Ceftazidime alone and in combination in patients with cystic fibrosis: lack of efficacy in treatment of severe respiratory infections caused by Pseudomonas cepacia

Gold, Ronald; Jin, E. H.; Levison, Henry; Isles, Alan; Fleming, Peter D.

doi:10.1093/jac/12.suppl_a.331

Cited by 71 publications

(43 citation statements)

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“…Treatment of these infections is difficult as Bcc bacteria are inherently resistant to most clinically relevant antimicrobial agents (Aaron et al, 2000;Burns et al, 1996;Gold et al, 1983), including antimicrobial peptides (APs) (Loutet et al, 2006;Turner et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Contributions of two UDP-glucose dehydrogenases to viability and polymyxin B resistance of Burkholderia cenocepacia

et al. 2009

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Burkholderia cenocepacia is highly resistant to antimicrobial peptides and we hypothesized that the conversion of UDP-glucose to UDP-glucuronic acid, a reaction catalysed by the enzyme UDPglucose dehydrogenase (Ugd) would be important for this resistance. The genome of B. cenocepacia contains three predicted ugd genes: ugd BCAL2946 , ugd BCAM0855 and ugd BCAM2034 , all of which were individually inactivated. Only inactivation of ugd BCAL2946 resulted in increased sensitivity to polymyxin B and this sensitivity could be overcome when either ugd BCAL2946 or ugd BCAM0855 but not ugd BCAM2034 was expressed from plasmids. The growth of a conditional ugd BCAL2946 mutant, created in the Dugd BCAM0855 background, was significantly impaired under non-permissive conditions. Growth could be rescued by either ugd BCAL2946 or ugd BCAM0855 expressed in trans, but not by ugd BCAM2034 . Biochemical analysis of the purified, recombinant forms of Ugd BCAL2946 and Ugd BCAM0855 revealed that they are soluble homodimers with similar in vitro Ugd activity and comparable kinetic constants for their substrates UDP-glucose and NAD + . Purified Ugd BCAM2034 showed no in vitro Ugd activity. Real-time PCR analysis showed that the expression of ugd BCAL2946 was 5.4-and 135-fold greater than that of ugd BCAM0855 and ugd BCAM2034 , respectively. Together, these data indicate that the combined activity of Ugd BCAL2946 and Ugd BCAM0855 is essential for the survival of B. cenocepacia but only the most highly expressed ugd gene, ugd BCAL2946 , is required for polymyxin B resistance.

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Section: Introductionmentioning

confidence: 99%

Contributions of two UDP-glucose dehydrogenases to viability and polymyxin B resistance of Burkholderia cenocepacia

et al. 2009

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“…In a noncomparative study, 14 patients colonized with P. cepacia received ceftazidime; only six demonstrated clinical improvement (7). Ceftazidime treatment did not significantly reduce sputum concentrations of the organism.…”

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confidence: 94%

Decreased Baseline β-Lactamase Production and Inducibility associated with Increased Piperacillin Susceptibility of Pseudomonas cepacia Isolated from Children with Cystic Fibrosis

1986

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ABSTRACT. The incidence of pulmonary infections in children with cystic fibrosis caused by Pseudomonas cepacia, an organism which may possess an inducible 8-lactamase, has increased since 1978. Seven of 13 sputum isolates of P. cepacia from children with cystic fibrosis were classified as inducible by quantitative enzyme production following preincubation with 100, 200, or 400 pg/ml of cefoxitin. The recovery of inducible strains tended to be associated with recent ceftazidime therapy. Susceptibility to aztreonam, ceftazidime, and piperacillin alone or combined with the b-lactamase inhibitors. YTR 830 or sulbactam, and isoelectric focusing for /3-lactamase were performed. Inducible isolates produced significantly more /3-lactamase than noninducible strains with or wihtout the addition of cefoxitin. Noninducible isolates were more susceptible than inducible isolates to 8 pg/ml of piperacillin, a difference that was eliminated with the addition of either P-lactamase inhibitor. Twelve of 13 strains produced a Plactamase band in the pH range of 7.9-8.1; no differences in satellite patterns were noted between the two groups of organisms. Increased production of /3-lactamase in the absence of an inducer may account for piperacillin resistance in P. cepacia in children with cystic fibrosis. creased since 1978 and is now recovered from 20% of patients in some centers (3, 4).Sputum isolates of P. cepacia from children with cystic fibrosis are resistant to most P-lactam agents in vitro. In an in vitro study comparing the susceptibilities of 62 consecutive sputum isolates, concentrations of 64 pg/ml of aztreonam and piperacillin were required to inhibit 79 and 87.1 % of the bacterial population, respectively; 90% of the isolates were inhibited by 8 pg/ml of ceftazidime (5). In vitro, ceftazidime has proven more active against P. cepacia than piperacillin, aztreonam, HR-810, or BMY-28 142 (5, 6). Although the mechanism(s) of resistance of P. cepacia to Plactam agents is unclear, at least three, inducible, isoelectrically distinct p-lactamases have been identified (9-1 1). Hirai et al. (10) noted that the enzyme produced by Pseudomonas cepacia GN I 1 164 hydrolyzed cefuroxime, cefotaxime, and cefamandole. The purpose of this study was to ascertain the role played by inducible enzyme production in resistance to piperacillin, aztreonam, and ceftazidime by sputum isolates of P. cepacia from patients with cystic fibrosis. MATERIALS AND METHODSTest strains. Thirteen isolates of P. cepacia recovered from the sputum of 12 children admitted to Rainbow Babies and Children's Hospital with pulmonary exacerbations of cystic fibrosis were studied. With one exception, all of the test strains were recovered between April and December 1984. Seven of the 13 test strains were recovered during or immediately after ceftazidime therapy; two isolates were recovered following ciprofloxacin therapy, one isolate after aztreonam therapy, and three isolates were obtained prior to parenteral antibiotic therapy. Pseudomonas aeruginosa ATCC 27853 was use...

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“…These adverse outcomes are commonly due to cepacia syndrome, a frequently fatal, necrotizing pneumonia characterized by sepsis (17,30). Burkholderia species adapt to a wide range of environmental conditions and are intrinsically resistant to most clinically relevant antibiotics, making it very difficult to treat Bcc infections (1,5,8,15,45). Antibiotic resistance in Burkholderia has been attributed to the presence of multiple efflux pumps, antibiotic-modifying enzymes, and the structure of lipopolysaccharide (LPS) on the outer membrane, but other factors remain to be identified (18,20,37,48).…”

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confidence: 99%

Hopanoid Production Is Required for Low-pH Tolerance, Antimicrobial Resistance, and Motility in Burkholderia cenocepacia

2011

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Hopanoids are pentacyclic triterpenoids that are thought to be bacterial surrogates for eukaryotic sterols, such as cholesterol, acting to stabilize membranes and to regulate their fluidity and permeability. To date, very few studies have evaluated the role of hopanoids in bacterial physiology. The synthesis of hopanoids depends on the enzyme squalene-hopene cyclase (Shc), which converts the linear squalene into the basic hopene structure. Deletion of the 2 genes encoding Shc enzymes in Burkholderia cenocepacia K56-2, BCAM2831 and BCAS0167, resulted in a strain that was unable to produce hopanoids, as demonstrated by gas chromatography and mass spectrometry. Complementation of the ⌬shc mutant with only BCAM2831 was sufficient to restore hopanoid production to wild-type levels, while introducing a copy of BCAS0167 alone into the ⌬shc mutant produced only very small amounts of the hopanoid peak. The ⌬shc mutant grew as well as the wild type in medium buffered to pH 7 and demonstrated no defect in its ability to survive and replicate within macrophages, despite transmission electron microscopy (TEM) revealing defects in the organization of the cell envelope. The ⌬shc mutant displayed increased sensitivity to low pH, detergent, and various antibiotics, including polymyxin B and erythromycin. Loss of hopanoid production also resulted in severe defects in both swimming and swarming motility. This suggests that hopanoid production plays an important role in the physiology of B. cenocepacia.

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Ceftazidime alone and in combination in patients with cystic fibrosis: lack of efficacy in treatment of severe respiratory infections caused by Pseudomonas cepacia

Cited by 71 publications

References 0 publications

Contributions of two UDP-glucose dehydrogenases to viability and polymyxin B resistance of Burkholderia cenocepacia

Contributions of two UDP-glucose dehydrogenases to viability and polymyxin B resistance of Burkholderia cenocepacia

Decreased Baseline β-Lactamase Production and Inducibility associated with Increased Piperacillin Susceptibility of Pseudomonas cepacia Isolated from Children with Cystic Fibrosis

Hopanoid Production Is Required for Low-pH Tolerance, Antimicrobial Resistance, and Motility in Burkholderia cenocepacia

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