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The value of polymixin B in endotoxaemia due to experimental obstructive jaundice and mesenteric ischaemia.

The role of polymixin B in endotoxaemia due to obstructive jaundice and mesenteric ischaemia has been examined. Rats made jaundiced by common bile duct ligation were challenged with intragastric endotoxin. Rats given polymixin B infusions had improved survival (11/15) compared with controls (4/14). Mesenteric ischaemia was induced in rats by clipping the mesenteric artery. Limulus assay revealed marked endotoxaemia in controls. Polymixin B infusions reduced the degree of endotoxaemia. Pre-treatment with non-absorbable intestinal antibiotics markedly reduced endotoxaemia. Polymixin B infusions gave no advantage of survival (3/10) compared with controls (2/10), but all animals pre-treated with intestinal antibiotics survived (12/12). The difference in results found between obstructive jaundice and mesenteric ischaemia may be due to different degrees of endotoxaemia. Polymixin B may have a place in the prophylaxis of endotoxaemia in clinical obstructive jaundice.

Animals↗

Inhibition of mitogen-induced human lymphocyte responsiveness by polymixin antibiotics.

Polymixin antibiotics, polymixin B and polymixin E (colistin) inhibited the mitogen-induced lymphoproliferative response of human lymphocytes. Inhibition of the lymphocyte response to PHA, PWM and Con A was evident at a low concentration of 1 U/ml of antibiotics. Lymphocytes in which the signals for proliferation had occurred were similarly prevented from proliferating. The effects were not due to cell death (toxicity). Since polymixin concentrations at which inhibition of lymphocyte proliferation was observed are employed in tissue culture medium and are also attained in plasma of patients, the results suggest that the use of the antibiotics in lymphocyte cultures limits lymphocyte responsiveness and that patients receiving polymixin antibiotics may experience a state of immunosuppression.

Colistin↗

Electron microscope observations on the effects of polymixin B sulfate on cell walls of Chlamydia psittaci.

The effects of polymixin B sulfate on cell walls of mature elementary body (EB) and of immature developmental reticulate body (RB) of Chlamydia psittaci were investigated. When purified EB were treated with polymixin (10(4) units per ml or more) at 37 C for 60 min, about 70% of EB was found to be covered with a number of projections. Further incubation did not increase the percentage affected. The infectivity after treatment as assayed by the inclusion counting technique was reduced by 70% of the original titer. These results suggest that EB with the projections are no longer infective. The projections had obscure outlines and were 20 to 40 nm in diameter when seen in thin sections. In the negatively stained preparations, the projections were composed of aggregations of fine particles 4 to 5 nm in diameter. Treatment with sodium dodecyl sulfate at the same concentration used for cell wall isolation removed the projections completely, and the cell walls were converted to rather ragged forms apparently composed of outside and inside layers. When RB cell walls prepared from infected cells at 18 hr after infection were treated with polymixin at the same concentration, the projections having the same morphology with those seen on treated EB cell walls were observed only on the inside surface of cell wall.

Animals↗

Mechanisms of failure to decontaminate the gut with polymixin E, gentamicin and amphotericin B in patients in intensive care.

The objective of the present work was to assess the possible mechanisms of the poor efficiency of selective decontamination of the digestive tract (SDD) in medical and surgical intensive care unit (ICU) patients. Sixty-four consecutive mechanically ventilated patients received gut decontamination with polymixin E, gentamicin and amphotericin B via a nasogastric tube and were assessed for oropharyngeal, gastric and fecal colonization and for the presence of each antibiotic in the stomach and feces. A decrease in fecal colonization with Escherichia coli was observed over 20 days but not with other gram-negative bacteria or gram-positive cocci. Fifteen and 26% of the fecal colonizing gram-negative bacteria were resistant to polymixin E and gentamicin, respectively, at admission. These proportions increased to up to 50% after 16 days of treatment. Although 50% of staphylococci were initially sensitive to gentamicin, all strains were resistant to this drug after four days of SDD. Both antibiotics were found in concentrations of less than 20 micrograms/g in 11 of 38 stools. Of these 38 stools, nine were not contaminated, 20 were colonized with resistant bacteria and 16 with strains sensitive to one antibiotic present in the stool. Therefore, the poor efficiency of gut decontamination observed was probably due to the great proportion of resistant strains on admission of the patients, to the selection of such resistant strains with SDD, to poor intestinal transit of the antibiotics, and to inactivation of the drugs by the feces. These results support stringent monitoring of fecal colonization in patients undergoing SDD in order to detect the fecal carriage of gram-positive and multiresistant gram-negative bacteria.

Adult↗

Accumulation of guanosine tetraphosphate induced by polymixin and gramicidin in Escherichia coli.

The effects of two polypeptide antibiotics, polymixin B and gramicidin S, on the intracellular pool size and turnover of guanosine tetraphosphate (ppGpp) were analyzed in stringent (relA+) and relaxed (relA) strains of Escherichia coli. When either one of these two drugs was added to stringent bacteria cultures at a final concentration that blocked protein and RNA synthesis, ppGpp was found to accumulate. Under similar conditions of inhibition of macromolecular synthesis, ppGpp also appeared to accumulate in relaxed bacteria. Moreover, in either type of strain, no significant accumulation of guanosine pentaphosphate (pppGpp) could be detected upon drug treatment. It was, therefore, concluded that polymixin and gramicidin elicit ppGpp accumulation through a mechanism independent of the relA gene product and, consequently, quite distinct from the stringent control system triggered by amino acid starvation. Further experiments performed by using tetracycline as an inhibitor of ppGpp synthesis, showed that the increase in the level of this nucleotide induced by drug action was due, in fact, to a strong restriction of its degradation rate.

Adenosine Triphosphate↗

Anandamide absorption by direct hemoperfusion with polymixin B-immobilized fiber improves the prognosis and organ failure assessment score in patients with sepsis.

PURPOSE: Direct hemoperfusion (DHP) with polymixin B-immobilized fiber (PMX) has been reported to be effective for patients with septic shock. The aim of this study was to clarify the mechanism of PMX-DHP effect on septic shock. METHODS: The following parameters were measured in septic shock patients who were treated with PMX-DHP: survival rate, sepsis-related organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE-II) score, and plasma concentrations of cannabinoids [anandamide (ANA) and 2-arachidonyl glyceride (2-AG)], cytokines [interleukin (IL)-6, IL-8, IL-10], transforming growth factor beta (TGF-beta), and calcitonin gene-related peptide (CGRP)]. The primary end point was mortality from all causes at day 28 after intensive care unit (ICU) admission or discharge. RESULTS: The survival rate of all patients at 28 days after ICU admission was 37.5% (9/24). The survival group showed significantly lower SOFA and APACHE-II scores than the nonsurvival group after PMX-DHP treatment (P = 0.008 and 0.028, respectively). The improved SOFA score group showed a better survival rate than the nonimproved SOFA score group (71.4% versus 23.5%, P = 0.028). Plasma ANA level significantly decreased after PMX-DHP treatment both in the improved SOFA score group and in the survival group. The level of 2-AG, however, showed no significant change in either group. CONCLUSION: ANA, an intrinsic cannabinoid that induces hypotension in septic shock, is inferred to be the main mechanism of the PMX-DHP effect. Removal of ANA by PMX-DHP could be key to successful septic shock treatment.

APACHE↗

Simultaneous identification and quantitative determination of neomycin sulfate, polymixin B sulfate, zinc bacytracin and methyl and propyl hydroxybenzoates in ophthalmic ointment by TLC.

A thin layer chromatographic-densitometric method for identification and quantitation of neomycin sulfate, polymixin B sulfate, zinc bacytracin and auxiliary substances (methyl and propyl hydroxybenzoates) in ophthalmic ointment was developed. To separate these constituents the silica gel coated TLC plates and two mobile phases were used. The suitable mobile phases were: methanol-n-butanol-ammonia 25%-chloroform (14:4:9:12, v/v/v/v) for determination of antibiotics and n-pentane-glacial acetic acid (66:9, v/v) for methyl and propyl hydroxybenzoates. The antibiotic chromatograms were detected by using ninhydrin ethanol solution, while densitometric measurements were made at lambda = 550 nm. Hydroxybenzoates were identified by UV measurements at lambda = 260 nm. The constituents under consideration were well separated at sufficient detection level. The recovery for all constituents ranged from 98.08% to 104.95%.

Anti-Bacterial Agents↗

Prophylactic intravenous immune globulin and polymixin B decrease the incidence of septic episodes and hospital length of stay in severely burned children.

After burn shock resuscitation, serum gamma globulin levels decrease well below normal before slowly recovering over the course of 1 to 2 months. During this period, patients are vulnerable to further insult as a result of this immunocompromise. We hypothesized that intravenous immune globulin and subtherapeutic polymixin B (IVIG-B) could decrease the incidence and/or severity of sepsis after major thermal injury. A retrospective chart review from 1997 through 2003 at two hospitals compared patients who received IVIG-B (Hospital A) with those who did not (Hospital B). Patients with burns 40% or greater TBSA were included, whereas patients with nonsurvivable injuries were excluded from data analysis. A total of 152 patients were included in the study. One hundred two patients received IVIG-B, and 50 did not. Total burn size was 63.4% TBSA at Hospital A and 63.1% TBSA at Hospital B, with full-thickness burns of 54.4 and 61.7% TBSA, respectively (P < .05). Patients treated at Hospital A had a 51.9% incidence of inhalation injury compared with 28% of the patients at Hospital B (P < .05). There was an average of 1.2 and 1.9 septic episodes for patients treated at Hospital A and Hospital B, respectively (P < .05). Length of hospital stay was 77.1 days at Hospital A compared with 103.8 days at Hospital B (P < .05). Mortality was 17.6% and 18% at Hospitals A and B, respectively, and was not significantly different. Our data suggest that prophylactic IVIG-B is associated with a reduction in the incidence of septic episodes and decreased hospital length of stay following major thermal injury.

Anti-Bacterial Agents↗

[Effects of polymixin B on I-kappaB kinase mRNA expression in lipopolysaccharide- induced pulmonary alveolar macrophages].

OBJECTIVE: To investigate effects of polymixin B (PMB) on I-kappaB kinase(IKK-beta), inhibitor protein(IkappaB-alpha) and nuclear factor-kappa B(NF-kappaB) in lipopolysaccharide(LPS)-induced pulmonary alveolar macrophages (PAM), and explore the anti-inflammatory mechanism of PMB. METHODS: PAM from rats collected by bronchoalveolar lavage was cultured and divided into three groups. In the control group, PAM was not stimulated with LPS and not treated with PMB. In the LPS stimulated group, PAM was stimulated with LPS. In the PMB treated group, PAM was pretreated with PMB half an hour prior to LPS stimulation. The expression of IKK-beta mRNA, level of IkappaB-alpha and the activity of NF-kappaB in PAM were measured by in situ hybridization(ISH), enzyme linked immunoadsorbent assay (ELISA) and electrophoretic mobility shift assay(EMSA), respectively. RESULTS: In the LPS stimulated group, the expression of IKK-beta mRNA (0.147+/-0.015) and activity of NF-kappaB (0.828+/-0.019) in PAM significantly increased, whereas levels of IkappaB-alpha (0.228+/-0.021) decreased (all P<0.01) in PMB treated groups. The expression of IKK-beta mRNA (0.112+/-0.022) and activity of NF-kappaB (0.358+/-0.011) were down-regulated while level of IkappaB-alpha (0.477+/-0.016) was up-regulated(P<0.01). CONCLUSION: LPS might induce expression of IKK-beta mRNA, degradation of IkappaB-alpha and activation of NF-kappaB PMB could inhibit the expression of IKK-beta, degradation of IkappaB-alpha and activation of NF-kappaB, showing marked anti-inflammatory property.

Animals↗

Antimycobacterial spectrum of colistin (polymixin E).

Minimal inhibitory concentrations and minimal bactericidal concentrations of colistin (polymyxin E) were determined for the type strains of fifteen mycobacterial species. Colistin was found to be active against pathogenic species Mycobacterium xenopi, M. intracellulare, M. tuberculosis, M. fortuitum and also against the rapidly growing, non-pathogenic species M. phlei and M. smegmatis. The discriminatory potential of susceptibility to colistin as a test was investigated on 25 strains of the M. fortuitum/M. chelonei complex, and also on 11 strains of the M. avium/M. intracellulare complex. The experimental data indicated the potential of colistin susceptibility testing for discriminating M. fortuitum from M. chelonei.

Colistin↗