Pseudomonas aeruginosa (Contact lens): Dose Response Models

Pseudomonas aeruginosa (Contact Lens related Keratitis)

Author: Sushil Tamrakar If you want to download this chapter in pdf format, please click here

General overview of Pseudomonas aeruginosa

Pseudomonas aeruginosa is a Gram-negative, aerobic rod belonging to the bacterial family Pseudomonadaceae. Like other members of the genus, Pseudomonas aeruginosa is a free-living bacterium, commonly found in soil and water. However, it occurs regularly on the surfaces of plants and occasionally on the surfaces of animals. Pseudomonas aeruginosa is an opportunistic pathogen, meaning that it exploits some break in the host defenses to initiate an infection. In fact, Pseudomonas aeruginosa is the epitome of an opportunistic pathogen of humans .

Pseudomonas aeruginosa generally invades the body or organs lacking natural defenses, and usually the infection are chronic rather than acute, evoking little systemic response. When introduced into the cornea, however, as in penetration by a foreign body or in contaminated medicines, it acts with extreme virulence, in many cases causing blindness and even necessitating enucleation . It is the organism most frequently implicated in contact lens related keratitis .

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Summary Data

Lawin-Brussel et al. (1993) studied the effect of Pseudomonas aeruginosa in experimental contact lens related microbial keratitis. Forty white New Zealand rabbits were used in the experiment. New and worn soft contact lenses soaked in 5 ml bacterial suspension of different concentration for an hour, then fitted into the eyes of the rabbit(one lense per rabbit). The clinical findings after seven days of contact lens wear and additional 48 hours of P. aeruginosa contaminated lens wear were recorded. The experimental dose unit was CFU/ml. However, Lawin-Brussel et al. (1993) had observed quantification of bacterial attachment on soft contact lens after an hour of soaking in different concentration of P. aeruginosa. Based on the figure, the bacterial attachment in a lens was calculated.

Dose Conversion Table

CFU/ml	CFU (per lens)
100	63.22
10000	2220.49
100000	13159.77
1000000	77991.7
10000000	86799.77
100000000	462219,6

Relationship between P. aeruginosa suspension and the amount of bacterial adherent on lens.

Experiment serial number Reference Host type Agent strain Route # of doses Dose units Response Best fit model Optimized parameter(s) LD50/ID50 299 white rabbit contact lens 5 CFU corneal ulceration beta-Poisson α = 3.55E-01 , N50 = 6.57E+03 6.57E+03 300 white rabbit contact lens 5 CFU Severe stromal ulceration beta-Poisson α = 1.09E-01 , N50 = 1.52E+05 1.52E+05 299 and 300* white rabbit contact lens 10 CFU corneal ulceration beta-Poisson α = 1.90E-01 , N50 = 1.85E+04 1.85E+04 *This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.

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Optimization Output for experiment 299

Rabbit/Pseudomonas aeruginosa Dose CORNEAL ULCERATION NOT CORNEAL ULCERATION Total 63.2 0 5 5 2220 2 3 5 13200 3 2 5 78000 3 2 5 462000 5 0 5

Goodness of fit and model selection Model Deviance Δ Degrees of freedom χ20.95,1 p-value χ20.95,m-k p-value Exponential 9.41 7.02 4 3.84 0.00807 9.49 0.0516 Beta Poisson 2.39 3 7.81 0.495 Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.

Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations Parameter MLE estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% α 3.55E-01 1.50E-01 1.72E-01 1.94E-01 1.38E+02 4.88E+02 9.31E+02 N50 6.57E+03 9.34E+02 1.68E+03 2.03E+03 3.59E+04 5.63E+04 8.13E+04

Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters

Beta-Poisson model plot, with confidence bounds around optimized model

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Optimization Output for experiment 300

Rabbit/Pseudomonas aeruginosa Dose SEVERE STROMAL ULCERATION NOT SEVERE STROMAL ULCERATION Total 63.2 0 5 5 2220 2 3 5 13200 1 4 5 78000 1 4 5 462000 4 1 5

Goodness of fit and model selection Model Deviance Δ Degrees of freedom χ20.95,1 p-value χ20.95,m-k p-value Exponential 13.2 8.73 4 3.84 0.00313 9.49 0.0105 Beta Poisson 4.43 3 7.81 0.219 Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.

Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations Parameter MLE estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% α 1.09E-01 3.34E-02 4.74E-02 5.68E-02 6.14E+02 1.02E+03 1.32E+03 N50 1.52E+05 7.70E+03 1.43E+04 1.64E+04 8.02E+06 3.51E+07 5.97E+10

Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters

Beta-Poisson model plot, with confidence bounds around optimized model

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Optimization Output for pooled data (experiment 299 and 300)

Pooled data of Rabbit/Pseudomonas aeruginosa Dose CORNEAL ULCERATION NOT CORNEAL ULCERATION Total 63.2 0 5 5 63.2 0 5 5 2220 2 3 5 2220 2 3 5 13200 3 2 5 13200 1 4 5 78000 3 2 5 78000 1 4 5 462000 5 0 5 462000 4 1 5

Goodness of fit and model selection Model Deviance Δ Degrees of freedom χ20.95,1 p-value χ20.95,m-k p-value Exponential 30.9 20.8 9 3.84 5.11e-06 16.9 0.000312 Beta Poisson 10.1 8 15.5 0.26 Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.

Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations Parameter MLE estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% α 1.9E-01 1.04E-01 1.16E-01 1.27E-01 5.20E-01 8.16E-01 3.03E+03 N50 1.85E+04 3.85E+03 4.99E+03 6.48E+03 7.45E+04 8.59E+04 1.45E+05

Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters

Beta-Poisson model plot, with confidence bounds around optimized model

Summary

The animals with corneal ulceration and animals with severe stromal ulceration (with ring abscess and hypopyon) could be pooled. Hence a single pooled model could describe the distribution of both type of diseases due to contaminated contact lenses.

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