A multicenter, double-blind, randomized, comparison study of the efficacy and safety of tigecycline to imipenem/cilastatin to treat complicated intra-abdominal infections in hospitalized subjects in China

Figures & data

Table 1 Definitions of clinical response and microbiological response

Definition	Clinical response
Cure	The study drug (ie, tigecycline or imipenem/cilastatin) and the initial intervention (operative and/or radiologically controlled drainage procedure) resolved the intra-abdominal infection. The relevant clinical signs and symptoms of infection at baseline disappeared or recovered to normal, and relevant non-microbiological results of laboratory tests returned to normal level (radiological test was at the discretion of investigators) or the resolution of signs and symptoms so that no further therapy was required. If the subject underwent a percutaneous drainage at baseline, did not respond to treatment within 72 hours of the initial drainage, and had to undergo an operation and then improved that he/she was considered a clinical cure, the reason for the failed percutaneous drainage was to be recorded, eg, bowel perforation. The subject must not have received additional antibacterial agents during treatment. During the completion of study drug (from the EOT to TOC), any non-study anti-infection products or treatments were prohibited.
Failure	The subject required additional surgical or radiologic intervention and/or received additional anti-infection therapy to cure the infection (included surgical wound infections) since administration of study drug until TOC; or death after study Day 2 due to the infection or a treatment-related AE or discontinuation from investigational product due to a treatment-related AE (as primary reason) or received greater than 120% of the prescribed number of investigational product doses. Subjects could have been declared a therapeutic failure after receiving at least 2 days (8 doses) of investigational product. Patients receiving oral switch therapy were considered clinical failures. If a subject was a clinical failure while receiving the study drug, the subject’s clinical response of failure was to be carried forward through the TOC visit (regardless if they were cured on other antibiotics). Subjects who were clinical failures were to have the TOC assessment performed prior to the initiation of the non-study antibiotic therapy.
Indeterminate	Subjects who were lost to follow-up (failure to have an outcome determination); or who died within 2 days after the first dose of the study drug for any reason; or who died after study Day 2 but prior to the TOC assessment because of non-infection-related reasons (as judged by the investigator).
Microbiological response at the baseline pathogen level
Eradication (documented or presumed)	The baseline pathogen was absent in repeat cultures obtained from the original site of the intra-abdominal infection through the TOC assessment; or a clinical response of cure precluded the necessity of a repeat intra-abdominal culture.
Persistence (documented or presumed)	Baseline pathogen was present in repeat cultures obtained from the original site of the intra-abdominal abscess, peritonitis, or surgical wound infection during the study, or clinical outcomes were failure in subjects from whom no repeat microbiological data was available.
Indeterminate	Subjects who were lost to follow-up (did not have an outcome determination); or who died within 2 days after the first dose of investigational product for any reason; or who died after 2 days but prior to the TOC assessment because of non-infection-related reasons (as judged by the investigator); or no baseline pathogens identified.
Microbiological response at the subject level
Eradication (documented or presumed)	None of the baseline pathogens were present in repeat intra-abdominal cultures from the original site of infection taken during the study or a clinical response of cure precluded the necessity of a repeat intra-abdominal culture.
Persistence (documented or presumed)	Documented: any baseline intra-abdominal pathogen was present in the cultures obtained from the original site of the intra-abdominal abscess, peritonitis, or surgical wound infection during the study; presumed: repeat microbiological data were not obtained for a subject with a clinical response of failure.
Superinfection	Emergence of a new pathogen during therapy, at the site of infection with emergence or worsening of clinical signs and symptoms of infection.
Indeterminate	Subjects who were lost to follow-up (failure to have an assigned clinical response); or who died within 2 days after the first dose of investigational product for any reason; or who died after 2 days but prior to the TOC assessment because of non-infection-related reasons (as judged by the investigator); or no baseline pathogens identified.

Abbreviations: EOT, end of treatment; TOC, test-of-cure; AE, adverse events.

Figure 1 Patient disposition.

Notes: ^aOne subject was randomized to imipenem/cilastatin group but received tigecycline throughout the treatment period. This subject was reported and analyzed under the tigecycline group for all efficacy and safety analyses and was excluded from the CE and ME populations. A sensitivity analysis to the primary end point of clinical response at the TOC assessment was conducted for the mITT population with this subject included in the imipenem/cilastatin group and the conclusions did not change. The procedures performed at TOC included: vital signs, assessment of clinical signs and symptoms of infection, urine or serum pregnancy test, urinalysis, hematology, serum chemistries, investigator assessment of clinical response, calculated creatinine clearance, microbiological determinations as in blood/intra-abdominal cultures, study drug administration, prior/concomitant medications/treatments, hospitalization information, and collection of adverse events. ^bIncluding the subject described in the above footnote.
Abbreviations: CE, clinically evaluable; cIAI, complicated intra-abdominal infection; c-mITT, clinical modified intent-to-treat; HIV, human immunodeficiency virus; ME, microbiologically evaluable; mITT, modified intent-to-treat; m-mITT, microbiological modified intent-to-treat; TOC, test-of-cure.

Table 2 Demographics and baseline characteristics of the CE population

Characteristic	Tigecycline	Imipenem/cilastatin
	N=207	N=205
Age (years)
Mean (SD)	47.3 (17.7)	48.7 (17.4)
Range	18–85	19–85
Sex, n
Male	132	133
Female	75	72
Race, n
Asian	207	205
Weight (kg)
Mean (SD)	61.7 (12.1)	62.0 (11.4)
Range	40.0–130.0	40.0–105.0
Body mass index (kg/m^2)
Mean (SD)	22.4 (3.6)	22.5 (3.4)
Range	16.3–38.0	15.5–33.1
Height (cm)
Mean (SD)	165.8 (8.1)	165.6 (8.1)
Range	136.0–186.0	143.0–185.0
Duration since diagnosis (days)
Mean (SD)	1.2 (0.53)	1.3 (1.39)
Range	0–5	0–12
APACHE II score
Mean (SD)	5.2 (3.38)	5.4 (3.38)
Range	0–15	0–15
APACHE II score categories, n (%)
≤15	207 (100.0)	205 (100.0)
>15	0	0
Primary diagnosis, n (%)
Complicated appendicitis	145 (70.0)	139 (67.8)
Peritonitis due to perforation of small intestine	21 (10.1)	21 (10.2)
Perforated stomach	18 (8.7)	18 (8.8)
Complicated cholecystitis	10 (4.8)	13 (6.3)
Peritonitis due to perforation of large intestinea	4 (1.9)	5 (2.4)
Liver abscess	3 (1.4)	4 (2.0)
Peritonitisb	1 (0.5)	4 (2.0)
Intra-abdominal abscess	3 (1.4)	1 (0.5)
Complicated diverticulitis	2 (1.0)	0 (0.0)

Notes:

a “Peritonitis due to perforation of large intestine due to diverticulitis” was included in this category;

b included post-traumatic peritonitis.

Abbreviations: APACHE, Acute Physiological and Chronic Health Evaluation; CE, clinically evaluable.

Table 3 Clinical response at the test-of-cure assessment

Response	Tigecycline 50 mg		Imipenem/cilastatin		Difference (tigecycline minus imipenem/cilastatin)a
	n/N	% (95% CI)b	n/N	% (95% CI)b	%	95% CI (%)	P-valuec	P-valued
CE population
Cure	186/207	89.9 (84.9, 93.6)	198/205	96.6 (93.1, 98.6)	−6.7	(−12.0, −1.4)	0.0008	0.0109
Failure	21/207	10.1 (6.4, 15.1)	7/205	3.4 (1.4, 6.9)
mITT population
Cure	192/232	82.8 (77.3, 87.4)	205/231	88.7 (83.9, 92.5)	−6.0	(−12.8, 0.8)	0.0040	0.0861
Failure	24/232	10.3 (6.7, 15.0)	8/231	3.5 (1.5, 6.7)
Indeterminatee	16/232	6.9 (4.0, 11.0)	18/231	7.8 (4.7, 12.0)
ME population
Cure	110/125	88.0 (81.0, 93.1)	102/107	95.3 (89.4, 98.5)	−7.3	(−15.2, 0.5)	0.0277	0.0689
Failure	15/125	12.0 (6.9, 19.0)	5/107	4.7 (1.5, 10.6)

Notes:

a CIs and P-values for between-group comparison were calculated by the asymptotic method corrected for continuity with normal distribution approximation.

b Within-group CIs were calculated using the method of Clopper and Pearson.

c P-value for test for non-inferiority, one-sided at the level of 0.025.

d P-value for test for superiority, two-sided at the level of 0.05.

e Subjects who were lost to follow-up (failure to have an outcome determination), or who died within 2 days after the first dose of investigational product for any reason, or who died after study Day 2 but prior to the test-of-cure assessment because of non-infection-related reasons (as judged by the investigator).

Abbreviations: CE, clinically evaluable; n, number of CE, mITT, or ME subjects in each response category; N, total number of subjects in CE, mITT, or ME populations; mITT, modified intent-to-treat; ME, microbiologically evaluable.

Table 4 Microbiological response at the subject level in the test-of-cure assessment for the ME population

Response	Tigecycline 50 mg		Imipenem/cilastatin		Difference (tigecycline minus imipenem/cilastatin)
	n/N	% (95% CI)a	n/N	% (95% CI)a	%	95% CI (%)	P-valueb	P-valuec
All subjects
Eradication	110/125	88.0 (81.0, 93.1)	102/107	95.3 (89.4, 98.5)	−7.3	(−15.2, 0.5)d	0.0277d	0.0689d
Persistence	13/125	10.4 (5.7, 17.1)	5/107	4.7 (1.5, 10.6)
Superinfectione	2/125	1.6 (0.2, 5.7)	0/107	0 (0, 3.4)
Subjects with monomicrobial infection
Eradication	76/84	90.5 (82.1, 95.8)	76/81	93.8 (86.2, 98.0)	−3.4	(−13.0, 6.3)f
Persistence	8/84	9.5 (4.2, 17.9)	5/81	6.2 (2.0, 13.8)
Superinfectione	0/84	0.0 (0.0, 4.3)	0/81	0.0 (0.0, 4.5)
Subjects with polymicrobial infectiong
Eradication	34/41	82.9 (67.9, 92.8)	26/26	100.0 (86.8, 100.0)	−17.1	(−32.6, 1.5)f
Persistence	5/41	12.2 (4.1, 26.2)	0/26	0.0 (0.0, 13.2)
Superinfectione	2/41	4.9 (0.6, 16.5)	0/26	0.0 (0.0, 13.2)

Notes:

a Within-group CIs were calculated using the method of Clopper and Pearson.

b P-value for test for non-inferiority, one-sided at the level of 0.025.

c P-value for test for superiority, two-sided at the level of 0.05.

d CIs and P-values for between-group comparison were calculated by the asymptotic method corrected for continuity with normal distribution approximation.

e Superinfection was defined as emergence of a new pathogen during therapy, at the site of infection with emergence or worsening of clinical signs and symptoms of infection.

f CIs were calculated based on the Wilson score method corrected for continuity.

g Subjects with polymicrobial infections were infected by ≥2 pathogens at baseline.

Abbreviations: ME, microbiologically evaluable; n, number of ME subjects with each microbiological response; N, number of ME subjects; n, number of ME subjects.

Table 5 Pathogen-level microbiological eradication rates by species or types of baseline isolates at the test-of-cure assessment for the ME population

Species or types of baseline isolates	Tigecycline		Imipenem/cilastatin
	n/N	% (95% CI)a	n/N	% (95% CI)a
All pathogensb	154/170	90.6 (85.2, 94.5)	131/136	96.3 (91.6, 98.8)
Escherichia coli	93/101	92.1 (85.0, 96.5)	81/84	96.4 (89.9, 99.3)
Klebsiella spp.c	13/16	81.3 (54.4, 96.0)	11/13	84.6 (54.6, 98.1)
Enterobacter spp.d	2/3	66.7 (9.4, 99.2)	2/2	100.0 (15.8, 100.0)
Other Enterobacteriaceaee	4/4	100.0 (39.8, 100.0)	1/1	100.0 (2.5, 100.0)
Other Gram-negative bacillusf	6/8	75.0 (34.9, 96.8)	6/6	100.0 (54.1, 100.0)
Enterococcus spp.g	11/11	100.0 (71.5, 100.0)	4/4	100.0 (39.8, 100.0)
Staphylococcus aureus	2/2	100.0 (15.8, 100.0)	NA	NA
Coagulase-negative staphylococci (CoNS)h	3/3	100.0 (29.2, 100.0)	10/10	100.0 (69.2, 100.0)
Streptococcus agalactiae	NA	NA	1/1	100.0 (2.5, 100.0)
Viridans group streptococci	9/10	90.0 (55.5, 99.7)	11/11	100.0 (71.5, 100.0)
Other Gram-positive coccij	1/2	50.0 (1.3, 98.7)	NA	NA
Bacteroides fragilis	4/4	100.0 (39.8, 100.0)	1/1	100.0 (2.5, 100.0)
Other Bacteroidesk	6/6	100.0 (54.1, 100.0)	2/2	100.0 (15.8, 100.0)
Clostridium perfringens	NA	NA	1/1	100.0 (2.5, 100.0)

Notes: A subject could have been counted more than once if multiple unique pathogens were isolated from this subject. Excluded Candida tropicalis and Curtobacterium.

a CIs were calculated using the method of Clopper and Pearson.

b For all pathogens, N, number of pathogens isolated from all subjects; n, number of pathogens isolated from all subjects that were eradicated.

c Included Klebsiella pneumoniae and Klebsiella oxytoca.

d Included Enterobacter aerogenes and Enterobacter cloacae.

e Included Proteus mirabilis, Proteus vulgaris group/Proteus penneri group, Plesiomonas shigelloides, and Hafnia alvei.

f Included Pseudomonas aeruginosa, Pseudomonas mendocina, Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas salmonicida, and Comamonas testosteroni.

g Included Enterococcus faecium and Enterococcus avium.

h Included Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus saprophyticus, and Staphylococcus xylosus.

i Included Streptococcus alactolyticus, Streptococcus anginosus, Streptococcus constellatus, Streptococcus gordonii, Streptococcus intermedius, Streptococcus mitis, Streptococcus salivarius, and Streptococcus sanguis.

j Included Lactococcus garvieae and Leuconostoc mesenteroides.

k Included Bacteroides ovatus/Bacteroides thetaiotaomicron, Bacteroides splanchnicus, Bacteroides stercoris, and Bacteroides thetaiotaomicron.

Abbreviations: ME, microbiologically evaluable; n, number of pathogens isolated from all subjects that were eradicated for each species or type of bacteria; N, number of pathogens isolated from all subjects for each species or type of bacteria; NA, not applicable; TOC, test-of-cure.

Table 6 Summary of treatment-emergent adverse events in the safety analysis set

Adverse events	Tigecycline 50 mg		Imipenem/cilastatin
	(N=232)		(N=231)
	All-causality	Treatment-related	All-causality	Treatment-related
Subjects in safety analysis seta, n	232	232	231	231
Number of AEs	296	88	253	70
Subjects with AEs, n (%)	131 (56.5)	53 (22.8)	108 (46.8)	29 (12.6)
Subjects with SAEs, n (%)	32 (13.8)	19 (8.2)	15 (6.5)	7 (3.0)
Subjects with severe AEs, n (%)	21 (9.1)	13 (5.6)	9 (3.9)	5 (2.2)
Subjects with dose reduced or temporary discontinuation due to AEs, n (%)	1 (0.4)	0	1 (0.4)	1 (0.4)
Subjects discontinued from study due to AEs, n (%)	22 (9.5)	13 (5.6)	7 (3.0)	6 (2.6)
Subjects permanently discontinued from study treatment due to AEs, n (%)	20 (8.6)	14 (6.0)	2 (0.9)	2 (0.9)

Notes:

a Included all data collected in the clinical database since the first dose of study drug. Per the protocol, SAEs occurring from the first dose of study treatment through last subject visit were required to be reported in the clinical database. AEs for one subject (imipenem/cilastatin group), which were reported after the database release, were not included in this table.

Abbreviations: AE, adverse event; N, total number of subjects; SAE, serious AE; n, number of subjects in each category.

Table 7 Treatment-emergent adverse events in ≥2% of subjects in either treatment group in the safety analysis set

System organ class preferred term	Tigecycline		Imipenem/cilastatin
	(N=232)		(N=231)
	All-causality	Treatment-related	All-causality	Treatment-related
Clinical findings
Gastrointestinal disorders
Abdominal distension	8 (3.4)	0	5 (2.2)	0
Diarrhea	11 (4.7)	4 (1.7)	7 (3.0)	2 (0.9)
Nausea	24 (10.3)	16 (6.9)	10 (4.3)	5 (2.2)
Vomiting	19 (8.2)	12 (5.2)	10 (4.3)	4 (1.7)
General disorders and administration site conditions
Drug ineffective	21 (9.1)	18 (7.8)	9 (3.9)	6 (2.6)
Pyrexia	18 (7.8)	1 (0.4)	19 (8.2)	2 (0.9)
Infections and infestations
Lung infection	7 (3.0)	1 (0.4)	2 (0.9)	0
Postoperative wound infection	21 (9.1)	3 (1.3)	3 (1.3)	1 (0.4)
Metabolism and nutrition disorders
Hyperproteinemia	4 (1.7)	0	9 (3.9)	0
Nervous system disorders
Dizziness	3 (1.3)	0	5 (2.2)	3 (1.3)
Respiratory, thoracic, and mediastinal disorders
Cough	5 (2.2)	0	9 (3.9)	0
Productive cough	5 (2.2)	0	1 (0.4)	0
Investigations
Alanine aminotransferase increased	5 (2.2)	3 (1.3)	10 (4.3)	8 (3.5)
Aspartate aminotransferase increased	4 (1.7)	3 (1.3)	10 (4.3)	8 (3.5)
Blood albumin decreased	6 (2.6)	0	6 (2.6)	1 (0.4)
Blood potassium decreased	2 (0.9)	0	5 (2.2)	1 (0.4)
Urine ketone body present	0	0	6 (2.6)	2 (0.9)
Urobilinogen urine increased	0	0	5 (2.2)	4 (1.7)

Notes: Values are n (%). AEs for one subject (imipenem/cilastatin group), which were reported after the database release, were not included in this table.

Abbreviations: AE, adverse event; N, total number of subjects; n, number of subjects in each category.