Biomedical subjects
M Vaara
Publications and source records attributed to M Vaara.
Lipid A: target for antibacterial drugs.
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Methanol extracts LPS from deep rough bacteria.
Several rough strains of Escherichia coli, Salmonella enterica and Proteus mirabilis were cultivated in the presence of (14C)acetate, which incorporated into their phospholipids and lipopolysaccharide. Phospholipids were removed from the cells with ethanol extraction. However, as shown by thin layer chromatography, methanol additionally extracted remarkable quantities of lipopolysaccharide from deep rough strains, but not from bacteria containing complete or nearly complete core.
Increased resistance among Staphylococcus epidermidis isolates in a large teaching hospital over a 12-year period.
The prevalence of drug resistance among clinically significant blood isolates of Staphylococcus epidermidis (n = 464) and consumption of antibiotics at a tertiary care teaching hospital (Meilahti Hospital, Helsinki) were analysed for the period 1983-1994. Resistance to methicillin increased from 28 to 77%. Simultaneously, usage of third-generation cephalosporins increased nearly sevenfold (from 8.6 kg/ to 56.4 kg/year). A significant correlation was found between percentages of methicillin resistance and usage of penicillinase-stable beta-lactam agents, including cloxacillin, imipenem, and first-, second-, and third-generation cephalosporins (r = 0.737, p < 0.0062). The increase in ciprofloxacin resistance occurred soon after the introduction of ciprofloxacin. Moreover, there was a remarkable increase in resistance to fusidic acid (from 10 to 40%) and rifampin (from 0 to 23%) despite the low usage of these agents. Overall, the rate of multiply resistant isolates roughly tripled (from 20 to 71%) and, by 1994, the frequency of isolates susceptible to vancomycin only was as high as 11%, which remarkably limits options for therapy.
Overgrowth of Enterococcus faecium in the feces of patients with hematologic malignancies.
The objective of this study was to characterize the overgrowth and susceptibility of Enterococcus faecium, compared with that of other enterococci, in the feces of patients with hematologic malignancy. During a 52-week period, surveillance samples of feces were cultured weekly. Three hundred thirty-three samples were obtained from 92 patients. E. faecium outnumbered other enterococci in 170 (44%) of the samples, while the opposite was true in 119 (31%) of the samples. Fecal overgrowth of E. faecium (> or = 9.0 log10 cfu/g) was found in 62 samples (16%), while overgrowth of other enterococci was documented in 20 samples (5%) (P < .001). Treatment with third-generation cephalosporins preceded the overgrowth of E. faecium in 93% of the patients. Resistance of E. faecium isolates to ampicillin, high-level gentamicin, and vancomycin was detected in 41%, 4%, and 2% of the patients, respectively. There were 6 patients with enterococcal bacteremia (due to E. faecium in 5 and Enterococcus faecalis in 1) during the study period. The high prevalence of resistance to ampicillin and imipenem rendered few (if any) intravenous antibiotics able to prevent fecal overgrowth of E. faecium.
Group of peptides that act synergistically with hydrophobic antibiotics against gram-negative enteric bacteria.
A synthetic peptide, KFFKFFKFFK [corrected], consisting of cationic lysine residues and hydrophobic phenylalanine residues was found to sensitize gram-negative bacteria to hydrophobic and amphipathic antibiotics. At a concentration of 3 micrograms/ml, it decreased the MIC of rifampin for smooth, encapsulated Escherichia coli by a factor of 300. Other susceptible bacterial species included Enterobacter cloacae, Klebsiella pneumoniae, and Salmonella typhimurium, but Pseudomonas aeruginosa was resistant. Similar results were obtained with another synthetic peptide, IKFLKFLKFLK [corrected]. The fractional inhibitory concentration indices for the synergism of these peptides with rifampin, erythromycin, fusidic acid, and novobiocin were very close to those determined for the previously characterized potent outer-membrane-disorganizing agents polymyxin B nonapeptide and deacylpolymyxin B. KFFKFFKFFK [corrected] had direct activity against the gram-positive organism Micrococcus strain ML36, was strongly hemolytic, and was as active on polymyxin-resistant E. coli mutants as on their parent. These three attributes made KFFKFFKFFK [corrected] different from polymyxin derivatives and similar to cationic detergents, such as cetylpyridinium chloride. However, whereas the MIC of cetylpyridinium chloride for E. coli is low (0.5 to 4 micrograms/ml), that of KFFKFFKFFK [corrected] is much higher (30 to 100 micrograms/ml). Other groups of synthetic peptides studied included polymyxin-like peptides with an intrachain disulfide bridge. Their synergism with antibiotics was less marked. Still other peptides, including KEKEKEKEKE and KKKKKKFLFL, lacked any synergism with the probe antibiotics.
[Yersinia Pseudotuberculosis, a rare cause of septicemia].
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Comparison of the phenotypes of the lpxA and lpxD mutants of Escherichia coli.
We compared the phenotype of two thermosensitive Escherichia coli mutants defective in lipid A biosynthesis, i.e. SM101 (lpxA) and CDH23-213 (lpxD). More than 40% of the periplasmic 27-kDa marker enzyme beta-lactamase was released from SM101 at 28 degrees C. At this temperature, the mutant still grew with a generation time (67 min), not much longer than that of the parent control strain (57 min). CDH23-213 released beta-lactamase only at higher temperatures. SM101 and CDH23-213 were both unable to grow in hypo-osmotic conditions. Derivatives of SM101 and CDH23-213 with mdoA::Tn10 had identical phenotypes (including thermosensitivity and defective outer membrane permeability barrier to hydrophobic probes) to those of SM101 and CDH23-213, indicating that the potential loss of membrane-derived oligosaccharides (MDO) did not explain these phenotype properties. A method for the estimation of lipid A synthesis rate was developed.
Plasma endotoxin and cytokine levels in neutropenic and non-neutropenic bacteremic patients.
Plasma endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 1 receptor antagonist (IL-1ra), and interleukin 6 (IL-6) concentrations in 69 bacteremic patients were compared with those in 54 nonbacteremic patients suffering from suspected bacterial infections. Only three (11%) of the 27 patients with gram-negative bacteremia showed detectable levels of endotoxin. TNF-alpha was detected in 6% of the bacteremic patients and in none of the nonbacteremic patients. Median IL-6 levels were significantly higher in bacteremic than in nonbacteremic patients (55 vs. 0 pg/ml, p = 0.0008). IL-6 concentrations were similar in neutropenic and non-neutropenic bacteremic patients (median 55 vs. 74 pg/ml). In contrast, neutropenic bacteremic patients had significantly lower concentrations of IL-1ra than non-neutropenic bacteremic patients (250 vs. 1,950 pg/ml, p < 0.0001). Patients with fatal bacteremia had significantly higher concentrations of IL-6 and IL-1ra than the survivors (median, 450 vs. 40, p = 0.012 and 7,600 vs. 420 pg/ml, p = 0.0075, respectively). Determinations of endotoxin or TNF-alpha in patients with suspected bacteremia failed to offer clinically relevant data on the prognosis of these patients. IL-6 levels correlated with both the presence of bacteremia and the risk of death. Granulocytopenic patients with bacteremia had lower levels of circulating IL-1ra than patients with normal granulocyte counts, and these levels correlated with poor outcome.
Bacteremia caused by Brevibacterium species in an immunocompromised patient.
A 46-year-old woman suffering from non-Hodgkin's lymphoma was admitted to the hospital because of high fever. Multiple blood cultures revealed an unusual finding, a Brevibacterium species, which was reisolated 16 days later from the tip of her long-term central venous catheter. This case indicates that Brevibacterium species isolated from normally sterile sites should be considered as a potential pathogen, especially in immunocompromised patients.
Report of four cases of Yersinia pseudotuberculosis septicemia and a literature review.
Yersinia pseudotuberculosis is a rare cause of disease in humans, the most common manifestation being mesenteric lymphadenitis accompanied by abdominal pain and fever. A septicemic form of Yersinia pseudotuberculosis infection has been reported only rarely. It is usually seen in patients with underlying disorders such as diabetes, hepatic cirrhosis or iron overload. Fifty-four cases of septicemic infection were found in the literature. The earlier published cases are reviewed, and four cases occurring in Finland during the period February to June 1992 are reported.
Capnocytophaga canimorsus septicemia: fifth report of a cat-associated infection and five other cases.
Capnocytophaga canimorsus is a fastidious, slow-growing, gram-negative, rod-shaped bacterium that belongs to the normal oral flora of dogs and cats. Human septicemic infections are associated with a high mortality; most cases occur in immunocompromised patients with a history of dog bite. The fifth case of cat-associated septicemia caused by Capnocytophaga canimorsus is described. The six case reports presented here point out the characteristics reported previously: (a) cats are a source of human infection; (b) alcohol abuse is an important risk factor for the development of septicemic Capnocytophaga canimorsus infection; (c) septicemic infection often manifests with disseminated intravascular consumption coagulopathy or purpura; and (d) some cases of septicemia in humans result from pets that lick skin ulcers.
Persistence of a multiresistant clone of Staphylococcus epidermidis in a neonatal intensive-care unit for a four-year period.
A cluster of cases of Staphylococcus epidermidis bacteremia in a neonatal intensive-care unit (NICU) during 1991 raised the question of whether these infections were caused by a single strain. Sixty-seven isolates of S. epidermidis from blood cultures of 56 neonates treated in the NICU between 1986 and 1992 and 54 control strains from other patients with bacteremia were characterized by three typing methods: antibiogram, plasmid profile, and ribotype. Plasmid profiles and ribotype patterns indicated that 11 (16%) of the 67 episodes of S. epidermidis bacteremia in the NICU were caused by a single strain. Although this epidemic strain did not account entirely for the increase in the incidence of bacteremia in the NICU, it did persist for 4 years during the study period. Other clones responsible for smaller outbreaks were also found. These results suggest that S. epidermidis cross-infections are very common in the NICU setting.
Neonatal Candida parapsilosis outbreak with a high case fatality rate.
A Candida parapsilosis outbreak of 58 cases in a neonatal intensive care unit lasted for 55 months. Patients infected by or colonized with C. parapsilosis were mainly very low birth weight infants (birth weight < 1500 g). Their mean birth weight was 817 g and their mean gestational age was 28 weeks. Statistical analysis including logistic regression confirmed that prematurity was the main risk factor. The analysis also suggested that C. parapsilosis infection (or colonization) was associated with a poor prognosis. In infants with gestational age < 29 weeks the risk for death in C. parapsilosis-infected patients was 16-fold greater than in those with no C. parapsilosis infection. The case fatality rate of C. parapsilosis patients was higher than that of the controls (9 of 23 vs. 1 of 40; P < 0.0001). The outbreak was most likely a result of cross-infection because C. parapsilosis could be isolated only from the patients and from the hands of four nurses immediately after they had cared for a colonized patient. Cessation of the outbreak was temporally associated with long term parenteral fluconazole (6 mg/kg/day) prophylaxis.
Lipopolysaccharides of polymyxin B-resistant mutants of Escherichia coli are extensively substituted by 2-aminoethyl pyrophosphate and contain aminoarabinose in lipid A.
Lipopolysaccharides (LPS) of two polymyxin-resistant (pmr) mutants and the corresponding parent strain of Escherichia coli were chemically analysed for composition and subjected to 31P-NMR (nuclear magnetic resonance) for assessment of phosphate substitution. Whereas the saccharide portions, fatty acids, and phosphate contents were similar in wild-type and pmr LPS, the latter contained two- to threefold higher amounts of 2-aminoethanol. The pmr LPS also contained 4-amino-4-deoxy-L-arabinopyranose (L-Arap4N), which is normally not a component of E. coli LPS. This aminopentose has been assigned to be linked to the 4'-phosphate of lipid A. Comparative 31P-NMR analysis of the de-O-acylated LPS of the wild-type and pmr strains revealed that phosphate groups of the pmr LPS were mainly (71-79%) diphosphate diesters, which accounted for only 20% in the wild-type LPS. Diphosphate monoesters were virtually nonexistent in the pmr LPS, whereas they accounted for 42% of all phosphates in wild-type LPS. In the lipid A of the pmr strains, the 4'-phosphate was to a significant degree (35%) substituted by L-Arap4N, whereas in the wild-type LPS the L-ArapN was absent. In the pmr lipid A, 2-aminoethanol was completely substituting the glycosidic pyrophosphate but not the glycosidic monophosphate, forming a diphosphate diester linkage at this position in 40% of lipid A molecules. In the wild-type LPS the glycosidic position of lipid A carried mostly unsubstituted monophosphate and pyrophosphate. Thus the polymyxin resistance was shown to be associated, along with the esterification of the lipid A 4'-monophosphate by aminoarabinose, with extensive esterification of diphosphates in LPS by 2-aminoethanol.
Low levels of cytokines and endotoxin in a fatal case of myocardial depression and septic shock due to Yersinia pseudotuberculosis.
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Increased substitution of phosphate groups in lipopolysaccharides and lipid A of polymyxin-resistant mutants of Salmonella typhimurium and Escherichia coli.
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Chemical structure of the lipid A component of lipopolysaccharides of the genus Pectinatus.
The chemical structure of the lipid A components of smooth-type lipopolysaccharides isolated from the type strains of strictly anaerobic beer-spoilage bacteria Pectinatus cerevisiiphilus and Pectinatus frisingensis were analyzed. The hydrophilic backbone of lipid A was shown, by controlled degradation of lipopolysaccharide combined with chemical assays and 31P-NMR spectroscopy, to consist of the common beta 1-6-linked disaccharide of pyranosidic 2-deoxy-glucosamine (GlcN), phosphorylated at the glycosidic position and at position 4'. In de-O-acylated lipopolysaccharide, the latter phosphate was shown to be quantitatively substituted with 4-amino-4-deoxyarabinose, whereas the glycosidically linked phosphate was present as a monoester. Laser-desorption mass spectrometry of free dephosphorylated lipid A revealed that the distal (non-reducing) GlcN was substituted at positions 2' and 3' with (R)-3-(undecanoyloxy)tridecanoic acid, whereas the reducing GlcN carried two unsubstituted (R)-3-hydroxytetradecanoic acids at positions 2 and 3. The lipid A of both Pectinatus species were thus of the asymmetric hexaacyl type. The linkage of lipid A to polysaccharide in the lipopolysaccharide was relatively resistant to acid-catalyzed hydrolysis, enabling the preparation of a dephosphorylated and deacylated saccharide backbone. Methylation analysis of the backbone revealed that position 6' of the distal GlcN of lipid A was the attachment site of the polysaccharide. Despite the quantitative substitution of the lipid A 4'-phosphate by 4-amino-4-deoxyarabinose, which theoretically should render the bacteria resistant to polymyxin, P. cerevisiiphilus was shown to be susceptible to this antibiotic. P. cerevisiiphilus was, however, also susceptibile to vancomycin and bacitracin, indicating that the outer membrane of this bacterium does not act as an effective permeability barrier.