Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model

Figures & data

Figure 1. Survival curves and cause of death in NHPs after TBI and treatment with sargramostim and/or azithromycin. (A) Survival curve comparisons of Groups 1 (reference item/vehicle 48 h) and 2 (sargramostim 48 h). (B) Survival curve comparisons of Groups 6 (reference item/vehicle 48 h + azithromycin) and 7 (sargramostim 48 h + azithromycin). Logistic regression model for comparing the mortality frequencies at Day 60 showed an overall statistically significant dose effect (t-test, p = .0032). (C) Most likely cause of death of moribund animals in each group.

Table 1. Summary of neutrophil- and platelet-related hematology parameters.

Group no.		ANC nadir (×10^9/L)	Duration severe neutropenia (<100/µL) (days)	Duration severe neutropenia (<500/µL) (days)	Duration febrile neutropenia (<500/µL and BT ≥ 39.4 °C) (days)	Time to ANC recovery (≥500/µL) (days)	Time to ANC recovery (≥1000/µL) (days)	PLT nadir (×10^9/L)	Duration severe thrombocytopenia (<20,000/µL) (days)	Time to PLT recovery (≥20,000/µL) (days)
1 (control)	Mean	0.011	6	13.3	2.6	19.7	21.2	4.614	4.1	17.4
	Sd	0.012	2.3	1.3	1.5	1	1.3	4.819	3.2	2.3
	N	44	12	11	17	11	10	44	12	12
	p value	–	–	–	–	–	–	–	–	–
2	Mean	0.023	4.6	10.1	3.3	18	18.8	5.159	4.6	16.6
	Sd	0.044	2.9	1.8	2	1.1	1.1	8.605	2.5	1.1
	N	44	17	16	27	16	16	44	16	16
	p value	–	–	≤.001	–	.001	.001	–	–	.05
3	Mean	0.011	6.6	11.1	4.3	18.1	18.7	3.182	6.3	17.5
	Sd	0.008	1.9	1.3	2.4	0.8	1	1.956	1.7	1.2
	N	44	19	15	16	15	15	44	16	16
	p value	–	–	.01	–	.001	.001	–	–	–
4	Mean	0.01	6.7	10.8	2.9	18	18.8	3.705	5.9	17.6
	Sd	0.01	1.8	1.6	2.1	0.9	1.1	4.168	2.5	1.7
	N	44	21	20	17	20	19	44	19	19
	p value	–	–	.001	–	.001	.001	–	–	–
5	Mean	0.009	5.8	11.4	4.2	18.3	19	3.136	5.5	17.4
	Sd	0.008	1.8	1.4	2.3	1.1	1	2.792	1.7	0.9
	N	44	15	12	18	12	11	44	12	12
	p value	–	–	.05	–	.01	.001	–	–	–
6	Mean	0.013	5.6	12.9	3.2	19.6	20.6	14.25	3.1	15.4
	Sd	0.016	2.5	1.2	1.6	1.1	1.1	65.043	3.4	4.6
	N	44	10	8	14	8	7	44	7	7
	p value	–	–	–	–	–	–	–	–	–
7	Mean	0.01	6.2	10.3	3.7	17.8	18.7	3.5	4.9	16.8
	Sd	0.007	1.8	1.3	2.3	1.6	2	3.195	2.1	1.2
	N	44	14	12	20	12	11	44	13	13
	p value	–	–	.001	–	.001	.001	–	–	.001

All statistical analysis and comparisons are to the control group (Group 1). Group 1: Reference item/vehicle 48 h. Group 2: Sargramostim/48 h. Group 3: Sargramostim/72 h. Group 4: Sargramostim/96 h. Group 5: Sargramostim/120 h. Group 6: Reference item/vehicle 48 h + azithromycin. Group 7: Sargramostim/48 h + azithromycin.

Figure 4. Percentage of animals with sepsis following irradiation and treatment with sargramostim and/or azithromycin. (A) Percentage of total animals across all groups, both moribund and surviving, presenting as septic or non-septic (n = 308). Septic is defined as animals presenting with at least two positive bacteriology results in organ and blood culture. (B) Percentage of total animals within each group, both moribund and surviving, presenting as septic or non-septic (n = 44 per group; 22 males and 22 females). Group 1 (reference item/vehicle 48 h); Group 2 (sargramostim 48 h); Group 6 (reference item/vehicle 48 h + azithromycin); Group 7 (sargramostim 48 h + azithromycin). **p≤.01.

Figure 5. Bacteriology of study animals post irradiation. (A) Percentage of total animals with at least one positive bacterial identification in the brain, heart, liver, lung (left and right caudal lobes), spleen, and kidneys post mortem. Moribund is defined as animals which were removed before endpoint of 60 days. (B) Categorization of the species of bacteria found in both organ and hemocultures of study animals (both moribund and surviving to termination) from all groups. n = 308.

Table 2. Gram-positive and -negative bacteria identified in organ and hemocultures.

Bacterial strains isolated	Number of animals with at least one organ or hemoculture positive (n = 161)	Bacterial strains isolated	Number of animals with at least one organ or hemoculture positive (n = 161)
Gram-positive		Gram-negative
Staphylococcus aureus	125	Escherichia coli	19
Streptococcus oralis	28	Stenotrophomonas (X.) maltophilia	13
Enterococcus faecalis	10	Pseudomonas species	8
Staphylococcus cohnii	7	Morganella morganii	4
Enterococcus casseliflavus	6	Pseudomonas putida	4
Staphylococcus epidermidis	5	Sphingomonas (p.) paucimobilis	4
Streptococcus mitis	5	Nonfermenter species	3
Aerococcus viridans	3	Ochrobactrum anthropic	3
Lactobacillus salivarius	3	Pseudomonas koreensis	3
Staphylococcus saprophyticus	3	Acinetobacter iwoffi	2
Streptococcus parasanguinis	3	Acinetobacter johnsonii	2
Staphylococcus capitis	2	Acinetobacter species	2
Streptococcus pluranimalium	2	Bordetella bronchiseptica	2
Streptococcus salivarius	2	Brevundimonas diminuta	2
Vagococcus fluvialis	2	Chryseobacterium joostei	2
Weissella confusa	2	Klebsiella pneumoniae	2
Alpha Hemolytic Streptococcus	1	Leclercia adcarboxylata	2
Bacillus species	1	Pseudomonas monteilii	2
Brochothrix thermosphacta	1	Brevundimonas vesicularis	1
Corynebacterium renale	1	Campylobacter hyointestinalis	1
Gemella species	1	Chryseobacterium tructue	1
Kocuria rosae	1	Klebsiella species	1
Lactococcus lactis	1	Klebsiella variicola	1
Leuconostoc citreum	1	Lelliottia (Enterobacter) amnigena	1
Microbacterium liquefaciens	1	Moraxella osloensis	1
Staphylococcus haemolyticus	1	Pantoea septica	1
Staphylococcus hyointestinalis	1	Pseudoxanthomonas mexicana	1
Staphylococcus sciuri	1	Stenotrophomonas species	1
Staphylococcus wameri	1
Streptococcus dysgalactinae	1
Streptococcus lutetiensis	1
Streptococcus pseudoporcinus	1

Figure 6. Summary of the antibiogram of the top five most common bacterial strains identified in organ and hemocultures. The cumulative resistance of the identified bacterial strains against a panel of commonly used broad-spectrum antibiotics. Results are pooled from animals of all groups (n = 308), both moribund and surviving.