Real-time telemetric monitoring in whole-body 60Co gamma-photon irradiated rhesus macaques (Macaca mulatta).

BACKGROUND: Animals undergoing experimental manipulations, such as exposure to radiation, may exhibit physiologic and behavioral signs of pain and distress. Telemetry permits close monitoring of these parameters for early and effective management during procedures. METHODS: Radiotelemetric units were surgically implanted into 24 Macaca mulatta before 6.5-Gy cobalt-60 γ-photon irradiation. Each unit transmitted electrocardiogram, intrathoracic pressure, and body temperature leads. Primate irradiation-restraint boxes and housing cages were modified to collect telemetric signals before, during, and after irradiation. RESULTS: Differences in respiratory rate, heart rate, or body temperature in telemetric-collected recordings, which were observed during non-irradiation and irradiation sessions, were statistically insignificant. CONCLUSIONS: Insignificant changes in the physiological parameters during monitoring suggest that the animals experienced no detectable pain or distress during irradiation.

COX-2 inhibitors are contraindicated for treatment of combined injury.

Casualties of radiation dispersal devices, nuclear detonation or major ionizing radiation accidents, in addition to radiation exposure, may sustain physical and/or thermal trauma. Radiation exposure plus additional tissue trauma is known as combined injury. There are no definitive therapeutic agents. Cyclooxygenase-2 (COX-2), an inducible enzyme expressed in pathological disorders and radiation injury, plays an important role in inflammation and the production of cytokines and prostaglandin E(2) (PGE(2)) and could therefore affect the outcome for victims of combined injury. The COX-2 inhibitors celecoxib and meloxicam were evaluated for their therapeutic value against combined injury in mice. In survival studies, the COX-2 inhibitors had no beneficial effect on 30-day survival, wound healing or body weight gain after radiation injury alone or after combined injury. Meloxicam accelerated death in both wounded and combined injury mice. These drugs also induced severe hepatic toxicity, exaggerated inflammatory processes, and did not enhance hematopoietic cell regeneration. This study points to potential contraindications for use of COX-2 inhibitors in patients undergoing therapy for radiation injury and combined injury.

Resident bacteria in a mixed population of rhesus macaque (Macaca mulatta) monkeys: a prevalence study.

BACKGROUND: Microflora populations residing in oropharyngeal and gastrointestinal sites defend against pathogenic bacterial colonization. Perturbations in these microbial communities may allow opportunistic pathogenic bacteria to establish themselves and cause morbidity and mortality from sepsis particularly after stressful experimental procedures. This study determined the prevalent facultative bacteria in a resident population of Macaca mulatta prior to use in experimentally induced immunosuppressive radiation studies. METHODS: Standard microbiological methods were used to assess prevalent facultative bacteria in the oropharynx and rectum of 24 male M. mulatta. RESULTS: The majority of the bacteria isolated from the oropharyngeal and rectal sites were gram-positive cocci. Species of Staphylococcus and Streptococcus predominated in all samples. Few gram-negative bacteria were isolated. CONCLUSIONS: Bacteriological assessment is recommended to identify predominant bacterial species to be prepared to provide appropriate antimicrobial therapy in non-human primates that are expected to undergo stressful immunocompromising procedures.

Clindamycin and quinolone therapy for Bacillus anthracis Sterne infection in 60Co-gamma-photon-irradiated and sham-irradiated mice.

OBJECTIVES: Sublethal ionizing doses of radiation increase the susceptibility of mice to Bacillus anthracis Sterne infection. In this study, we investigated the efficacy of clindamycin in 60Co-gamma-photon-irradiated and sham-irradiated mice after intratracheal challenge with B. anthracis Sterne spores. Clindamycin has in vitro activity against B. anthracis and inhibits the production of toxin from other species, although no direct evidence exists that production of B. anthracis toxin is inhibited. METHODS: Ten-week-old B6D2F1/J female mice were either sham-irradiated or given a sublethal 7 Gy dose of 60Co-gamma-photon radiation 4 days prior to an intratracheal challenge with toxigenic B. anthracis Sterne spores. Mice were treated twice daily with 200 mg/kg clindamycin (subcutaneous or oral), 100 mg/kg moxifloxacin (oral), 50 mg/kg ciprofloxacin (subcutaneous) or a combination therapy (clindamycin + ciprofloxacin). Bacteria were isolated and identified from lung, liver and heart blood at five timed intervals after irradiation. Survival was recorded twice daily following intratracheal challenge. RESULTS: The use of clindamycin increased survival in gamma-irradiated and sham-irradiated animals challenged with B. anthracis Sterne in comparison with control mice (P < 0.001). Ciprofloxacin-treated animals had higher survival compared with clindamycin-treated animals in two experiments, and less survival in a third experiment, although differences were not statistically significant. Moxifloxacin was just as effective as clindamycin. Combination therapy did not improve survival of sham-irradiated animals and significantly decreased survival among gamma-irradiated animals (P = 0.01) in comparison with clindamycin-treated animals. B. anthracis Sterne was isolated from lung, liver and heart blood, irrespective of the antimicrobial treatment. CONCLUSIONS: Treatment with clindamycin, ciprofloxacin or moxifloxacin increased survival in sham-irradiated and gamma-irradiated animals challenged intratracheally with B. anthracis Sterne spores. However, the combination of clindamycin and ciprofloxacin increased mortality associated with B. anthracis Sterne infection, particularly in gamma-irradiated animals.

WR-151327 increases resistance to Klebsiella pneumoniae infection in mixed-field- and gamma-photon-irradiated mice.

PURPOSE: To determine the efficacy of WR-151327 (WR) [S-3-(3-methylaminopropylamino) propylphosphorothioic acid; (CH3-HN-(CH2)3-NH-(CH2)3-S-PO3H2)] in increasing resistance to bacterial infection after a sublethal dose of gamma-photons or mixed-field neutrons plus gamma-photons. MATERIALS AND METHODS: B6D2F1/J female mice received 200 mg/kg WR i.p. or saline vehicle 20-30 min before or after sham (0 Gy) or 7.0 Gy 60Co gamma-photon irradiation. WR or saline vehicle was given only before 3.5 Gy TRIGA-reactor-produced mixed-field [n/(n+y) = 0.67] irradiation. Four days after drug treatment or drug treatment and irradiation, graded doses of Klebsiella pneumoniae were injected s.c. into mice, and 30-day survival was recorded. To assess haemopoietic changes other unirradiated and irradiated mice not injected with bacteria were given WR or saline. Peripheral blood (PB) and femoral bone marrow (BM) cells were measured 1, 3 or 4, 7, 10 and 14 or 15 days later. RESULTS: WR pretreatment increased resistance to infection in irradiated but not in unirradiated mice. Bacterial CFU-LD50/30 values for 0 Gy saline-treated mice were 1.20x10(6); for 0 Gy WR-treated mice 1.16x10(6); for gamma-photon-irradiated saline-treated mice 3.02x10(1); for gamma-photon-irradiated WR-treated mice 1.24x10(4); for mixed-field-irradiated saline-treated mice 1.94x10(2); and for mixed-field-irradiated WR-treated mice 6.13x10(3). WR-induced resistance to infection paralleled increased numbers of PB white cells, neutrophils, platelets, femoral BM cells and granulocyte macrophage colony-forming cells (GM-CFC) in irradiated mice not given bacteria. CONCLUSIONS: These studies quantify the resistance to bacterial infection in mice treated with WR before sublethal irradiation. The findings suggest that WR treatment increases resistance to infection in immunocompromised hosts.

Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice.

The ionizing radiation-induced hemopoietic syndrome is characterized by defects in immune function and increased mortality due to infections and hemorrhage. Since the steroid 5-androstene-3beta, 17beta-diol (5-androstenediol, AED) modulates cytokine expression and increases resistance to bacterial and viral infections in rodents, we tested its ability to promote survival after whole-body ionizing radiation in mice. In unirradiated female B6D2F1 mice, sc AED elevated numbers of circulating neutrophils and platelets and induced proliferation of neutrophil progenitors in bone marrow. In mice exposed to whole-body (60)Co gamma-radiation (3 Gy), AED injected 1 h later ameliorated radiation-induced decreases in circulating neutrophils and platelets and marrow granulocyte-macrophage colony-forming cells, but had no effect on total numbers of circulating lymphocytes or erythrocytes. In mice irradiated (0, 1 or 3 Gy) and inoculated four days later with Klebsiella pneumoniae, AED injected 2 h after irradiation enhanced 30-d survival. Injecting AED 24 h before irradiation or 2 h after irradiation increased survival to approximately the same extent. In K. pneumoniae-inoculated mice (irradiated at 3-7 Gy) and uninoculated mice (irradiated at 8-12 Gy), AED (160 mg/kg) injected 24 h before irradiation significantly promoted survival with dose reduction factors (DRFs) of 1.18 and 1.26, respectively. 5-Androstene-3beta-ol-17-one (dehydroepiandrosterone, DHEA) was markedly less efficacious than AED in augmenting survival, indicating specificity. These results demonstrate for the first time that a DHEA-related steroid stimulates myelopoiesis, and ameliorates neutropenia and thrombocytopenia and enhances resistance to infection after exposure of animals to ionizing radiation.

Ionizing radiation and bacterial challenge alter splenic cytokine gene expression.

Irradiation increases susceptibility to bacterial infection. Exogenous proinflammatory cytokines can alter the response of mice to gamma radiation, but the role of endogenous inflammatory cytokines after bacterial infection in irradiated animals is not known. Gene expression of hematopoietic (GM-CSF) and proinflammatory (IL-1 beta, IL-6 and TNF-alpha) cytokines were examined in spleens of B6D2F1/J female mice after irradiation alone (1.0- and 7.0-Gy), and after irradiation followed by Klebsiella pneumoniae s.c. challenge 4 days postirradiation by using the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization. At 4, 8, and 24 h after bacterial challenge in 7.0-Gy-irradiated mice, GM-CSF mRNA increased (p < 0.05). TNF-alpha mRNA in irradiated mice were slightly decreased, whereas after bacterial challenge, TNF-alpha mRNA elevated at 30 h in 7.0-Gy-irradiated mice; at 4, and 8 h in 1.0-Gy-irradiated mice, and at 1 h in sham-irradiated mice (p < 0.05). IL-6 mRNA displayed a biphasic response in 7.0-Gy-irradiated mice, and, after bacterial challenge, in both irradiated mice (1.0- and 7.0-Gy) and sham-irradiated mice. IL-1 beta mRNA remained at or below normal for 8 h and increased at 24 h after bacterial challenge on day 4 in 7.0-Gy-irradiated mice. These results indicate that sublethal gamma radiation alters the patterns of the hematopoietic and proinflammatory cytokine responses to bacterial challenge in vivo. Consequently, treatment protocols may need to take into account changes in cytokine gene responses to resolve infection after irradiation.

Synthetic trehalose dicorynomycolate (S-TDCM): behavioral effects and radioprotection.

This study evaluated synthetic trehalose dicorynomycolate (S-TDCM), an immunomodulator, for its survival enhancing capacity and behavioral toxicity in B6D2F1 female mice. In survival experiments, mice were administered S-TDCM (25-400 micrograms/mouse i.p.) 20-24 hr before 5.6 Gy mixed-field fission-neutron irradiation (n) and gamma-photon irradiation. The 30-day survival rates for mice treated with 100-400 micrograms/mouse S-TDCM were significantly enhanced compared to controls. Toxicity of S-TDCM was measured in nonirradiated mice by locomotor activity, food intake, water consumption, and alterations in body weight. A dose-dependent decrease was noted in all behavioral measures in mice treated with S-TDCM. Doses of 100 and 200 micrograms/mouse S-TDCM significantly reduced motor activity beginning 12 hr postinjection with recovery by 24 hr. A dose of 400 micrograms/mouse significantly decreased activity within the first 4 hr after administration and returned to control levels by 32 hr following injection. Food and water intake were significantly depressed at doses of 200 and 400 micrograms/mouse on the day following drug administration, and were recovered in 24 hr. Body weight was significantly decreased in the 200 micrograms/mouse group for 2 days and in the 400 micrograms/mouse group for 4 days following injection. A dose of 100 micrograms/mouse effectively enhanced survival after fission-neutron irradiation with no adverse effect on food consumption, water intake, or body weight and a minimal, short-term effect on locomotor activity.

Mixed-field neutrons and gamma photons induce different changes in ileal bacteria and correlated sepsis in mice.

High doses of radiation induce septicaemia, from bacterial translocation, and death in animals. Mice were exposed to either comparable lethal (LD90/30) or sublethal (LD0/30) doses of mixed-field [n/(n + y) = 0.67] or pure 60Co gamma-photon radiation. The relative biological effectiveness of these comparable doses of radiation was 1.82, determined by probit analysis. Mice given a lethal dose of mixed-field radiation developed a significant (p < 0.01), 10(9)-fold increase in Gram-negative facultative bacteria in their ilea over values in control mice. In contrast, mice given a lethal dose of gamma-photon radiation developed a significant (p < 0.01) increase in only Gram-positive bacteria in their ilea, while the number of Gram-negative bacteria remained near values in control mice. Data correlated with bacteria that were isolated and identified from the livers of mice that were given comparable lethal doses (LD99/30) of mixed-field or gamma-photon radiation. In sublethally irradiated mice, fluctuation in the total number of bacteria was detected in their ilea during the first week following irradiation, after which the number approximated the value in control mice. This difference in the predominant facultative bacteria in ilea resulting from different qualities of radiation has important implications for the treatment of septicaemic-irradiated hosts.

Survival of irradiated mice treated with WR-151327, synthetic trehalose dicorynomycolate, or ofloxacin.

Spaceflight personnel need treatment options that would enhance survival from radiation and would not disrupt task performance. Doses of prophylactic or therapeutic agents known to induce significant short-term (30-day) survival with minimal behavioral (locomotor) changes were used for 180-day survival studies. In protection studies, groups of mice were treated with the phosphorothioate WR-151327 (200 mg/kg, 25% of the LD(10)) or the immunomodulator, synthetic trehalose dicorynomycolate (S-TDCM; 8 mg/kg), before lethal irradiation with reactor-generated fission neutrons and gamma-rays (n/gamma=1) or 60Co gamma-rays. In therapy studies, groups of mice received either S-TDCM, the antimicrobial ofloxacin, or S-TDCM plus ofloxacin after irradiation. For WR-151327 treated-mice, survival at 180 days for n/gamma=1 and gamma-irradiated mice was 90% and 92%, respectively; for S-TDCM (protection), 57% and 78%, respectively; for S-TDCM (therapy), 20% and 25%, respectively; for ofloxacin, 38% and 5%, respectively; for S-TDCM combined with ofloxacin, 30% and 30%, respectively; and for saline, 8% and 5%, respectively. Ofloxacin or combined ofloxacin and S-TDCM increased survival from the gram-negative bacterial sepsis that predominated in n/gamma=1 irradiated mice. The efficacies of the treatments depended on radiation quality, treatment agent and its mode of use, and microflora of the host.

Gene expression of hematoregulatory cytokines is elevated endogenously after sublethal gamma irradiation and is differentially enhanced by therapeutic administration of biologic response modifiers.

Prompt, cytokine-mediated restoration of hematopoiesis is a prerequisite for survival after irradiation. Therapy with biologic response modifiers (BRMs), such as LPS, 3D monophosphoryl lipid A (MPL), and synthetic trehalose dicorynomycolate (S-TDCM) presumably accelerates hematopoietic recovery after irradiation by enhancing expression of cytokines. However, the kinetics of the cytokine gene response to BRMs and/or irradiation are poorly defined. One hour after sublethal (7.0 Gy) 60Cobalt gamma irradiation, B6D2F1/J female mice received a single i.p. injection of LPS, MPL, S-TDCM, an extract from Serratia marcescens (Sm-BRM), or Tween 80 in saline (TS). Five hours later, a quantitative reverse transcription-PCR assay demonstrated marked splenic gene expression for IL-1 beta, IL-3, IL-6, and granulocyte-CSF (G-CSF). Enhanced gene expression for TNF-alpha, macrophage-CSF (M-CSF), and stem cell factor (SCF) was not detected. Injection of any BRM further enhanced cytokine gene expression and plasma levels of CSF activity within 24 h after irradiation and hastened bone marrow recovery. Mice injected with S-TDCM or Sm-BRM sustained expression of the IL-6 gene for at least 24 h after irradiation. Sm-BRM-treated mice exhibited greater gene expression for IL-1 beta, IL-3, TNF-alpha, and G-CSF at day 1 than any other BRM. When challenged with 2 LD50/30 of Klebsiella pneumoniae 4 days after irradiation, 100% of Sm-BRM-treated mice and 70% of S-TDCM-treated mice survived, whereas < or = 30% of mice treated with LPS, MPL, or TS survived. Thus, sublethal irradiation induces transient, splenic cytokine gene expression that can be differentially amplified and prolonged by BRMs. BRMs that sustained and/or enhanced irradiation-induced expression of specific cytokine genes improved survival after experimental infection.

Quinolone therapy in the prevention of endogenous and exogenous infection after irradiation.

The effect of oral therapy with 6 quinolones, lomefloxacin, ofloxacin, sparfloxacin, temafloxacin, CI-960, and CI-990 in the prevention of post-irradiation bacteraemia and mortality was tested in mice. Two models were used, the C3H/HeN mouse strain for endogenously acquired infection and the B6D2F1 mouse strain for studies of exogenously acquired Pseudomonas aeruginosa infection. Each therapy or water-fed control group included 40 mice, 20 for monitoring survival and 20 for obtaining liver cultures. In C3H/HeN mice, mortality in the groups that received each of the quinolones except CI-960 was significantly lower (P < 0.05) than in the water-treated mice. Survival was 54/60 (90%) with lomefloxacin 51/60 (85%) with ofloxacin, 50/60 (83%) with CI-990, 45/60 (75%) with sparfloxacin, 37/60 (62%) with temafloxacin, 9/60 (15%) for the control group, and 6/60 (10%) for CI-960. Enterobacteriaceae were isolated from 38 of 53 (72%) and Streptococcus spp. from 13 of 53 (25%) of the livers of control mice. The number of Enterobacteriaceae was lower in quinolone-treated mice. However, isolation of streptococci was similar to controls, except in those treated with sparfloxacin and CI-990. In B6D2F1 mice, mortality and isolation of P. aeruginosa in each of the quinolone group was significantly lower than for controls (P < 0.001). These data illustrate the efficacy of the quinolones in the therapy of exogenous infection, and the inability of those effective against anaerobic bacteria to prevent endogenous infection.

The treatment of irradiated mice with polymicrobial infection caused by Bacteroides fragilis and Escherichia coli.

The effects on the faecal flora and the efficacies of various antibiotic regimens administered as treatment for a mixed infection caused by Bacteroides fragilis and Escherichia coli in the irradiated host were investigated in a subcutaneous abscess model with C3H/HeN mice which had been exposed to 60Co. The regimens used included imipenem, ofloxacin, metronidazole and the combination of ofloxacin and metronidazole. The incidence of mortality associated with each regimen was as follows: 2 of 20 (10%) mice treated with ofloxacin; 16 of 20 (80%) given metronidazole (P < 0.05 compared with ofloxacin); 8 of 20 (40%) given imipenem (P < 0.05 compared with ofloxacin); 5 of 20 (25%) given the combination of ofloxacin and metronidazole (P = NS compared with ofloxacin); and 15 of 20 (75%) controls given a placebo (P < 0.05 compared with ofloxacin). Compared with the control group, the mean number of lactose-fermenting facultative anaerobes in the faeces of irradiated mice decreased significantly during treatment with either ofloxacin or ofloxacin combined with metronidazole; rose significantly from day 6 during treatment with metronidazole and was similar during treatment with imipenem. The numbers of strict anaerobes fell with all regimens (including the placebo) but, compared with the control group, were significantly higher in the ofloxacin and imipenem groups and significantly lower in the groups which received metronidazole (with or without ofloxacin). Imipenem and the combination of ofloxacin and metronidazole led to significant reductions in the numbers of cfu of both E. coli and B. fragilis in the abscesses compared with the placebo; ofloxacin alone caused a reduction in the number of cfu of E. coli only and metronidazole alone caused a reduction in the number of cfu of B. fragilis only. While the administration of metronidazole had a favourable effect on the B. fragilis component of the localized infection, there was a higher incidence of mortality with this agent, probably because it led to an increase in the number of Enterobacteriaceae in the faeces at the expense of a reduction in the number of strict anaerobes. Antimicrobial agents such as imipenem or the combination of a quinolone, such as ofloxacin, and metronidazole may be used successfully to treat localized infections in the irradiated host while avoiding potentially deleterious increases in the number of facultative anaerobes in the bowel.

Effect of antimicrobial therapy on the gastrointestinal bacterial flora, infection and mortality in mice exposed to different doses of irradiation.

The effect of antimicrobial therapy on gut flora, sepsis, and mortality was investigated in C3H/HeN female mice irradiated with 7.0, 8.0 or 8.5 Gy or 60Co. The antimicrobial agents tested were metronidazole, penicillin, imipenem, gentamicin and ofloxacin. In control mice, the greatest reduction of lactose fermenting organisms (1.7-2.8 logs) occurred on day 8 after irradiation and were related directly to radiation doses. After day 8, lactose fermenting organism levels increased and the increases were associated with mortality due to Enterobacteriaceae sepsis. Irradiation reduced the populations of strict anaerobic bacteria in control mice by 2-8 logs, and these remained at low levels. Treatment with either metronidazole or penicillin resulted in greater reductions of strict anaerobic bacteria than occurred in the controls and induced earlier and greater increases in lactose fermenting organisms and associated mortality. Therapies with either gentamicin or ofloxacin resulted in lesser reductions of strict anaerobic bacteria (1.1-2.2 logs) than occurred in controls, and caused greater decreases in lactose fermenting organisms and mortality. The changes in the bacterial flora and mortality following imipenem treatment were similar to controls. These data demonstrate that in animals exposed to irradiation, antimicrobial agents effective against strict anaerobic bacteria can be deleterious, but antimicrobial agents effective against lactose fermenting organisms may be beneficial.

Quinolone and glycopeptide therapy for infection in mouse following exposure to mixed-field neutron-gamma-photon radiation.

The effects of increased doses of mixed-field neutron-gamma-photon irradiation on bacterial translocation and subsequent sepsis, and the influence of antimicrobial therapy on these events, were studied in the C3H/HeN mouse. Animals were given 4.25, 4.50, 4.75, 5.00 and 5.25 Gy of mixed-field [n/(n+gamma) = 0.7] radiation. The mortality rate of mice and recovery of bacteria were directly related to the radiation dose. Enterobacteriaceae were mostly isolated from the livers of mice exposed to 5.00 and 5.25 Gy, and aerobic Gram-positive cocci were recovered from those exposed to 4.50 and 4.75 Gy. Oral therapy with L-ofloxacin reduced mortality of all groups of animals except those given 4.25 and 4.50 Gy. This reduction was associated with a decrease in the number of the recovered Enterobacteriaceae. However, the number of Gram-positive cocci was unaffected. Addition of i.m. glycopeptide therapy failed to prevent Gram-positive coccal infection, due to the development of glycopeptide-resistant Enterococcus faecalis. These data demonstrate a relationship between the doses of mixed-field radiation and the rates of infection due to Enterobacteriaceae. While L-ofloxacin therapy reduces the infection rate, prolongs survival and prevents mortality, the addition of a glycopeptide can enhance systemic infection by resistant bacteria in the irradiated host.

Development of infection with Streptococcus bovis and Aspergillus sp. in irradiated mice after glycopeptide therapy.

The use of ofloxacin and glycopeptides was evaluated for the treatment of infections arising in C3H/HeN female mice irradiated with 8.3 Gy from a 60Co source. The 21 day regimen began 72 h after irradiation when each of five sets of experimental animals received three antimicrobial therapy regimens and a saline-treated control group. With 40 mice in each group, 20 were used to monitor survival, 20 for the recovery of bacteria from the liver culture. Treatment groups were oral ofloxacin 20 mg/kg/day; oral or intramuscular vancomycin 50 mg/kg/day; oral teicoplanin 50 mg/kg/day; ofloxacin and vancomycin; ofloxacin and teicoplanin; or saline. Bacteria recovered from saline treated mice were Enterobacteriaceae and Streptococcus spp. By comparison, fewer Enterobacteriaceae were isolated from ofloxacin treated mice and fewer Streptococcus spp. in both vancomycin and teicoplanin treated mice. However, glycopeptide-treated mice developed infection with Aspergillus fumigatus and glycopeptide resistant Streptococcus bovis. Mortality rates within 60 days of irradiation were 100% in all treatment and control groups with the exception of ofloxacin which was 25%-35%. These data suggest that glycopeptide therapy increases rates of systemic infection with fungi and antibiotic resistant bacteria in irradiated mice.

Use of selective decontamination in the prevention of infection after accidental irradiation. A review.

Exposure to radiation induces a reduction in the number of gastrointestinal, anaerobic bacterial flora, and an increase in the number of Enterobacteriaceae that are associated with sepsis and mortality. Antimicrobials that suppress anaerobic flora have a deleterious effect on survival by promoting earlier enterobacterial sepsis. In contrast, in studies of animals and immunosuppressed patients, antimicrobials that inhibit gram-negative enteric bacteria and preserve the anaerobic flora have shown a beneficial effect by preventing bacterial translocation and fatal sepsis. The quinolone antimicrobials hold potential for therapy of endogenous and exogenous infection after irradiation.

Short and long courses of ofloxacin therapy of Klebsiella pneumoniae sepsis following irradiation.

Exposure to whole-body irradiation is associated with fatal gram-negative sepsis. The optimal length of therapy of such infection is not established. The effect of short and long courses of oral therapy with the quinolone ofloxacin for orally acquired Klebsiella pneumoniae infection was tested in B6D2F1 mice exposed to 8.0 Gy of bilateral radiation from 60Co. A dose of 10(8) organisms was given orally 4 days after irradiation, and therapy was started 1 day later. Cultures of the ileum 7 days after irradiation showed the recovery of K. pneumoniae in 7 of 10 untreated mice and in 3 of 20 treated with ofloxacin. However, 14 days after irradiation K. pneumoniae was isolated in 5 of 6 untreated mice, in 7 of 9 that received the short course of therapy, and in one of those that received the long course of therapy (P less than 0.05). At Day 7, K. pneumoniae was isolated from the livers of 6 of 10 untreated mice, and from none of those receiving ofloxacin (P less than 0.05). At 14 days, K. pneumoniae was isolated in 4 of 6 untreated animals, in 4 of 9 that received the short course of therapy, and in none of the mice that received the long course of therapy (P less than 0.05). Only 3 of 20 (15%) untreated mice survived for 30 days as compared to 11 of 20 (55%) mice treated for 7 days with ofloxacin and 18 of 20 (90%) mice treated for 21 days with ofloxacin (P less than 0.05). These survival data illustrate the efficacy of a 21-day course over a 7-day course of ofloxacin therapy for orally acquired K. pneumoniae infection in irradiated hosts.

Role of interleukin 6 (IL-6) in protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor.

Primary responsibility for the induction of various acute phase reactions has been ascribed to interleukin 1 (IL-1), tumor necrosis factor (TNF), or IL-6, suggesting that these cytokines may have many overlapping activities. Thus, it is difficult to identify the cytokine primarily responsible for a particular biologic effect, since IL-1 and TNF stimulate one another, and both IL-1 and TNF stimulate IL-6. In this work, the contribution of IL-6 in radioprotection, induction of adrenocorticotropic hormone (ACTH), and induction of hypoglycemia was assessed by blocking IL-6 activity. Administration of anti-IL-6 antibody to otherwise untreated mice greatly enhanced the incidence of radiation-induced mortality, indicating that like IL-1 and TNF, IL-6 also contributes to innate resistance to radiation. Anti-IL-6 antibody given to IL-1-treated or TNF-treated mice reduced survival from lethal irradiation, demonstrating that IL-6 is also an important mediator of both IL-1- and TNF-induced hemopoietic recovery. A similar IL-1/IL-6 interaction was observed in the case of ACTH induction. Anti-IL-6 antibody blocked the IL-1-induced increase in plasma ACTH, whereas recombinant IL-6 by itself did not induce such an increase. Anti-IL-6 antibody also mitigated TNF-induced hypoglycemia, but did not reverse IL-1-induced hypoglycemia. It is, therefore, likely that TNF and IL-1 differ in their mode of induction of hypoglycemia. Our results suggest that an interaction of IL-6 with IL-1 and TNF is a prerequisite for protection from radiation lethality, and its interaction with IL-1 for induction of ACTH.