legionellosis is a life-threatening disease. The clinical superiority of quinolones or macrolides for treating patients with legionellosis has not been established. METHODS: We performed a systematic review and meta-analysis of studies reporting data that allowed the comparison of quinolones versus macrolides in the treatment of proven legionellosis published from 1 January 1985 to 31 January 2013. We collected baseline aggregate patient characteristics. Studied outcomes included mortality, clinical cure, time to apyrexia, length of hospital stay and occurrence of complications in each treatment group. Treatment effect was assessed using a Mantel-Haenszel random effects model. RESULTS: Among 1005 abstracts reviewed, 12 studies were selected (n=879 patients). No randomized controlled trial was performed directly comparing quinolone and macrolide efficacy in legionellosis. Mean age was 58.3 years, 27.7% were women and Fine score was ≥ 4 in 35.8%. Among 253 patients who received quinolone monotherapy, 10 died (4.0%). Among 211 patients who received macrolide monotherapy, 23 died (10.9%). The pooled OR of death for treatment with a quinolone versus a macrolide was 0.5 (95% CI 0.2-1.3, n=8 studies, 464 patients). Length of stay was significantly shorter in the quinolone monotherapy group. The difference was 3.0 days (95% CI 0.7-5.3, P=0.001, n=3 studies, 263 patients). Neither of two tests for heterogeneity was significant (I (2)=0% for both, P=1). Other studied outcomes were not significantly different among treatment groups. CONCLUSIONS: Few clinical data on legionellosis treatment are available. This first meta-analysis showed a trend toward a lower mortality rate and a significant decrease in length of hospital stay among patients receiving quinolones. These results must be confirmed by a randomized controlled trial.

Quinolone-resistant Escherichia coli from the faecal microbiota of healthy volunteers after ciprofloxacin exposure are highly adapted to a commensal lifestyle.

OBJECTIVES: Quinolone-resistant Escherichia coli (QREC) primarily emerge in commensal bacteria under selective pressure. The aim of this work was to investigate the characteristics of QREC from the faecal microbiota after quinolone exposure, as they remain largely unknown. METHODS: Forty-eight healthy volunteers received ciprofloxacin from day 1 to day 14. QREC were detected in stools from 14 subjects at day 42. QREC were compared in terms of genetic background, metabolic properties, stress resistance and intestinal colonization abilities with quinolone-susceptible E. coli (QSEC) from the same 14 individuals and from 29 volunteers who remained QREC-free. RESULTS: QREC always belonged to a single clone for a given volunteer and to restricted phylogenetic groups. QREC carried significantly more iron capture systems than QSEC. Maximum growth rates in minimal medium with gluconate, general stress regulator RpoS activity assessed by iodine staining and resistance to oxidative and acid stresses were significantly higher for QREC than for QSEC. In a mouse colonization model, QREC efficiently colonized the intestine microbiota despite the presence of QSEC competitors. At day 42, QREC and QSEC faecal counts from the 14 volunteers were comparable except in three subjects where only QREC could be detected. CONCLUSIONS: These results suggest that QREC do not have a fitness cost, probably as a result of genetic co-selection, but are highly adapted to a commensal lifestyle. They may not be eliminated easily from the faecal microbiota from healthy subjects once selected.

Persistence of yellow fever vaccine-induced antibodies after solid organ transplantation.

Immunization using live attenuated vaccines represents a contra-indication after solid organ transplantation (SOT): consequently, transplant candidates planning to travel in countries where yellow fever is endemic should be vaccinated prior to transplantation. The persistence of yellow fever vaccine-induced antibodies after transplantation has not been studied yet. We measured yellow-fever neutralizing antibodies in 53 SOT recipients vaccinated prior to transplantation (including 29 kidney recipients and 18 liver recipients). All but one (98%) had protective titers of antibodies after a median duration of 3 years (min.: 0.8, max.: 21) after transplantation. The median antibody level was 40 U/L (interquartile range: 40-80). For the 46 patients with a known or estimated date of vaccination, yellow-fever antibodies were still detectable after a median time of 13 years (range: 2-32 years) post-immunization. Our data suggest there is long-term persistence of antibodies to yellow fever in SOT recipients who have been vaccinated prior to transplantation.

Recalibration of somesthetic plantar information in the control of undisturbed upright stance maintenance.

To assess the effects of changes in somesthetic plantar information on upright quiet stance, a rotary plantar massage was applied under the feet of healthy subjects for ten minutes. The controlling variable, the centre of pressure (CP) displacements, were recorded, before and after massage, through a force platform and decomposed into two elementary motions: the vertical projection of the centre of gravity (CG(v)) and the difference between the latter and the CP (CP-CG(v)) along medio-lateral ML and antero-posterior AP directions. These motions were processed through frequency analysis and modelled as fractional Brownian motion. For CP-CG(v) motions, the frequency analysis shows that massage under the plantar soles induces a decrease of the amplitudes along the ML direction suggesting reduced overall muscular activity (abductor-adductor muscles of the hip according to Winter et al.). A general trend is that the CG(v) amplitudes are also diminished after massage especially in the ML direction, indicating a better distribution of the body weight on the two supports. On the other hand, the effects tend to vanish after about 8 minutes. Conversely, when the massage was given under the toes, no particular effect on any elementary motion was observed, suggesting that the plantar mechanoreceptors under the toes necessitate stronger stimulation to respond significantly and/or that the greater sensitivity obtained was not used by the CNS. Overall, this data emphasises the fact that a recalibration of somesthetic cues may occur when enhanced afferent information is fed to the postural system.

Backward and forward leaning postures modelled by an fBm framework.

Body leaning effects on postural control have been assessed by recording the centre of pressure (CP) displacements in healthy subjects under three experimental conditions (REF, BWD and FWD corresponding to upright, backward leaning and forward leaning of the body, respectively). The CP displacements were used to compute the motions of the vertical projections of the centre of gravity (CG(v)) and those of the difference CP-CG(v). A frequential analysis shows that the main effect takes place on CP-CG(v) motions, suggesting increased muscular activity in these leaning postures. In addition, changes also occur on CG(v) motions, especially in the antero-posterior (AP) direction. Modelling these motions as fractional Brownian motion (fBm) indicates that leaning the body induces, in the AP direction, a shift in the time interval Deltat at which the corrective process takes over the initial one operating in open-loop. In FWD and BWD conditions, the Deltat is diminished whilst the mean distance covered at this Deltat is increased for both CG(v) and CP-CG(v) motions. Moreover, more determinism in the overall upright stance control is observed in the corrective (closed-loop) process involving CG(v) motions. These facts emphasize the inability for the CP displacements to express properly the overall body sway in upright stance control.

CD40 ligand-independent B cell activation revealed by CD40 ligand-deficient T cell clones: evidence for distinct activation requirements for antibody formation and B cell proliferation.

We report the capacity of CD40 ligand (CD40L)-negative T cell clones to activate human B cells. CD40L-negative T cells induce a level of B cell proliferation 10-20% of that seen with normal T cells. The signal provided by the negative clones is synergistic with that derived from a CD40L transfectant, and restores B cell proliferation to normal levels, showing that CD40L-negative T cell clones are not inherently inhibitory for B cells. Although their capacity to induce proliferation was much reduced, CD40L-negative T cell clones were still strong inducers of B cell differentiation to plasma cells. This differentiation to plasma cells was inhibited by a CD40L transfectant. The data are discussed with regard to the normal in vivo mechanism for maintaining B cell memory and memory antibody responses to T-dependent antigens.

IL-7 transgenic mice: analysis of the role of IL-7 in the differentiation of thymocytes in vivo and in vitro.

We have generated a high copy number transgenic mouse line in which expression of mouse IL-7 cDNA is under the control of the mouse MHC class II E alpha promoter. These mice were generated in order to see if IL-7 over-production in the thymus altered either thymocyte differentiation or the process of negative selection. Using in situ hybridization, IL-7 transcripts could be detected in the thymic cortex and medulla as well as the spleen and lymph nodes of transgenic mice but was undetectable in normal controls. Phenotypic and molecular analysis of thymocytes from embryonic and adult transgenic mice failed to reveal a dramatic effect of IL-7 on thymocyte differentiation and negative selection of the TCR V beta repertoire appeared to be intact. In peripheral lymph nodes, there was a massive (30-fold) increase in the number of T cells (CD8+ > CD4+) and simultaneous presence of immature (B220+, Ig-) B cells. TCR repertoire analysis showed that the expansion of peripheral T cells was polyclonal. Using the polymerase chain reaction (PCR), transgene-specific IL-7 transcripts could be detected in the thymus from day 14 of fetal development. However, using semi-quantitative PCR, there was no dramatic increase in the degree of TCR beta or TCR alpha gene rearrangements during thymocyte ontogeny in vivo. Similarly, when fetal mouse thymus lobes were cultured with IL-7 in vitro, there was no dramatic increase in the degree of TCR beta or TCR alpha gene rearrangements. We conclude that IL-7 is probably not an important differentiation factor for immature mouse thymocytes.

Lymphoproliferative disorders in IL-7 transgenic mice: expansion of immature B cells which retain macrophage potential.

Transgenic mice carrying the murine IL-7 gene under the MHC class II (E alpha) promoter are described which develop lymphoid tumours at a high incidence when maintained in conventional or specific pathogen-free environments. Cells obtained from the lesions were relatively monomorphic, expressed a variety of B cell associated markers (BP-1, B220, CD43) but lacked surface Ig. Some mice, showed expanded populations of cells phenotypically similar to the recently reported bipotent B/macrophage stem cell subset (AA4.1high, B220-, Ig-) which could be cloned and maintained in vitro. These cells expressed IL-7 receptors, proliferated in response to IL-7 and in most cases had germline configuration of the Ig heavy chain locus. Cell lines cloned from two such tumours generated macrophages spontaneously in culture, consistent with their bipotent B cell/macrophage phenotype. These results suggest that IL-7 plays a role in very early stages of B cell ontogeny prior to bona fide B cell commitment.