Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches

Figures & data

Table 1. Susceptibility breakpoints (μg/ml) of colistin.

Colistin committee (year)	Enterobacteriaceae			Pseudomonas aeruginosa			Acinetobacter baumannii
	S	I	R	S	I	R	S	I	R
CLSI (2013)				≤ 2	4	≥ 8	≤ 2		≥ 4
EUCAST (2014)	≤ 2		> 2	≤ 4		> 4	≤ 2		> 2
BSAC (2013)	≤ 2		> 2	≤ 4		> 4	≤ 2		> 2

Data taken from [45,46].

BSAC: British Society for Antimicrobial Chemotherapy; CLSI: Clinical and Laboratory Standards Institute; EUCAST: European Committee on Antimicrobial Susceptibility Testing; I: Intermediate; R: Resistant; S: Susceptible.

Figure 1. Graphical representation of CMS and colistin concentrations observed at a dose 3 MU q8 h and with a loading dose of 6 MU and 9 MU (infusion over 0.5 h and 1 h).

Table 2. Suggested loading and maintenance dosage of colistin methanesulfonate in million international unit in various patient categories.

Patient categories	Dose to target average serum level 2 mg/l in MU
	Loading dose
All patients	Body weight*(kg)/ 7.5 MU (maximum: 10 MU)
	Maintenance total daily dose
Not on renal replacement	Creatinine clearance (ml/min)/10 + 2 MU administrated in 2 to 3 divided doses First maintenance dose 24 h after loading dose
Intermittent hemodialysis	2 MU administrated in 2 divided doses + 30% on the day of hemodialysis after session or +50% on the day of hemodialysis at the end of session
Continuous renal replacement	10 MU administrated in 2 divided doses^‡
Continuous ambulatory peritoneal dialysis	5 MU every 24 h

Data taken from [19,22].

*Lower or either actual or ideal.

^‡Based on model fitted parameter estimates, doses up to 12 MU on continuous renal replacement therapy have been suggested. However, based on current upper limit product information and lack of clinical evidence, maximum dosage of 10 MU is preferred.

MU: Million international unit.

Table 3. Main plasma pharmacokinetic parameters of tigecycline in humans.

Plasma parameter	Pharmacological studies		Efficacy studies
	50 mg	100 mg	50 mg
Cmax (μg/ml)
30-min infusion	0.87 ± 0.23	1.15 ± 0.32	0.80 ± 0.46
60-min infusion	0.63 ± 0.10	0.90 ± 0.27	0.49 ± 0.28
Cmin (μg/ml)	0.13 ± 0.08	NA	0.16 ± 0.09
CL (L/h)	23.8 ±7.8	21.8 ± 8.9	19.9 ± 8.1
t1/2 (h)	42.4 ± 35.3	27.1 ± 14.3	NA
AUC24 (mg h/l)	4.70 ± 1.70	NA	5.85 ± 2.48
Vd (L)	639 ± 307	568 ± 244	NA

Data taken from [49].

AUC_t: AUC time t; CL: Totally body clearance; C_min: Minimum concentration; NA: Not available; Vd: Volume of distribution.

Table 4. Pharmacokinetics of parenteral fosfomycin in various tissue and sites.

Tissue/site	Fosfomycin parenteral dose (i.v.)	Site concentration (μg/ml)
Interstitial fluid	30 mg/kg	50.5 ± 16.3
Lung	2 g	12 – 18.3
Bronchial	4 g	13.1 ± 11.37
secretions
Pleural fluid	30 mg/kg	42.6 ± 16.02
CSF (noninflamed)	5 g	9 – 10
	10 g	14 – 17
CSF (inflamed)	8 g	62 ± 38
Muscle	4 – 8 g	50 – 60% of corresponding serum level
Subcutaneous tissue	4 – 8 g	30 – 50% of corresponding serum level
Aqueous humor	4 g	14.63 ± 5.54
Abscess fluid	8 g	64 ± 67
Bone
Cancellous	4 g	18 ± 14.8
Cortical	30 mg/kg	17.2 ± 12.5
Cardiac valves
Aortic valves	5 g	27.1 – 76.9
Mitral valves	5 g	39.6 – 69.4
Prostatic tissue	3 g (single oral dose)	6.5 ± 4.9 (mean level)
		0.7 – 22.1 (range)
Transition zone		8.3 ± 6.6
Peripheral zone		4.4 ± 4.1

Data taken from [81].

CSF: Cerebrospinal fluid.

Table 5. Phase II and Phase III of newer antibiotics.

	Phase II*	Results	Phase III*	Recruitment
Ceftolozane/tazobactam (CXA -201)	Safety and efficacy of i.v. ceftolozane 1000 mg q8 h and i.v. ceftazidime 1000 mg q8 h in patients with cUTI (NCT00921024) Prospective, randomized, double-blind study of C/T (1000/500 mg q8 h) and metronidazole (500 mg q8 h) i.v. vs meropenem i.v. (1000 mg q8 h) for the treatment of adults with cIAI (NCT01147640)	Microbiological eradication rates: complicated urinary tract: 83 vs 76% complicated lower urinary tract: 82 vs 73% pyelonephritis: 86 vs 83% Clinical cure rates: CE population: 91 vs 94% ME population: 89 vs 96% MITT population: 84 vs 96%	Prospective, randomized, double-blind, double-dummy study of C/T(1.5 g i.v. q8 h) vs levofloxacin (750 mg i.v. q24 h) for the treatment of adults with cUTI, including pyelonephritis (NCT01345929)	Completed
			Prospective, randomized, double-blind, double-dummy study of C/T (1.5 g i.v. q8 h) and metronidazole (500 mg i.v. q8 h) vs meropenem (1 g i.v. q8 h) for the treatment of adults cIAI (NCT01445678)	Completed
			Prospective, randomized, open-label study of C/T 3 g i.v. q8 h with piperacillin/tazobactam 4.5 g i.v. q6 h in VAP (NCT01853982)	Terminated
Plazomicin (ACHN-490)	Double-blind, randomized, comparator-controlled study of i.v. plazomicin 10 – 15 mg/kg vs i.v. levofloxacin 750 mg q24 h for cUTI and acute pyelonephritis (NCT01096849)	Microbiological eradication rates: ME population: 88.1 vs 81% MITT population: 58.7 vs 58.6%	Randomized, open-label, superiority study comparing plazomicin with colistin when combined with a second antibiotic (either meropenem or tigecycline) in the treatment of patients with BSI or nosocomial pneumonia due to CRE (NCT01970371)	Not yet recruiting
		Clinical cure rates: ME: 76.2 vs 76.2% MITT: 69.8 vs 65.5%
Eravacycline (TP-434)	Double-blind, double-dummy, prospective study to assess the efficacy, safety and PK of two doses of eravacycline (1.5 mg/kg q24 h and 1 mg/kg q12 h i.v.) compared with ertapenem 1000 mg q24 h i.v. in the treatment of adult community-acquired cIAI (NCT01265784)	Clinical cure in the ME population: -92.9% (eravacycline 1.5 mg/kg q24 h) -100% (eravacycline 1 mg/kg q12 h) -92.3% (ertapenem 1000 mg q24 h)	Double-blind, double-dummy, prospective study to assess the efficacy, safety and PK of eravacycline 1 mg/kg q12 i.v. compared with ertapenem 1000 mg q24 h i.v. in the treatment of adult cIAI (NCT01844856)	Recruiting participants
			Double-blind, double-dummy, prospective study to assess the efficacy and safety of eravacycline 1.5 mg/kg i.v. q24 h followed by 200 or 250 mg orally q12 h compared with levofloxacin 750 mg i.v. q24 h followed by 750 mg orally q24 h in cUTI (NCT01978938)	Not yet recruiting
Ceftazidime/avibactam (NXL-104)	Investigator-blinded, randomized, comparative study estimates safety, tolerability and efficacy of ceftazidime-avibactam 500/250 q8 h i.v. vs imipenem-cilastatin 500 mg q6 h i.v. in adults with cUTI (NCT00690378)	Microbiological eradication rates: ME population: 70.4 vs 71.4% Clinical cure rate: ME population: 85.7 vs 80.6%	Double-blind, double dummy, parallel-group, comparative study to determine the efficacy, safety and tolerability of ceftazidime-avibactam 2000/500 mg q8 h compared with doripenem 500 mg q8 h followed by oral therapy in hospitalized adults with cUTI (NCT01595438)	Recruiting participants
	Double-blind, randomized, comparative study to estimate the safety, tolerability and efficacy of ceftazidime-avibactam 2000/500 mg plus metronidazole 500 mg q8 h i.v. vs meropenem 1000 mg q8 h i.v. in the treatment of cIAI in hospitalized adults (NCT00752219)	Clinical cure rates: CE population: 92 vs 94.4% ME population: 91.2 vs 93.4% MITT population: 82.4 vs 88.8%	Double-blind, double dummy, parallel-group, comparative study to determine the efficacy, safety and tolerability of ceftazidime-avibactam 2000/500 mg + metronidazole 500 mg q8 h vs meropenem 1000 mg q8 h in adults with cIAI (NCT01500239)	Recruiting participants
		Microbiological eradication rates: ME population: 91.2 vs 93.4%	Open-label, randomized, multicenter study of ceftazidime avibactam and best available therapy for the treatment of infections due to ceftazidime-resistant Gram negative pathogens (NCT01644643)	Recruiting participants
			Double-blind, double dummy, parallel-group, comparative study to determine the efficacy, safety and tolerability of ceftazidime-avibactam 2000/500 mg + metronidazole 500 mg q8 h vs meropenem 1000 mg q8 h in hospitalized adults with cIAI (NCT01726023)	Recruiting participants
			Double-blind, double dummy, parallel-group, comparative study to determine the efficacy, safety and tolerability of ceftazidime-avibactam 2000/500 mg q8 h and doripenem 500 mg q8 h followed by oral therapy in hospitalized adults with cUTI (NCT01599806)	Recruiting participants
			Double-blind, double dummy, parallel-group, comparative study to determine the efficacy, safety and tolerability of ceftazidime-avibactam 2000/500 mg q8 h vs meropenem500 mg q8 h in hospitalized adults with nosocomial pneumonia (NCT01808092)	Recruiting participants

Data taken from [111,115,119-121].

*Data extracted from clinicaltrials.gov. [Identifier Number of clinical trial is shown in the parenthesis].

BSI: Bloodstream infections; CE: Clinically evaluable; cIAI: Complicated intra-abdominal infections; CRE: Carbapenem-resistant Enterobacteriaceae; C/T: Ceftolozane/tazobactam; cUTI: Complicated urinary tract infections; i.v.: Intravenous; ME: Microbiologically evaluable; MITT: Microbiological intent-to-treat; PK: Pharmacokinetic; q6 h: Every 6 hours; q8 h: Every 8 hours; q12 h: Every 12 hours; q24 h : Every 24 hours; VAP: Ventilator-associated pneumonia; vs: Versus.

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