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If scientific and social obstacles can be overcome, the use of plants and animals as living production facilities to effect protein expression could be the key to reducing R&D costs - and ultimately, the cost of therapies that will benefit millions of people.

To investigate the mechanism of rheumatoid synovial hyperplasia (RASH), the influence of tumour necrosis factor alpha (TNF-alpha) on Fas-mediated apoptotic cell death (Fas-ACD) was examined on cultured rheumatoid synovial cells (RASCs). RASCs were obtained from the synovial tissues of eight patients with rheumatoid arthritis (RA) and SCs from eight patients with osteoarthritis (OA) were used as a control. To examine the influence of TNF-alpha on Fas-ACD, SCs were cultured with anti-Fas antibody (CH11) for 16 h in the absence or presence of different doses of recombinant TNF-alpha. ACD was determined by electron microscopic analysis and the percentage of apoptotic cells was calculated by trypan blue staining. In addition, the expression of Fas and Bcl-2 on RASCs was examined by flow cytometry. As a result, RASCs were more susceptible to Fas-ACD in vitro than OASCs. TNF-alpha interfered with Fas-ACD on RASCs in a dose-dependent manner. Moreover, removal of TNF-alpha activity by a neutralizing anti-TNF-alpha antibody (cA2) restored Fas-ACD. Flow cytometric analysis showed no significant changes in either Fas or Bcl-2 expression on RASCs after the culture with TNFalpha. These results suggest the following: (1) Fas-ACD might be diminished in vivo by local excessive TNF-alpha and this might contribute in part to RASH. (2) The inhibition of Fas-ACD on RASCs by TNF-alpha might not be associated with changes in the expression of Fas or Bcl-2. (3) In addition, considering a magnetic resonance imaging (MRI) finding of marked reduction in the RASH after cA2 treatment, blockade of TNF-alpha activity could restore Fas-ACD in RA synovium, implicating a clinical benefit of anti-TNF-alpha therapy for RA., (Copyright 2000 Academic Press.)

Objective: To investigate the regulation of expression of the angiogenic cytokine vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA), in order to determine whether new blood vessel formation could be a potential therapeutic target in RA., Methods: Dissociated RA synovial membrane cells were cultured in the presence of cytokine inhibitors, or under hypoxic conditions. Serum VEGF levels were serially measured in RA patients enrolled in clinical trials of anti-tumor necrosis factor alpha (anti-TNFalpha) monoclonal antibody treatment., Results: Combined neutralization of TNFalpha and interleukin-1 (IL-1) in RA synovial membrane cultures reduced VEGF release by 45% (P < 0.05 versus control), although blockade of either TNFalpha or IL-1 activities alone resulted in only small inhibitory effects. In addition, release of VEGF from RA synovial membrane cells was selectively up-regulated by hypoxia. Serum VEGF levels were significantly elevated in RA patients relative to control subjects, and correlated with disease activity. Treatment of RA patients with anti-TNFalpha significantly decreased serum VEGF, and this effect was enhanced by cotreatment with methotrexate., Conclusion: Inhibition of TNFalpha and IL-1 activity in vivo could reduce the drive to new blood vessel formation, and hence pannus mass, adding to other therapeutic effects of anti-TNFalpha therapy in RA.

Objectives: To evaluate the timing of foregoing life-sustaining treatments in patients enrolled in a sepsis trial and to determine their influence on patient outcome and trial results., Design: Subset of patients in a prospective, randomized, double-blind, placebo-controlled study., Setting: Twenty-three academic medical centers., Patients: Enrolled patients who had life-sustaining therapies withheld or withdrawn., Measurements and Main Results: The number of patients, types of disorders and interventions, reasons, and timing of withholding and withdrawing life-sustaining treatments and their effect on mortality and trial results were assessed. Foregoing of life-sustaining therapies took place in 117 (22%) of 543 patients and occurred within 72 hrs of study drug administration in 38 (32%) patients. Withholding treatment (60%) was more common than withdrawing treatment (40%), but withdrawing treatment was more frequent (51%) than withholding treatment (20%) in the first 72 hrs of the trial (p < .01). Sixty-one (52%) patients had severe underlying disorders with a poor prognosis. The hospital mortality rate was 94% (of the 117 patients). The mean time (SEM) from withholding or withdrawing of treatment until death was 2.83 +/- 0.57 and 0.32 +/- 0.13 days, respectively (p < .001). Patients who had therapies foregone in the first 24, 48, and 72 hrs after receiving the study drug had higher mortality rates in the first 72 hrs (p < .01)., Conclusions: A substantial number of patients enrolled in a sepsis trial had severe underlying diseases and had foregoing of therapies early in the course of the trial, which led to a higher early mortality rate. Enrollment of patients in clinical trials with severe underlying disorders with a high likelihood of having therapies foregone may bias the potential for showing the efficacy of new therapeutic modalities.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to stimulate human immunodeficiency virus type 1 (HIV-1) replication, has been implicated in the pathogenesis of HIV-1 infection. Inhibition of TNF-alpha by a chimeric humanized monoclonal antibody, cA2, was investigated in 6 HIV-1-infected patients with CD4 cell counts < 200/mm3. Two consecutive infusions of 10 mg/kg 14 days apart were well tolerated, and a prolonged serum half-life for cA2 (mean, 257 +/- 70 h) was demonstrated. Serum immunoreactive TNF-alpha concentrations fell from a mean prestudy value of 6.4 pg/mL (range, 4.2-7.9) to 1.1 pg/mL (range, 0.5-2.2) 24 h after the first infusion and returned to baseline within 7-14 days. A similar response was seen after the second infusion. No consistent changes in CD4 cell counts or plasma HIV RNA levels were observed over 42 days. Future studies evaluating the therapeutic utility of long-term TNF-alpha suppression using anti-TNF-alpha antibodies are feasible and warranted.

Objective: To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gram-negative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia., Design: Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial., Setting: 603 investigators at 513 community and university-affiliated hospitals in the United States., Patients: Within 6 hours before enrollment, the patients had been in shock with a systolic blood pressure of less than 90 mm Hg after adequate fluid challenge or had received vasopressors to maintain blood pressure. These episodes of shock began within 24 hours of enrollment. A presumptive clinical diagnosis of gram-negative infection as the cause of the shock episode and a commitment from the patients' physicians to provide full supportive care were required., Measurements: Blood cultures were obtained within 48 hours of enrollment, and death at day 14 after treatment was recorded. Adverse events occurring within 14 days after enrollment were also tabulated., Results: 2199 patients were enrolled; 621 (28.2%) met all enrollment criteria, received HA-1A or placebo, and had confirmed gram-negative bacteremia. Mortality rates in this group were as follows: placebo, 32% (95 and HA-1A, 33% (109 of 328) (P = 0.864, Fisher exact test, two-tailed; 95% CI for the difference, -6.2% to 8.6%). Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785) (P = 0.073, Fisher exact test, one-tailed; CI, -0.8% to 8.8%)., Conclusions: In this trial, HA-1A was not effective in reducing the 14-day mortality rate in patients with gram-negative bacteremia and septic shock. These data do not support using septic shock as an indication for HA-1A treatment. If HA-1A is effective in reducing the mortality rate in patients dying from endotoxemia, these patients must be identified using other treatment criteria.

Purpose: This multicenter study was designed to compare an exclusively oral regimen with "usual care" in patients hospitalized with acute bacterial pneumonia., Patients and Methods: One hundred forty-seven patients were enrolled. All patients presented with a clinical picture consistent with pneumonia: (1) clinical symptoms of a lower respiratory tract infection, such as chest pain, cough, and production of purulent sputum; (2) roentgenographic infiltrate compatible with acute infection; and (3) Gram's stain of purulent sputum or other appropriate bronchopulmonary specimen containing gram-negative organisms, staphylococci, or pneumococci. All patients required hospitalization. The design was a parallel-group, open-label study with randomization in blocks of four. Ofloxacin, a new fluoroquinolone antimicrobial agent, was administered orally or by nasogastric tube, 400 mg every 12 hours. This was compared with the individual investigator's best selection of therapy that was administered parenterally, at least initially., Results: One hundred thirty-three patients were evaluable after exclusions for deviation from protocol, early death due to unrelated causes, incorrect diagnosis, or early adverse drug reactions. All 69 patients treated with ofloxacin and 61 of 64 control patients had favorable clinical and microbiologic responses. There were no statistically significant differences between the groups in terms of demographics, therapeutic outcome, and duration of therapy. There were few side effects overall and rates were similar for the two groups., Conclusions: An exclusively oral regimen, in this case ofloxacin, may be substituted for parenteral therapy in selected patients with pneumonia. This might significantly reduce costs and risks to the patient.

The acylureido penicillin mezlocillin is active against gram-positive, gram-negative, and anaerobic bacteria. It easily penetrates the outer membrane of gram-negative bacteria, and it has a strong affinity for penicillin binding protein 3. Its stability to beta-lactamases is weak. Mezlocillin is synergistic when given in combination with aminoglycoside antibiotics. In pharmacokinetic studies mezlocillin conforms to a two compartment open model; its pharmacokinetic properties are dose-dependent. The half-life of the drug is about 1 hour after intravenous injection and 1.5 hours after intramuscular injection. Protein binding ranges from 16 to 42%, and 55% of a dose is excreted in the urine. Biliary excretion ranges from 0.5 to 25%. Clinical trial cure rates were as follows: bacteremia (78%), respiratory tract (62%), urinary tract (81%), gynecological (86%), bone and joint (55%), intraabdominal (67%) and skin and soft tissue (59%). The frequency of adverse reactions was 7.7%. Interstitial nephritis, CNS toxicity, and bleeding have not been reported.

The antimicrobial activity of carumonam (formerly RO-17-2301), a monocyclic beta-lactam antibiotic, was compared with those of aztreonam, cefotaxime, cefoperazone, ceftazidime, piperacillin, and gentamicin against 455 bacterial isolates. Carumonam did not possess activity against gram-positive cocci and was generally comparable to aztreonam and ceftazidime for most gram-negative bacilli. However, carumonam was the most active beta-lactam against gentamicin-resistant Pseudomonas aeruginosa strains (90% MIC, 8 micrograms/ml).

Cefoxitin is a useful new chephamycin antibiotic available for IM of IV administration. It is a bactericidal beta-lactam antibiotic indicated for treatment of serious infections caused by a wide spectrum of gram-negative aerobic and anaerobic bacteria. Specific indications include: 1) polymicrobial infections (aerobic gram-negative rods and anaerobic bacteria); 2) nosocomial cephalothin-resistant gram-negative bacillary infections; 3) penicillin-resistant staphylococcal infections, and 4) anaerobic infections (pelvic, intraabdominal). Cefoxitin can be used as a single drug alternate to a two-drug antibiotic regimen (such as a cephalosporin-aminoglycoside combination) in polymicrobic infections of the pelvis, abdomen, skin, bones, or muscles. Cefoxitin is a significant drug in the armamentarium against anaerobic bacteria, particularly Bacteroides species. Since cefoxitin is highly resistant to staphylococcal beta-lactamase, it is effective against penicillin-resistant staphylococci. Cefoxitin has been effective in treating serious nosocomial infections caused by resistant aerobic gram-negative rods and anaerobic bacteria.

The clinical and bacteriologic efficacy of ceftriaxone given once or twice daily was evaluated in 153 studies. A total of 2,635 patients received ceftriaxone given intramuscularly or intravenously, 930 received comparative antibiotics, and 81 received placebo. For the 10 major categories of infections treated (central nervous system, upper and lower respiratory tract, intraabdominal, skin and skin structure, bone and joint, urinary tract, gynecologic, and bacterial sepsis), the clinical response rates were 89 percent or greater. Bacteriologic cure rates were 84 percent or greater overall and 90 percent or greater for seven of 10 categories. Ceftriaxone achieved a satisfactory clinical response (cure or improvement) for 89 (intraabdominal) to 99 percent (urinary tract) of the infections treated. Additionally, pediatric central nervous system infections responded to twice-daily ceftriaxone injection; ceftriaxone, in a single dose as low as 250 mg, cured gonorrhea, and a single dose of ceftriaxone was as effective as multiple doses of cefazolin in surgical prophylaxis.

The objective of this double-blind study was to compare the efficacy and safety of piperacillin with that of cefoxitin in patients with bacterial infections. Seventy hospitalized patients were treated with intravenous piperacillin (18 g/day) or cefoxitin (12 g/day) for a mean period of 11.5 days. Multiple serious underlying conditions were present in 91% of the patients in both treatment groups. The infection sites were the respiratory, urinary, and gastrointestinal tracts, the skin and skin structures, and the bones. Among the patients with evaluated courses of therapy, 87% (20 of 23) of the patients in the piperacillin-treated group and 90% (19 of 21) of the cefoxitin-treated patients were cured or improved. Multiple sites of infection were present in 6 patients given piperacillin and in 11 patients given cefoxitin. Gram-negative aerobic bacteria were the most frequently isolated organisms (56% of isolates). In each treatment group, 91% of the pathogens were eradicated. Three piperacillin-treated patients (9%) and four cefoxitin-treated patients (11%) had adverse clinical effects related to therapy; most of the effects were moderate in intensity. In conclusion, both piperacillin and cefoxitin were clinically safe and effective antibiotics for the treatment of these patients, most of whom had severe underlying conditions.

The efficacy, safety, and tolerability of cefotaxime, a new parenteral cephalosporin resistant to beta-lactamase, were evaluated in a multicenter open trial. The study population comprised 594 hospitalized patients with infections of the skin or subcutaneous tissue. Of these, 409 patients fulfilled the protocol requirements for assessment of clinical efficacy. Usual dosages of cefotaxime were in the range of 1.5 to 12 gm/day for 5 to 85 days. Staphylococcus aureus was the most frequent gram-positive organism; Proteus mirabilis, Escherichia coli, and Pseudomonas aeruginosa, the most frequent gram-negative bacilli; and Peptococcus sp, the most frequent anaerobic organism isolated. Of the 409 evaluable patients, 382 (93.4%) were clinically cured. Bacteriological cures were obtained in 316 of 372 (84.9%) patients. Reactions to cefotaxime included asymptomatic eosinophilia, rash, drug fever, phlebitis, and elevated hepatic enzyme levels. All reactions were transient, and drug therapy had to be terminated in only eight patients. Cefotaxime proved effective for treating a variety of skin and soft tissue infections. The lack of serious toxicity and adverse reactions associated with cefotaxime, together with its broad antimicrobial spectrum, makes it a suitable substitute for aminoglycosides in certain clinical settings.

The antibacterial activity of N-formimidoyl thienamycin was compared with those of cefotaxime, cefoperazone, and piperacillin against 536 clinical aerobic isolates.

Cefmenoxime, a new semisynthetic third-generation cephalosporin, was evaluated in 105 patients (45 men and 60 women) with the following infections: skin or skin structure (33), pulmonary (22), urinary tract (30), and septicemia (20). Forty-two infections were hospital-acquired, 85 patients had underlying diseases, 29 patients required concomitant surgery, and 32 patients had positive results of blood culture. Cefmenoxime dosages ranged from 4 to 12 g per day intravenously for one and a half to 51 days. Cultures revealed 183 organisms in the 105 patients. Minimal inhibitory concentrations were obtained for cefmenoxime, cefoperazone, cefotaxime, cefamandole, cefoxitin, and moxalactam. Cefmenoxime and cefotaxime exhibited nearly equivalent activities against all organisms tested and were the most active agents tested against all aerobic and facultative organisms except Staphylococcus aureus. Mean serum peak and trough levels obtained after 2 g every six hours were 84.1 micrograms/ml (peak), 8.3 micrograms/ml (trough); and after 2 g every four hours, 106 micrograms/ml (peak) and 10.9 micrograms/ml (trough). Of 105 infections, 86 were clinically cured, three were not cured, and 16 were not evaluable. Safety studies revealed 24 transient reactions in 23 patients including eosinophilia, diarrhea, leukopenia, rash, elevated liver enzyme levels, Antabuse effect, and phlebitis. On the basis of these clinical and in vitro results, cefmenoxime is a safe drug for the treatment of infections caused by gram-negative and gram-positive aerobic organisms.

Discrepancies were observed between results of different beta-lactamase induction tests with amdinocillin, which appeared to be a strong inducer in whole-cell assays but a weak inducer in assays with cell-free sonic extracts. Results of a nitrocephin-disk test with constitutive beta-lactamase producers indicated that the positive results obtained in whole-cell assays were due to drug-produced leakage of enzyme from the cell and not to induction. Imipenem was also found to cause leakage of beta-lactamase from a similar number of constitutive enzyme producers, while cefoxitin was much less likely to cause leakage. A split-dose regimen was employed to treat mice infected with a strain of Enterobacter cloacae which appeared to leak enzyme on exposure to amdinocillin. Results indicated that prior treatment with amdinocillin significantly enhanced (P less than 0.025) the efficacy of azlocillin, an enzyme-labile drug, but did not affect the efficacy of cefotaxime, a relatively enzyme-stable drug. Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs. Thus, it appears that amdinocillin may potentiate the activity of other beta-lactam drugs not only by binding to a complementary penicillin-binding protein but also by causing leakage of beta-lactamase from the cell. This effect may be related to its ability to bind to penicillin-binding protein 2 and subsequently produce changes in outer membrane permeability.

In a series of open, noncomparative studies, cefotaxime was given to 360 hospitalized patients with bacterial wound infections such as cellulitis, abscesses, or necrotizing ulcers of the skin or subcutaneous tissues. The drug was administered intramuscularly or intravenously in a mean dosage of 4 g per day (range, 1.4-12.0 g per day) in three or four equal doses for at least five days. Clinical response to therapy could not be evaluated for 100 patients, and bacterologic response could not be evaluated for 145 patients. Clinical response was satisfactory in 93.5% of the 260 patients for whom therapy could be evaluated, and bacterial response was satisfactory in 84% of the 225 patients for whom therapy could be evaluated. These rates of response include both single- and multiple-pathogen infections. There were nine instances of superinfection.

Ehrlichia Canis, a canine rickettsia, produces an acute infection in humans characterized by thrombocytopenia, leukopenia, and anemia. Patients should be closely questioned and examined for tick bites. Rash is not prominent, leading to the interesting if somewhat inaccurate label of "spotless spotted fever." The diagnosis is made by clinical presentation, absence of positive Lyme disease or Rocky Mounted Spotted Fever (RMSF) serology, and positive E. canis titers. Tetracyclines are preferred treatment. Ehrlichiosis should be considered in the differential diagnosis of fevers of unknown origin, Lyme disease, idiopathic thrombocytopenia, and hypoplastic anemia.

Ninety-eight adult patients with skin and soft tissue infections caused by a variety of bacterial pathogens were treated with imipenem/cilastatin (71), cefazolin (21), or moxalactam (six) at three medical centers. Favorable clinical responses were observed in 87 of the 90 evaluable cases (97 percent). Most etiologic pathogens were eradicated during treatment including five of seven which demonstrated in vitro resistance to the therapeutic agent. Strains that persisted during treatment were not associated with therapeutic failure except in one cefazolin-treated patient who was infected with Bacteroides fragilis. All three drugs were well tolerated and no specific patterns of adverse reactions were observed.

The minimal inhibitory concentrations of nine antimicrobial agents was determined for over 750 clinical isolates of the Bacteroides fragilis group of anaerobic bacteria collected from nine centers in the United States during 1981. High resistance rates were documented for cefoperazone, cefotaxime, and tetracycline. Cefoxitin had the best activity of the beta-lactam antibiotics, whereas moxalactam and piperacillin had good activities. The resistance rate for clindamycin was 6%. There were no metronidazole- or chloramphenicol-resistant isolates encountered. There were significant differences in susceptibility among the various species of the B. fragilis group, particularly with moxalactam, cefoxitin, and clindamycin. Clustering of clindamycin-, piperacillin-, and cefoxitin-resistant isolates was observed at different hospitals. The variability of resistance rates with the beta-lactam antibiotics and clindamycin indicates that susceptibility testing of significant clinical isolates should be performed to define local resistance patterns.

Cefoxitin was administered intravenously to 143 patients, 67% of whom were seriously ill. The rate of cure or improvement was 93%. The study was conducted in two phases; the first was an open, controlled clinical comparison of cefoxitin and cephalothin. In this phase, 28 patients received cefoxitin and 29 received cephalothin. In the second phase, cefoxitin alone was used for the treatment of an additional 115 patients. Twenty bacteremic patients treated with cefoxitin were cured or improved in 95% of cases. The infecting organism was eradicated in all bacteremic patients. All of 14 anaerobic or predominantly anaerobic infections were cured or improved. The infecting anaerobic organism was eliminated in 86% of the cases. Twenty-five patients infected by cephalothin-resistant, cefoxitin-susceptible gram-negative rods were cured. Three patients each with infective endocarditis and osteomyelitis were cured. The incidence of adverse experiences was: 1.4% drug eruption; 2% each asymptomatic serum transaminase elevation and leukopenia; and 2.5% asymptomatic eosinophilia. The incidence of severe thrombophlebitis was 5%. No permanent or serious adverse reactions were encountered. Although the numbers of patients in some categories were too small to permit statistical evaluation, I feel that cefoxitin may be a useful new antibiotic for treatment of infections caused by cehalothin-resistant bacteria and by anaerobic organisms.

One hundred and eighty-six patients were randomized to receive either imipenem-cilastatin (94 patients) or cefazolin (92 patients). Imipenem-cilastatin (250 mg 6 hourly iv) or cefazolin (1000 mg 6 hourly iv) were given for 5 to 14 days. An assessment of efficacy could be made in 141 patients, 72 of whom received imipenem-cilastatin and 69 of whom received cefazolin. Reasons for exclusion included failure to isolate a causative organism (20 patients), less than 5 days of treatment (16 patients), inadequate follow up or culture (5 patients), concomitant administration of another antibiotic (1 patient), and resistance to the study drug (3 patients, all of whom were in the cefazolin group). No isolates resistant to imipenem were found. Sites of infection included skin and soft tissue (91 patients), lower respiratory tract (21 patients), urinary tract (16 patients), bone and joint (8 patients), primary bacteraemia (4 patients) and miscellaneous other sites (1 patient). Bacteria isolated included Staphylococcus aureus (65 patients), group A streptococcus (42 patients), Escherichia coli (17 patients), other Gram-negative bacilli (37 patients), anaerobic bacteria (34 patients) and other bacteria. Imipenem was more active than cephalothin in vitro against pathogenic bacteria isolated from evaluable patients. Cure or improvement was seen in 68 of the 72 imipenem-cilastatin patients (94%) and in 68 of the 69 cefazolin patients (99%). Relatively few abnormal laboratory tests and adverse experiences were noted, and there were no differences in this between the two treatment groups. We concluded that imipenem-cilastatin is safe at the dose used. It is as effective as cefazolin in mild to moderate infections caused by common pathogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefoxitin was administered by the intramuscular route to 102 patients who had infections of mild or moderate severity. The assessment of clinical and bacteriologic outcome was derived from data for 79 patients. Assessments of tolerance and safety were made for all patients who received 1 g of cefoxitin diluted in 1 ml of 0.5% or 1.0% lidocaine four times daily. Cure or improvement occurred in 45 of 47 patients with skin or soft tissue infections, in all of 16 patients with lower respiratory tract infections, and in 10 of 12 patients with urinary tract infections. One patient developed acute tubular necrosis. Eosinophilia was seen in 7% of patients treated with cefoxitin. The intramuscular preparation was not painful to 96% of the patients. Cefoxitin given by the intramuscular route can be used as an alternative to intravenous cefoxitin for treatment of mild or moderate infections, for continuation of treatment when the intravenous route is not appropriate, and for treatment of ulcers of polymicrobial etiology on ischemic extremities or on extremities of diabetic patients.

Antibiotics for eye infection can be given topically, by subconjunctival or intravitreous injection, or systemically. The bacteria responsible are reviewed and pharmacokinetics influencing topical concentration are discussed. An approach to treatment by the primary care specialist is suggested.

Phagocytosis and killing of Mima polymorpha and Herellea vaginicola by the liver, lungs, spleen, and kidneys from neonatally thymectomized nonwasted mice and their sham-thymectomized litter mates were compared. The removal of M. polymorpha from blood by these organs, measured 2 and 4 hr after intravenous injection of bacteria, was not affected by thymectomy. Because significantly fewer viable organisms persisted in the liver, spleen, and kidneys, it is concluded that bacterial killing increased after thymectomy. Phagocytosis of M. polymorpha by peritoneal macrophages increased in thymectomized mice. Removal of H. vaginicola from the blood by the lungs was greater after thymectomy. Thymectomy did not affect the killing of H. vaginicola by the liver, spleen, lungs, or kidneys. Killing of H. vaginicola by the kidney was less than that by other organs, although this was not affected by thymectomy. Chronic reticuloendothelial stimulation associated with infection was not an adequate explanation for these findings because no wasting syndrome was encountered.

Six patients undergoing chronic hemodialysis and 10 patients with chronic renal insufficiency hospitalized for nondialytic therapy received 1.0 g of cephapirin sodium by the intravenous route. The concentrations of cephapirin in arterial and venous plasma, dialysate, venous blood, and urine were measured during the ensuing 6 hr. The serum half-life of cephapirin was 105 to 108 min for the dialyzed patients and 95.9 min for the nondialyzed patients. Dialysis removed 22.8% of the administered dose. Nondialyzed patients excreted 19.5% of the administered dose in the urine. The concentration of cephapirin in the urine of all nondialyzed patients exceeded 50 mug/ml. The recovery of cephapirin in the urine collected for 6 hr after injection was from 34 to 770 mg (mean 195 mg). To maintain a concentration of cephapirin in the blood and urine which exceeds the minimal inhibitory concentration for most gram-positive and gram-negative microorganisms, nondialyzed patients should receive 15 to 18 mg of cephapirin per kg every 12 hr. Dialyzed patients should receive the same dose just prior to dialysis and every 12 hr thereafter.