Development of resistance in Pseudomonas aeruginosa obtained from patients with cystic fibrosis at different times

Spencker, F.B.; Staber, L.; Lietz, T.; Schille, R.; Rodloff, A.C.

doi:10.1046/j.1469-0691.2003.00534.x-i2

Cited by 4 publications

(4 citation statements)

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“…We calculated the PTA expectation value based on published MIC distributions. These values comprised susceptibility data for Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae from the 2002 MYSTIC program in North America (35) and in South America (34), Pseudomonas aeruginosa data from the Hartford Hospital, Connecticut (36), and data for nonmucoid and mucoid Pseudomonas aeruginosa isolates from CF patients in Freiburg, Germany (62), and Leipzig, Germany (65).…”

Section: Vol 51 2007 Population Pkpd In Cystic Fibrosis Patients 2499mentioning

confidence: 99%

Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta

Duffull

Kinzig‐Schippers

et al. 2007

Antimicrob Agents Chemother

109

102

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Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ؎ 7.8 kg) and 26 healthy volunteers (WT, 71.1 ؎ 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) betweensubject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (>90%) probability-of-target attainment (PTA) for MICs of <12 mg/liter in CF patients and <16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of <16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.

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Section: Vol 51 2007 Population Pkpd In Cystic Fibrosis Patients 2499mentioning

confidence: 99%

Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta

Duffull

Kinzig‐Schippers

et al. 2007

Antimicrob Agents Chemother

109

102

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“…Unfortunately, the pattern of quiescence followed by exacerbation results in slowly declining pulmonary function. In addition to this loss of pulmonary function, the mucoid strains, already refractory to immune clearance, become increasingly drug resistant [7].…”

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confidence: 99%

Is there value in susceptibility testing ofPseudomonas aeruginosacausing chronic infection in patients with cystic fibrosis?

Gilligan

2006

Expert Review of Anti-infective Therapy

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“…aeruginosa is known for its intrinsic and acquired resistance against a wide range of antimicrobial agents, which has led to difficulty in treating infections, especially in cystic fibrosis patients (47,65). Antibiotic resistance in P. aeruginosa has been partially attributed to active efflux pumps that expel antimicrobial compounds (1,17,52).…”

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confidence: 99%

Down Regulation of Virulence Factors of Pseudomonas aeruginosa by Salicylic Acid Attenuates Its Virulence on Arabidopsis thaliana and Caenorhabditis elegans

et al. 2005

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Salicylic acid (SA) is a phenolic metabolite produced by plants and is known to play an important role in several physiological processes, such as the induction of plant defense responses against pathogen attack. Here, using the Arabidopsis thaliana-Pseudomonas aeruginosa pathosystem, we provide evidence that SA acts directly on the pathogen, down regulating fitness and virulence factor production of the bacteria. Pseudomonas aeruginosa PA14 showed reduced attachment and biofilm formation on the roots of the Arabidopsis mutants lox2 and cpr5-2, which produce elevated amounts of SA, as well as on wild-type Arabidopsis plants primed with exogenous SA, a treatment known to enhance endogenous SA concentration. Salicylic acid at a concentration that did not inhibit PA14 growth was sufficient to significantly affect the ability of the bacteria to attach and form biofilm communities on abiotic surfaces. Furthermore, SA down regulated three known virulence factors of PA14: pyocyanin, protease, and elastase. Interestingly, P. aeruginosa produced more pyocyanin when infiltrated into leaves of the Arabidopsis transgenic line NahG, which accumulates less SA than wild-type plants. This finding suggests that endogenous SA plays a role in down regulating the synthesis and secretion of pyocyanin in vivo. To further test if SA directly affects the virulence of P. aeruginosa, we used the Caenorhabiditis elegans-P. aeruginosa infection model. The addition of SA to P. aeruginosa lawns significantly diminished the bacterium's ability to kill the worms, without affecting the accumulation of bacteria inside the nematodes' guts, suggesting that SA negatively affects factors that influence the virulence of P. aeruginosa. We employed microarray technology to identify SA target genes. These analyses showed that SA treatment affected expression of 331 genes. It selectively repressed transcription of exoproteins and other virulence factors, while it had no effect on expression of housekeeping genes. Our results indicate that in addition to its role as a signal molecule in plant defense responses, SA works as an anti-infective compound by affecting the physiology of P. aeruginosa and ultimately attenuating its virulence.Pseudomonas aeruginosa is a prevalent opportunistic pathogen in humans, causing chronic lung infections in cystic fibrosis patients, burn victims, and other immunocompromised people (61, 62). Pathogenesis of P. aeruginosa is mediated by a suite of cell-associated and excreted virulence factors. The cell-associated factors include flagella that aid in motility, systems that are involved in the delivery of effector proteins into the host cells (67), and lipopolysaccharide that suppresses host immune responses as well as being involved in the establishment of persistent infections (13). Secreted factors such as elastase and protease cause the degradation of host proteins such as elastin, collagen, and transferrins, destroying the integrity of the host tissues (2, 34), while low-molecular-weight toxins such as pyocyanin affect mu...

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Development of resistance in Pseudomonas aeruginosa obtained from patients with cystic fibrosis at different times

Abstract: Tables 1 and 5 in the above article have been published incorrectly. The correct tables are below. We apologise for any inconvenience caused.

Cited by 4 publications

References 0 publications

Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers

Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers

Is there value in susceptibility testing ofPseudomonas aeruginosacausing chronic infection in patients with cystic fibrosis?

Down Regulation of Virulence Factors of Pseudomonas aeruginosa by Salicylic Acid Attenuates Its Virulence on Arabidopsis thaliana and Caenorhabditis elegans

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