Pseudomonas aeruginosa (Contact lens): Dose Response Models

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Pseudomonas aeruginosa (Contact Lens related Keratitis)

Author: Sushil Tamrakar
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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 [1].

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 [2]. It is the organism most frequently implicated in contact lens related keratitis [3].



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 [3] white rabbit contact lens 5 CFU corneal ulceration beta-Poisson α = 3.55E-01 , N50 = 6.57E+03 6.57E+03
300 [3] 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* [3] 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.


a:
Exponential and betapoisson model.jpg

Optimization Output for experiment 299

Rabbit/Pseudomonas aeruginosa [3]
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



Optimization Output for experiment 300

Rabbit/Pseudomonas aeruginosa [3]
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




Optimization Output for pooled data (experiment 299 and 300)

Pooled data of Rabbit/Pseudomonas aeruginosa [3]
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.



References

  1. Todar, K. (2012). Todar's Online Textbook of Bacteriology. Pseudomonas aeruginosa [1]
  2. Spencer, W. H. (1953). "PSEUDOMONAS AERUGINOSA INFECTIONS OF THE EYE." California Medicine 79(6): 438-443. Full text
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Lawin-Brüssel, C. A., M. F. Refojo, et al. (1993). "Effect of Pseudomonas aeruginosa Concentration in Experimental Contact Lens--Related Microbial Keratitis." Cornea 12(1): 10-18.PubMed Cite error: Invalid <ref> tag; name "Lawin-Brussel" defined multiple times with different content Cite error: Invalid <ref> tag; name "Lawin-Brussel" defined multiple times with different content Cite error: Invalid <ref> tag; name "Lawin-Brussel" defined multiple times with different content Cite error: Invalid <ref> tag; name "Lawin-Brussel" defined multiple times with different content Cite error: Invalid <ref> tag; name "Lawin-Brussel" defined multiple times with different content Cite error: Invalid <ref> tag; name "Lawin-Brussel" defined multiple times with different content