Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones

Figures & data

Table I. Antibiotics approved by the FDA and the EMA since 2000.

		Date of approval
Molecule	Antibiotic class	FDA	EMA
Linezolid	oxazolidinone	April 2000	(decentralized procedure; ∼ 2001)
cefditoren pivoxil	β-lactam	August 2001	(available in specific countries)
Ertapenem	β-lactam	November 2001	April 2004
Gemifloxacin	fluoroquinolone	April 2003	Not available
Daptomycin	lipopeptide	September 2003	January 2006
Telithromycin	ketolide	April 2004	July 2007
Tigecycline	glycylcycline	2005	April 2006
Retapamulin	pleuromutilin	April 2007	May 2007
Doripenem	β-lactam	October 2007	July 2008
Telavancin	lipoglycopeptide	September 2009	September 2009
Ceftaroline	β-lactam	November 2010	August 2012
Fidaxomicin	fluoroquinolone	May 2011	December 2011
Dalbavancin	lipoglycopeptide	May 2014	Not yet approved
Tedizolid	oxazolidinone	June 2014	Not yet approved

Figure 1. Chemical structure of oritavancin as compared to vancomycin. Major changes are highlighted together with their main consequences for activity or pharmacokinetics.

Table II. Susceptibility of relevant pathogens to antibiotics in development and their comparators.

Species	Phenotype	Antibiotic	MIC50 (mg/L)	MIC90 (mg/L)	MIC range (mg/L)	Reference ^a
S. aureus	MRSA—all	vancomycin	1 1	1 1 1	≤ 0.12–2 0.5–2 ≤ 0.25–2	(18) (143) (144)
		oritavancin	0.03 0.06	0.06 0.12 0.12	≤ 0.008–0.5 0.015–0.25 ≤ 0.004–4	(18) (143) (144)
		erythromycin	> 2 > 4	> 2 > 4	≤ 0.25–> 2 0.25–> 4	(145) (65)
		clarithromycin	0.25 > 8	> 128 > 8	0.25–> 128 ≤ 0.12–> 8	(146) (147)
		cethromycin	0.03 ≤ 0.002	0.03 ≤ 0.002	0.015–0.12 ≤ 0.002–0.125	(146) (147)
		solithromycin	0.06 0.12	> 4 > 16	0.03–> 4 0.03–> 16	(145) (65)
		levofloxacin	8	32	0.03–> 32	(129)
		moxifloxacin	4 0.125	16 4	0.03–> 64 0.03–8	(112) (127)
		zabofloxacin	2	4	0.008–32	(112)
		delafloxacin	0.125 0.03	0.5 0.5	≤ 0.004–16 0.008–1	(129) (127)
	hVISA	vancomycin		2	1–2	(148)
		oritavancin		1	0.12–2	(148)
	VISA	vancomycin	4	8 8	4–8 4–8	(143) (148)
		oritavancin	1	2 2	0.25–2 0.5–4	(143) (148)
		erythromycin	> 4	> 4	> 4	(65)
		solithromycin	> 16	> 16	0.06–> 16	(65)
		nemonoxacin	0.5	2	0.03–8	(149)
	VRSA	vancomycin	> 64	> 64	32–> 64	(143)
		oritavancin	0.5	1	0.25–1	(143)
	MRSA ML-R	erythromycin	> 512	> 512	> 512	(150)
		cethromycin	> 64	> 64	> 64	(150)
	MRSA FQ-S	moxifloxacin	0.06 0.06 0.06 0.03/0.25^b	0.12 0.06 0.06 0.125/0.5	0.06–0.25 ≤ 0.015–0.12 0.03–0.12 0.06–0.125/0.25–0.5	(116) (151) (152) (101)
		finafloxacin	0.125/0.06	0.25/0.125	0.125–0.25/0.06–0.125	(101)
		zabofloxacin	0.031	0.125	0.016–1	(153)
		avarofloxacin	≤ 0.008	≤ 0.008	≤ 0.008–0.015	(152)
		nemonoxacin	0.03 0.03	0.06 0.06	≤ 0.008–0.12 ≤ 0.008–0.06	(116) (151)
		delafloxacin			0.008–0.03	(154)
	MRSA FQ-R	moxifloxacin	8 4 4 4 2/8	16 4 8 > 16 32 / 32	1–16 0.12–8 0.25–> 16 1–> 16 2–32/0.5–64	(116) (151) (155) (152) (101)
		finafloxacin	2/1	16 / 4	0.25–32/0.25–32	(101)
		zabofloxacin	2	32	0.016–64	(153)
		avarofloxacin	0.25 0.25	0.25 1	0.015–2 0.12–4	(155) (152)
		nemonoxacin	0.5 4 1	1 16 1	0.5–1 0.25–64 0.06–4	(149) (116) (151)
		delafloxacin			0.5–2	(154)
E. faecium	VAN-S	vancomycin	1	1 1	0.03–4 0.25–4	(144) (156)
		oritavancin	≤ 0.008	0.03 ≤ 0.008	≤ 0.0005–0.25 ≤ 0.008–0.03	(144) (156)
		erythromycin	> 4	> 4	≤ 0.12–> 4	(65)
		solithromycin	0.25	2	0.03–2	(65)
		nemonoxacin	4	4	0.06–8	(149)
	VAN-R	vancomycin	≥ 64 > 16	≥ 64 > 256	8–> 256 > 256 > 16	(17) (144) (156)
		oritavancin	0.015 0.03	0.06 0.25 0.06	≤ 0.0005–1 ≤ 0.008–0.25	(17) (144) (156)
		erythromycin	> 4	> 4	0.25–> 4	(65)
		solithromycin	2	2	0.25–2	(65)
		nemonoxacin	4	16	0.06–16	(149)
S. pneumoniae	all	vancomycin		0.25	≤ 0.06–0.5	(144)
		oritavancin		0.008	≤ 0.0005–0.5	(144)
		clarithromycin	0.06 0.25	> 128 64	0.03–> 128 0.004–64	(146) (72)
		cethromycin	0.015	0.12	0.008–16	(146)
		solithromycin	0.015	0.06	0.002–1	(72)
		moxifloxacin	0.12 0.5	0.25 1	0.008–> 8 0.125–0.5	(105) (101)
		finafloxacin	1	2	0.5–4	(101)
		zabofloxacin	0.015 0.063	0.03 1	0.015–0.06 0.008–4	(112) (153)
		avarofloxacin	0.008	0.015	≤ 0.004–1	(105)
	S	moxifloxacin	0.12 0.12 0.5	0.25 0.12 0.5	0.03–0.25 0.06–0.25 0.125–0.5	(157) (151) (112)
		zabofloxacin	0.016 0.015	0.03 0.03	≤ 0.001–0.06 0.015–0.06	(157) (112)
		nemonoxacin	0.12	0.12	0.06–0.25	(151)
	Pen-R	vancomycin		0.25	0.25–0.5	(144)
		oritavancin		0.008	0.002–0.015	(144)
		moxifloxacin	0.12 0.12	0.25 0.25	0.03–0.25 0.06–0.25	(157) (116)
		zabofloxacin	0.016	0.03	0.004–0.03	(157)
		nemonoxacin	0.015	0.015	0.015–0.06	(116)
	ML-S	erythromycin	0.062	0.125	0.015–0.125	(150)
		clarithromycin	0.03	0.06	0.015–0.06	(158)
		cethromycin	≤ 0.007	0.031	≤ 0.007–0.31	(150)
		solithromycin	0.008	0.015	0.002–0.015	(158)
	ML-R	vancomycin		0.5	0.12–0.5	(144)
		oritavancin		0.25	0.008–0.5	(144)
		erythromycin	64	> 128	1–> 128	(150)
		clarithromycin			1–> 64	(158)
		cethromycin	0.031	0.25	≤ 0.007–2	(150)
		solithromycin			0.015–1	(158)
	FQ-R	moxifloxacin	2 2 1 4	4 8 16 8	2–8 2–> 8 4–16 0.25–> 8	(157) (151) (155) (105)
E. coli	all	ciprofloxacin	0.015 0.063 0.06	0.5 0.5 16	0.008–64 0.008–8 0.06–16	(112) (153) (116)
		zabofloxacin	0.06 0.125	1 0.5	0.015–64 0.008–32	(112) (153)
		nemonoxacin	0.12	32	≤ 0.015–≥ 512	(116)
	FQ-S	ciprofloxacin	0.016/0.125 0.015	0.03/0.25 0.25	≤ 0.008–0.125/0.06–2 0.08–0.25 0.008–2	(101) (154) (155)
		finafloxacin	0.125/0 .016	0.25/0.03	0.03–1/≤ 0.008–0.125	(101)
		avarofloxacin	0.06	0.25	0.015–0.5	(155)
		delafloxacin			0.016–0.25	(154)
	FQ-R	ciprofloxacin	128 / > 256 64	> 256 / > 256 256	8–> 256 / > 256 64–> 128 16–> 256	(101) (154) (155)
		finafloxacin	128 / 8	256 / 32	164–> 256 / 2–64	(101)
		avarofloxacin	4	16	1–16	(155)
		delafloxacin			2–128	(154)
Enterobacter spp.		ciprofloxacin	≤ 0.03/0.125	≤ 0.03/0.25	≤ 0.03 / 0.06–0.5	(101)
		finafloxacin	0.125/≤ 0.03	0.125/≤ 0.03	0.06–0.5/≤ 0.03–0.125	(101)
P. aeruginosa	all	ciprofloxacin	0.25 0.5 0.25	2 16 0.5	0.002–16 0.06–16 0.125–1	(153) (116) (155)
		zabofloxacin	1	32	0.016–64	(153)
		nemonoxacin	1	32	0.12–≥ 512	(116)
		avarofloxacin	1	2	0.5–4	(155)
	FQ-S	ciprofloxacin	0.25/0.5	0.5 / 1	0.03–1/0.125–2 0.25–2	(101) (154)
		finafloxacin	1 / 0.5	32 / 2	4–16 / 0.25–8	(101)
		delafloxacin			0.016–1	(154)
	FQ-R	ciprofloxacin			64–> 128	(154)
		delafloxacin			4–32	(154)

S = susceptible; FQ-R = fluoroquinolone-resistant; FQ-S = fluoroquinolone-susceptible; hVISA = heterogenous vancomycin-intermediate S. aureus; ML-R = macrolide-resistant; ML-S = macrolide-susceptible; MRSA = methicillin-resistant S. aureus; Pen-R = penicillin-resistant (based in most cases on CLSI = (Clinical and Laboratory Standards Institute) susceptibility breakpoints for marketed comparators); VISA = vancomycin-intermediate S. aureus; VRSA = vancomycin-resistant S. aureus.

^aComparison of MIC distributions among antibiotics should be performed using data from the same bibliographic reference.

^bValues in italics: MICs determined at acidic pH (∼5.2).

Table III. Main pharmacokinetic properties of antibiotics.

Antibiotic	Dose and route	Cmax (mg/L)^a	AUC (mg.h/L)^a	Protein binding (%)	T1/2 (h)	Tissue/serum conc. ratio	References
Oritavancin	1200 mg IV	19.4 (free)	132	85	31.3 (β) 393 (γ)	0.03–0.1 (ELF) 1–56 (AM)	(24,33)
Solithromycin	400 mg IV	0.8	7	85	6.6	2.4–28.6 (ELF) 44–515 (AM)	(59,60)
Finafloxacin	800 mg oral	11	28		10		(103)
Avarofloxacin	250 mg oral	2	35	65	14	17–64 (ELF) 74–157 (AM)	(109)
Zabofloxacin	400 mg oral	2	11				(114)
Nemonoxacin	500 mg oral	3.5–5	32	16	10–15		(119,120)
Delafloxacin	300 mg IV	10	24	16	8–12		(132,133)

ELF = epithelial lining fluid; AM = alveolar macrophages.

^aTotal concentration, unless stated otherwise.

Table IV. Recent clinical trials posted on the clinicaltrials.gov repository for antibiotics under development.

Study number and development phase	Drugs and doses	Study title	Status
Oritavancin
NCT01784536; phase I	Single-dose IV oritavancin diphosphate; dose not specified	Open Label Study Evaluating the Effects of a Single Oritavancin Infusion on Cytochrome P450 in Healthy Volunteers	Completed (2013)
NCT01762839; phase I	Single-dose IV oritavancin diphosphate (single dose 1600 mg); comparators: placebo, moxifloxacin single dose 400 mg	A Study to Assess the Cardiac Safety of Oritavancin in Healthy Volunteers	Completed (2013)
NCT00514527; phase II	Oritavancin single dose (1200 mg), infrequent dose (800 mg at day 1 and 400 mg at day 5); comparator: versus daily dose of oritavancin (200 mg) for 3–7 days	A Study for Patients With Complicated Skin and Skin Structure Infections (SIMPLIFI)	Completed (2008)
NCT01252719; phase III	Single-dose IV oritavancin diphosphate (1200 mg day 1 followed by placebo); comparator: IV vancomycin	Oritavancin Versus IV Vancomycin for the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infection (SOLO I)	Completed (2012)
NCT01252732; phase III	Single-dose IV oritavancin diphosphate (1200 mg day 1 followed by placebo); comparator: IV vancomycin for 7–10 days (dose not specified)	Oritavancin Versus IV Vancomycin for the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infection (SOLO II)	Completed (2013)
EDP-322 / EDP-788
NCT00989872; phase I	Single ascending dose of EDP-322; comparator: placebo	Safety and Pharmacokinetics of Ascending Single Oral Doses of EDP-322 in Non-fasting and Fasting Healthy Volunteers	Completed (2009)
NCT00990145; phase I	Multiple oral doses of EDP-322 ranging from 200 to 800 mg; comparator: placebo	Multiple Ascending-Dose Study of EDP 322 in Healthy Adult Volunteers	Completed (2009)
NCT01999725; phase I	Single doses with dose escalation to continue in successive cohorts; comparator: placebo	Evaluation of the Safety and Pharmacokinetics of a Single Oral Dose of EDP-788	Not yet recruiting
Solithromycin
NCT01966055; phase I	Solithromycin; dose not specified	Pharmacokinetics and Safety of Solithromycin Capsules in Adolescents	Recruiting
NCT01168713; phase II	Oral solithromycin (800 mg QD day 1; 400 mg QD days 2–5) ; comparator: oral levofloxacin (750 mg QD days 1–5)	Efficacy and Safety Study of Oral CEM-101 Compared to Oral Levofloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia	Completed (2011)
NCT01591447; phase II	Single dose solithromycin 1000 mg by oral route	Safety and Efficacy Study of Single-Dose Oral CEM-101 in Patients With Uncomplicated Urogenital Gonorrhea	Completed (2013)
NCT01968733; phase III	Solithromycin (intravenous with the potential step-down to oral); comparator: moxifloxacin (intravenous with the potential step-down to oral); doses not specified	Efficacy and Safety Study of Intravenous to Oral Solithromycin (CEM-101) Compared to Intravenous to Oral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SOLITAIRE-IV)	Recruiting
NCT01756339; phase III	Solithromycin (800 mg orally on day 1 followed by 400 mg daily on days 2 through 5, followed by placebo on days 6 and 7); comparator: moxifloxacin (400 mg orally on day 1 to 7)	Efficacy and Safety Study of Oral Solithromycin (CEM-101) Compared to Oral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SOLITAIRE-ORAL)	Recruiting
Finafloxacin
NCT00723502; phase II	Finafloxacin 400 mg BID + amoxicillin 1000 mg BID; finafloxacin 400 mg BID + esomeprazole 40 mg BID in patients with Helicobacter pylori infection	Efficacy and Safety Study of Finafloxacin Used in Helicobacter pylori Infected Patients	Completed (2009)
NCT01910883; phase I	Dose-escalating study of single and multiple (7 days) oral doses (200–1000 mg) of finafloxacin IV	Safety and Tolerability of Single and Multiple Intravenous Doses of Finafloxacin in Healthy Subjects	Completed (2012)
NCT01907867; phase I	Finafloxacin 800 mg (4 × 200 mg tablet) QD for 3 days	Pharmacokinetic Profile in Plasma and Epithelial Lining Fluid of Finafloxacin	Completed (2012)
NCT01904162; phase I	Single dose of finafloxacin hydrochloride	Effect of Age and Gender on the Pharmacokinetics and Tolerability of Finafloxacin	Completed (2010)
NCT00483158; phase I	Dose-escalating study of single and multiple oral doses of finafloxacin hydrochloride	First Time in Man Study of Finafloxacin Hydrochloride	Completed (2008)
NCT01928433; phase II	Finafloxacin 800 mg (IV or oral) QD; comparator: ciprofloxacin 400 mg IV or 500 mg oral BID	Finafloxacin for the Treatment of Complicated Urinary Tract Infections (cUTI) and/or Acute Pyelonephritis	Recruiting
NCT00722735, phase II	Oral finafloxacin 300 mg BID for 3 days; comparator: oral ciprofloxacin 250 mg BID for 3 days	Finafloxacin 300 mg Twice a Day (BID) Versus Ciprofloxacin 250 mg Twice a Day (BID) in Patients With Lower Uncomplicated UTI (uUTI) (FLUT)	Completed (2009)
Zabofloxacin
NCT01341249; phase I	Single oral administration in healthy male volunteers of 488 mg zabofloxacin aspartate tablet and 400 mg zabofloxacin hydrochloride capsule	A Study to Compare the Pharmacokinetic Profiles of DW224aa (Zabofloxacin aspartate) and DW224a (Zabofloxacin hydrochloride)	Completed (2011)
NCT01081964;	Zabofloxacin (400 mg orally QD for 3 or 5 days); comparator: levofloxacin (500 mg orally QD for 7 days)	Safety and Efficacy Study of Oral Zabofloxacin in Community Acquired Pneumonia	Completed (2012)
NCT01658020; phase III	Zabofloxacin (400 mg orally QD); comparator: moxifloxacin (400 mg orally QD)	A Study to Evaluate Efficacy and Safety Profile of Zabofloxacin Tablet 400 mg and Moxifloxacin Tablet 400 mg (DW224-III-3) after Multi-dose Oral Administration in Patients With Acute Bacterial Exacerbation of Chronic Obstructive Pulmonary Disease.	Ongoing, not recruiting
Nemonoxacin
NCT01395108; phase I	Single and multiple ascending oral doses of nemonoxacin	Clinical Study on Oral Nemonoxacin Malate Capsules	Completed (2008)
NCT01529957; phase I	Single and multiple ascending IV doses of nemonoxacin	A Study of Nemonoxacin Malate Sodium Chloride Injection Administered by Intravenous Infusion	Completed (2011)
NCT00434291; phase II	Not provided	Safety and Efficacy Comparison of TG-873870 (Nemonoxacin) to Levofloxacin in Community-Acquired Pneumonia	Completed (2009)
NCT00685698; phase II	Nemonoxacin 750 mg, oral administration, once daily for 7 ± 1 and 14 ± 1 days	Safety and Efficacy Study of TG-873870 (Nemonoxacin) in Diabetic Foot Infections	Completed (2009)
NCT01537250; phase II	Nemonoxacin (750 mg orally 2 tablets or 500 mg orally 3 tablets) ; comparator: levofloxacin (500 mg orally QD + placebo) for 7 days	Study to Assess the Efficacy and Safety of Nemonoxacin Malate in Treating Adult Patients With Community-acquired Pneumonia (CAP)	Completed (2010)
NCT01944774; phase II	Nemonoxacin (500 mg or 650 mg QD IV for 7–14 days); comparator: moxifloxacin (400 mg QD IV for 7–14 days)	Study to Evaluate the Efficacy and Safety of Intravenous Infusion With TG-873870 (Nemonoxacin) Versus Moxifloxacin in Treating Adult Patients With Community Acquired Pneumonia (CAP)	Recruiting
NCT01529476; phase III	Nemonoxacin (500 mg orally); comparator levofloxacin (500 mg orally) for 7–14 days	Study to Evaluate the Efficacy and Safety of Oral Administration With Nemonoxacin and Levofloxacin in Patients With Community-acquired Pneumonia (CAP)	Completed (2012)
Delafloxacin
NCT00719810; phase II	Delafloxacin (300 mg or 450 mg IV BID); comparator: tigecycline (100 mg on day 1 then 50 mg IV BID)	Safety and Efficacy Study of a Fluoroquinolone to Treat Complicated Skin Infections	Completed (2008)
NCT01283581; phase II	Delafloxacin (300 mg IV BID) for 5–14 days; comparators: linezolid (600 mg IV BID) and vancomycin (15 mg/kg, up to 1250 mg, IV BID) for 5–14 days	A Study to Assess Objective Endpoint Measurements of Response in Bacterial Skin Infections	Completed (2011)
NCT02015637; phase III	Delafloxacin 900 mg orally (2 × 450 mg) QD; comparator: ceftriaxone (250 mg IM QD)	Comparison of Delafloxacin Versus Ceftriaxone for the Treatment of Uncomplicated Gonorrhea	Recruiting
NCT01811732; phase III	Delafloxacin (300 mg IV BID) for 5–14 days; comparator: vancomycin (15 mg/kg IV) + aztreonam (2 g) BID	Delafloxacin Versus Vancomycin and Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections	Recruiting
NCT01984684; phase III	Delafloxacin (300 mg IV BID 300 mg iv BID for 3 days) followed by 450 mg oral BID for 5–14 days total; comparator: vancomycin (15 mg/kg IV) + aztreonam (2 g) BID	Delafloxacin vs Vancomycin and Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections	Not yet recruiting

Figure 2. Chemical structure of ketolides in development as compared to telithromycin. Major changes are highlighted together with their main consequences for activity or pharmacokinetics. The structure of EDP-322 having not yet been released, modithromycin is presented as an exemplative typical bridged bicyclic ketolide.

Figure 3. Chemical structure of new fluoroquinolones in clinical development. The substituents in position 1 and 8 known to confer high intrinsic activity are on a gray background. Other specific features are highlighted by black arcs.

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