Open Forum Infectious Diseases REVIEW ARTICLE An Updated Review of Iclaprim: A Potent and Rapidly Bactericidal Antibiotic for the Treatment of Skin and Skin Structure Infections and Nosocomial Pneumonia Caused by Gram-Positive Including Multidrug-Resistant Bacteria 1 3 3 2 4 5 David B. Huang, Catherine D. Strader, James S. MacDonald, Mark VanArendonk, Richard Peck, and Thomas Holland 1 2 3 4 Motif BioSciences, New York, New York; Rutgers New Jersey Medical School, Vermeer Pharma, Morristown, New Jersey, Synergy Partners R&D Solutions, Chester, New Jersey; Hemex, Liestal, Switzerland, Duke University Medical Center, Durham, North Carolina New antibiotics are needed because of the increased morbidity and mortality associated with multidrug-resistant bacteria. Iclaprim, a bacterial dihydrofolate reductase inhibitor, not currently approved, is being studied for the treatment of skin infections and noso- comial pneumonia caused by Gram-positve bacteria, including multidrug-resistant bacteria. Iclaprim showed noninferiority at –10% to linezolid in 1 of 2 phase 3 studies for the treatment of complicated skin and skin structure infections with a weight-based dose (0.8 mg/kg) but did not show noninferiority at –10% to linezolid in a second phase 3 study. More recently, iclaprim has shown noninferiority at –10% to vancomycin in 2 phase 3 studies for the treatment of acute bacterial skin and skin structure infections with an optimized fixed dose (80 mg). A phase 3 study for the treatment of hospital-acquired bacterial and ventilator-associated bacterial pneumonia is upcoming. If, as anticipated, iclaprim becomes available for the treatment of skin and skin structure infections, it will serve as an alternative to current antibiotics for treatment of severe infections. This article will provide an update to the chemistry, preclinical, pharmacology, microbiology, clinical and regulatory status of iclaprim. Keywords. bactericidal; iclaprim; multidrug-resistant bacteria; pneumonia; skin infections. Antimicrobial resistance is a growing public health threat world- Over decades, methicillin-resistant Staphylococcus aureus wide . The US Centers for Disease Control and Prevention esti- (MRSA) has become increasingly common . MRSA causes mates that each year in the United States, 2 million people become significantly higher rates of morbidity and mortality compared infected with antibiotic-resistant bacteria and at least 23 000 with nonresistant S. aureus . Furthermore, vancomycin-in- people die each year as a direct result of these infections . The termediate S. aureus (VISA) and heterogeneous VISA (hVISA) economic impact of antibiotic-resistant infections has been exten- are reported in cases of vancomycin treatment failures . With sively documented; the estimated cost to the health care system the increased use of vancomycin to treat MRSA, the emergence in the United States has been placed at more than $8 billion . of vancomycin resistance became inevitable , although still a Patients with resistant infections require longer hospital stays, relatively uncommon phenomenon. Resistance is also reported more doctors’ visits, and lengthier recuperations and experience among S. aureus isolates to linezolid and daptomycin . a higher incidence of long-term disability . Considering these Iclaprim is an antibiotic, not currently approved, that is effect- costs, the total economic burden has been estimated at $20 billion, ive against Gram-positive multidrug-resistant bacteria such as plus $35 billion a year in lost productivity [3, 5]. MRSA. Iclaprim also has activity against some Gram-negative bacteria (ie, Haemophilus inu fl enzae and Moraxella catarrhalis ). er Th e exists only 1 other antibiotic in its class as a dihydrofolate reductase inhibitor, trimethoprim . Iclaprim was designed to overcome trimethoprim resistance with increased potency with- Received 21 September 2017; editorial decision 22 December 2017; accepted 5 January out the need for co-administration of sulphonamides, thereby Correspondence: D. Huang, MD, PhD, FACP, FIDSA, MotifBioSciences, 125th Park Avenue, avoiding the sulphonamide-associated safety issues such as rashes, 25th Floor, New York, NY 10017 (email@example.com) hypersensitivity reactions (eg, Stevens Johnson Syndrome), blood Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases dyscrasias, drug-drug interactions leading to hypoglycemia or Society of America. This is an Open Access article distributed under the terms of the Creative gastrointestinal hemorrhage, and life-threatening hyperkalemia Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any . This article is intended to provide an update to the chem- medium, provided the original work is not altered or transformed in any way, and that the work istry, pharmacology, microbiology, and preclinical, clinical, and is properly cited. For commercial re-use, please contact firstname.lastname@example.org regulatory status of iclaprim for health care providers. DOI: 10.1093/ofid/ofy003 Iclaprim for Skin Infections and Nosocomial Pneumonia • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 DISCOVERY AND MOLECULAR CHARACTERIZATION Iclaprim is a racemate, and both enantiomers have been OF ICLAPRIM shown to be equipotent against various bacterial DHFR enzymes and to exhibit similar antimicrobial activity against a Iclaprim is a selective and potent inhibitor of the bacterial en- broad range of bacteria (Table 2) . zyme dihydrofolate reductase (DHFR), a key enzyme required for the synthesis of thymidine. The discovery of iclaprim relied ADMINISTRATION on crystallography to optimize its interactions with DHFR, and the compound was specifically designed to bind to tri- Iclaprim is produced as a sterile concentrate already in solution methoprim-resistant DHFR by making additional hydrophobic that is dosed at 80 mg intravenously by dilution into 250-mL or contacts in the substrate-binding pocket of the enzyme . 500-mL common solutions such as normal saline, 5% dextrose, Therefore, iclaprim retains activity against trimethoprim-re- or lactated ringers; these are infused over 120 minutes every sistant DHFRs, including the F98Y mutant enzyme most com- 12 hours for 5 to 14 days for the treatment of acute bacterial monly associated with trimethoprim resistance in S. aureus and skin and skin structure infections and nosocomial pneumonia the I100L mutation associated with trimethoprim resistance in caused by or suspected to be Gram-positive bacteria. In add- S. pneumoniae . This improved enzymological profile trans- ition, an oral dosage formulation of iclaprim is being developed. lates to improved bacterial minimal inhibitory concentrations PRECLINICAL SAFETY (MICs) against both wild-type and trimethoprim-resistant bac- teria in microbiology studies (see the “Microbiology” section Iclaprim has been extensively evaluated for potential adverse below). effects in in vitro studies and conventional toxicology studies Iclaprim is 20-fold more potent in inhibiting DHFR than tri- in animals following oral and intravenous (IV) drug adminis- methoprim . From a structural perspective, iclaprim shares tration (unpublished data). Iclaprim is rapidly distributed to many similarities and some key differences when compared tissues after IV administration and achieves plasma levels in with trimethoprim. Iclaprim is a tricyclic, and trimethoprim is humans that provide adequate exposure multiples to the desired a dicyclic diaminopyrimidine. Both trimethoprim and iclaprim therapeutic exposures (unpublished data). The drug is exten- interrupt the folate synthesis pathway at the same point, block- sively metabolized by both phase I and phase II enzymes; none ing the progression from dihydropteroic acid to tetrahydrafolic of the metabolites show antimicrobial activity. Urinary excre- acid (Figure 1). tion is the primary route of elimination of the drug in humans. OH OH Dihydropteroate diphosphate p-amino benzoic acid P P N O OH H N O 2 H N N N H H Dihydropteroate synthetase O OH Dihydropteroic acid N N H N H H O OH N OH N N Dihydrofolic acid H O H N N N H H NH Dihydrofolate Iclaprim Reductase H N N O O OH O H Tetrahydrofolic acid N H O H HO H N N N H H Figure 1. Dihydrofolate reductase inhibited by iclaprim in the folate synthesis pathway. 2 • OFID • Huang et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 The drug is a substrate of CYP3A4 (eg, warfarin) and CYP2C19 passages in a similar experiment using subtherapeutic concen- (eg, omeprazole); no inhibition or induction of these enzymes trations of trimethoprim (unpublished data). has been observed in vitro or in human studies that would Pharmacokinetic/pharmacodynamic (PK/PD) analysis of suggest the potential for important drug interaction issues the data from a thigh infection model indicated that area under (unpublished data). The potential effect of the drug on major the curve (AUC)/MIC and time above MIC (T > MIC) were transporters was also evaluated. Similar to trimethoprim, sig- the parameters most closely associated with efficacy of iclaprim nificant inhibition of several primarily renal transporters was in vivo (unpublished data). No specific AUC/MIC or T > MIC observed (OCT1, OCT2 [eg, metformin], and MATE2-K) (un- target was identified in these experiments because of the high published data). Importantly, no consequent effect (ie, hypo- concentrations of thymidine in serum and tissues of mice (100- glycemia) of OCT inhibiton was seen clinically in patients fold greater than human), which bypasses the DHFR enzyme. receiving metformin and iclaprim, and this effect is thought to As shown in Figure 2 for S. pneumoniae, the correlation coeffient be clinically unimportant . R is 0.86 for efficacy vs both AUC/MIC and T > MIC, whereas Overall, the comprehensive preclinical safety studies with R = 0.4 for C /AUC; similar correlations were observed with max iclaprim demonstrate strong support for demonstration of S. aureus. These data suggest that duration of exposure is more safety of the drug in clinical studies. important than peak drug concentrations in optimizing the ef- ficacy of iclaprim. PHARMACOLOGY Human Pharmacokinetics Preclinical Pharmacology Iclaprim achieves high concentrations in skin and skin struc- Iclaprim is rapidly bactericidal against Gram-positive bacteria ture and lung compartments. Icalprim also rapidly concentrates in vitro, with > 99% reduction of bacterial colony-forming units in the gastrointestinal tract, adrenal glands, kidneys, and liver, (CFUs) occurring within 8–24 hrs of exposure to concentra- with a high volume of distribution exceeding 4–5 times the total tions as low as 2-fold above the MIC . In addition, iclaprim body water volume. Iclaprim has 93% plasma protein binding. exhibits a significant postantibiotic effect for up to 10 hours at Iclaprim and its metabolites are rapidly and extensively excreted sub-MIC concentrations, consistent with its effect on thymidine in the bile and urinary route. Iclaprim is metabolized by both biosynthetic pathways . This combination of rapid bacteri- phase 1 (CYP3A4 and CYP23C19) and phase 2 (CYP2C9 and cidal activity followed by a prolonged postantibiotic effect has CYP2D6) enzymes. Most of the phase 1 metabolites are subse- been exploited during development to maintain the efficacy of quently conjugated to glucuronide metabolites. Less than 2% of iclaprim between dosing periods in the clinic, thereby support- unchanged iclaprim was found in urine and feces, confirming ing twice-daily dosing regimens in clinical studies. extensive metabolism. Iclaprim has been studied in serial passage studies. Aer 17 ft Pharmacokinetic parameters of iclaprim from population serial passages of S. aureus strains in the presence of subther- PK in cSSSI pivotal studies with dosing of 0.8 mg/kg every 12 apeutic levels of iclaprim, there was only a modest increase in hours gave similar values to those obtained in phase 1 PK stud- MIC from 0.12 to 1 µg/mL, which returned to baseline aer r ft e- ies (Table 1). The initial phase 1 studies of weight-based doses of moval of iclaprim. In contrast, trimethoprim showed the devel- iclaprim showed the PK of iclaprim to be linear, with dose-pro- opment of high-level resistance (MIC > 128 µg/mL) within 12 portional increases in both AUC and C over a wide range max 1.0 2 2 2 R = 86% R = 40% R = 89% 0.5 0.0 –0.5 –1.0 –1.5 31030 100 2.5 51020406080 100 8-h AUC/MIC Peak/MIC T/MIC, % Figure 2. The AUC/MIC and T > MIC are the pharmacodynamics parameters associated with the efficacy of iclaprim against Streptococcus pneumoniae (ATCC 10813) in a thigh infection model of neutropenic mice. Abbreviations: AUC, area under the curve; CFU, colony-forming unit; MIC, minimal inhibitory concentration; T, time. Iclaprim for Skin Infections and Nosocomial Pneumonia • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Change in log CFU/thigh after 8 h of therapy Table 1. Key Pharmacokinetic Parameters of Iclaprim postantibiotic effect, this modified dosing regimen translated into an improved efficacy and safety profile in the REVIVE Pharmacokinetic Parameters Values studies, as detailed below. C , ng/mL 807 +/- 359 max MICROBIOLOGY Area under the curve (each 12-h interval after dose with 2164 +/- 987 q12h dosing regimen), ng*h/mL Iclaprim is active against common skin (ie, S. aureus Half life, h 4.61 (+/-3.84) MIC = 0.12 µg/mL, Streptococci pyogenes MIC = 0.25 µg/ Clearance, nl/min 67 +/- 227 90 90 Volume ss, L/kg 1.56 +/- 0.7 mL, Streptococci agalactiae MIC = 0.25 µg/mL, and other Streptococci spp.) (Table 2) and respiratory pathogens (ie, Streptococcus pneumoniae MIC = 2 µg/mL, S. aureus of doses . Exposure did not change over time for up to 10 MIC = 0.12 µg/mL, Haemophilus influenzae MIC = 0.12 µg/ sequential days of dosing, nor was exposure altered in subjects 90 90 mL, and Moraxella catarrhalis MIC = 0.12 µg/mL), including with renal impairment. A 2-fold increase in AUC was observed emerging drug-resistant pathogens (Table 2) . Comparison in subjects with moderate hepatic impairment, suggesting that of MICs shows that iclaprim is at least 8-fold more potent against dose adjustments may be indicated in that population. Iclaprim Gram-positive bacteria than trimethoprim. Iclaprim was active is not a potent inhibitor of CYP450 enzymes, and drug-drug (defined as an MIC ≤1 µg/mL) against MRSA isolates that were interaction (DDI) studies showed a less-than-2-fold increase in nonsusceptible to daptomycin (71%), linezolid (100%), or van- iclaprim levels in the presence of of the CYP3A4 inhibitor keto- comycin (67%). In time-kill curves analyses, iclaprim demon- conazole. Therefore, no dose adjustments are indicated when strated ≥3 log reduction in CFU/mL at 4–8 hours for tested iclaprim is co-administered with inhibitors or substrates of strains and isolates nonsusceptible to daptomycin, linezolid, or CYP450 enzymes. In addition, unlike trimethoprim-sulfameth- vancomycin (Figure 3) . oxazole, iclaprim has no effect on renal excretion of potassium and serum potassium concentrations. CLINICAL Clinical phase 1 drug distribution studies showed that IV-administered iclaprim diffuses readily into the lung. The One phase 2 and 2 phase 3 clinical trials have been completed concentrations in alveolar macrophages and pulmonary epithe- for iclaprim for the treatment of cSSSIs (called ASSIST-1 and lial fluid were 20–40-fold higher than in plasma, suggesting that ASSIST-2), 2 phase 3 clinical trials for the treatment of ABSSSI the drug accumulates in tissues that are relevant to pulmonary (called REVIVE-1 and REVIVE-2), and 1 phase 2 clinical trial infection . for the treatment of hospital-acquired bacterial pneumonia (HABP) (Table 3). Human Dose Optimization In order to optimize the dosing regimen for the REVIVE phase Phase 2 for the Treatment of cSSSI 3 clinical trials of ABSSSI [18, 19], the PK data from the phase A randomized, double-blind phase 2 study compared the effi- 3 ASSIST trials of cSSSI were analyzed for information that cacy and safety of iclaprim with those of vancomycin in patients could improve the efficacy and safety parameters in patients. with cSSSI . Eighty-seven patients were randomized to re- An important observation from the PK parameters in ASSIST, ceive 0.8 mg/kg or 1.6 mg/kg of iclaprim or 1 g of vancomycin, in which patients were dosed with 0.8 mg/kg of iclaprim using all administered twice a day for 10 days. Patient demographics a 30-minute infusion twice daily, was that the clearance of recorded at baseline were similar in all treatment groups. Nearly iclaprim does not change with body weight . Therefore, a all patients had signs and symptoms of discharge, erythema, fixed dose of iclaprim was pursued in REVIVE , rather than swelling, induration, heat, localized warmth, pain and tender- the weight-based dosing used in ASSIST. Population PK/PD ness to palpitation, and evidence of systemic signs and symp- modeling was conducted using the PK data obtained by sparse toms of infection such as fever (38°C/100.4°F), enlarged and/ sampling on patients in the ASSIST trials to examine the effect or tender proximal lymphadenopathy and/or lymphangitis, ele- of dose and infusion rate on the parameters most important for vated WBCs (>10 000/mm ), and/or >10% bands. efficacy (eg, maximize AUC/MIC and T > MIC) and for safety Clinical cure rates for the 0.8 mg/kg (26/28, 92.9%) and (eg, minimize C ). Through an interactive modeling process, 1.6 mg/kg (28/31, 90.3%) iclaprim intent-to-treat (ITT) treat- max a dose of 80 mg, given as a 2-hour infusion every 12 hours, was ment groups were comparable to that of the vancomycin treat- determined to provide the optimal regimen for all 3 parameters ment group (26/28, 92.9%). Infection sources and/or types . This regimen was projected to result in a 28% increase in included ulcers, cellulitis, animal bites, burns, and major AUC/MIC and a 32% increase in T > MIC compared with the abscesses. There were no signficant differences in the clinical weight-based regimen used in ASSIST, while keeping the mean cure rate for the infection types at day 10 or at the test of cure C below the 800 ng/mL level that was associated with QTc (TOC) visit across study arms. Iclaprim exhibited a micro- max prolongation in phase 1. Combined with the previously noted biological eradication rate for S. aureus, the pathogen most 4 • OFID • Huang et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Activity of Iclaprim and Comparator Agents Tested Against frequently isolated at baseline, of 80% for the 0.8 mg/kg group Staphylococcus aureus and Beta-Hemolytic Streptococci Isolates From and 72% for the 1.6 mg/kg group, compared with 59% for the the United States and the Rest of the World  group treated with vancomycin. Iclaprim exhibited a safety profile similar to that of vanco- Minimum Inhibitory Concentration, µg/mL mycin. Among patients reporting adverse events considered related to the study drug, 2 were from the 1.6 mg/kg iclaprim 2007–2008 2012–2014   group (pruritis and erythema) and 3 were from the vancomycin Organism and Antimicrobial Agent 50%/90% 50%/90% group (tremor, pruritis, and dermatitis medicamentosa). No Methicillin-sensitive Staphylococcus n = 1513 n = 596 drug-related adverse events were recorded in the 0.8 mg/kg aureus group. Iclaprim 0.06/0.12 0.06/0.12 Trimethoprim 1/1 1/2 Phase 3 for the Treatment of cSSSI Trimethoprim-sulfamethoxazole 0.06/0.06 0.06/0.06 Two randomized, double-blind phase 3 studies compared the ef- Clindamycin ≤0.12/≤0.12 NT ficacy and safety of iclaprim with those of linezolid in patients Tetracycline ≤0.5/≤0.5 ≤0.5/≤0.5 with cSSSI. In ASSIST-1, 497 patients were randomized to receive Linezolid 2/2 1/1 Vancomycin 1/1 1/1 0.8 mg/kg of iclaprim (n = 249) or 600 mg of linezolid (n = 248), Methicillin-resistant S. aureus n = 3003 n = 582 both administered twice a day for 7–14 days . In ASSIST-2, Iclaprim 0.06/0.12 0.06/0.5 494 patients were randomized to receive 0.8 mg/kg of iclaprim Trimethoprim 1 /2 2/8 (n = 251) or 600 mg of linezolid (n = 243), both administered Trimethoprim-sulfamethoxazole 0.06/0.25 0.06/0.25 twice a day for 7–14 days . The average treatment duration Clindamycin ≤0.12/>4 NT for both iclaprim and linezolid was 10 days. Patient demo- Tetracycline ≤0.5/>16 ≤0.5/>8 Linezolid 2/2 1/1 graphics (age, gender, race, body mass index), lesion types (ap- Vancomycin 1/1 1/1 proximately 25% major abscess, 30% wound infections, and 45% Streptococci pyogenes n = 604 n = 98 cellulitis/ulcers/burns), laboratory parameters (eg, WBC counts), Iclaprim 0.015/0.03 0.06/0.25 vital signs (eg, fever), and systemic signs and symptoms of in- Trimethoprim 0.25/0.5 1/2 fection recorded at baseline were similar in all treatment groups. Trimethoprim-sulfamethoxazole 0.06/0.12 0.12 . 0.25 Erythromycin ≤0.12/>4 ≤0.12/>16 The primary end point was clinical cure, as defined as resolution Clindamycin ≤0.12/≤0.12 NT of all signs and symptoms (discharge, erythema, swelling and/or Tetracycline ≤0.5/≤0.5 >8/>8 induration, heat and/or localized warmth, and/or pain or tender- Vancomycin ≤0.5/≤0.5 0.25/0.5 ness to palpation) present at baseline of cSSSI and not receiving Linezolid 1/1 1/1 any new systemic or topical antibacterial treatment. Penicillin ≤0.06/ ≤0.06 NT Based on the Sponsor analysis, in ASSIST-1, iclaprim clin- Streptococci agalactiae n = 204 n = 101 Iclaprim 0.12/0.25 0.06/0.25 ical cure rates at TOC were comparable with linezolid at 83.1% Trimethoprim 1/4 1/2 (207/249) and 88.7% (220/248), respectively (treatment differ - Trimethoprim-sulfamethoxazole 0.06/0.12 0.12/0.25 ence, –5.6%; 95% confidence interval [CI], –11.72% to 0.6%) Erythromycin ≤0.12/>4 ≤0.12/>16 . In ASSIST-2, iclaprim clinical cure rates at TOC were com- Clindamycin ≤0.12/>4 NT parable, with linezolid at 81.3% (204/251) and 81.9% (199/243), Tetracycline >16/>16 >8/>8 respectively (treatment difference, –0.6%; 95% CI, –7.7% to Vancomycin ≤0.5/≤0.5 0.25/0.5 Linezolid 1/1 1/1 6.5%) . The pooled clinical cure rates for iclaprim and lin- Penicillin ≤0.06/≤0.06 NT ezolid were 82.2% (411/500) and 85.3% (419/491), respectively Streptococci pneumoniae n = 785 (Zhanel 2009) n = 259 (treatment difference, –3.1%; 95% CI, –7.9% to 1.6%). Iclaprim Iclaprim ≤0.03/1 0.06/2 was well tolerated in both studies, with most adverse events, Trimethoprim NT 2 /64 such as headache, nausea, vomiting, and fatigue, categorized Trimethoprim-sulfamethoxazole NT 0.25/8 as mild. However, because the 2 studies did not independently Clarithromycin/erythromycin 0.06/0.12 ≤0.12/>16 Ciprofloxacin/levofloxacin ≤0.03/0.06 1 /1 meet the noninferiority margin of 10% for clinical cure, the Doxycycline/tetracycline ≤0.03/0.06 ≤0.5/>8 Food and Drug Administration (FDA) did not approve iclaprim Vancomycin NT 0.25/0.5 for the treatment of cSSSI. Linezolid NT 1 /1 Penicillin ≤0.03/0.06 ≤0.6/2 Phase 3 for the Treatment of ABSSSI Two randomized, double-blind phase 3 studies compared the Abbreviation: NT, not tested. efficacy and safety of iclaprim with those of vancomycin in Iclaprim for Skin Infections and Nosocomial Pneumonia • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 MRSA, daptomycin-resistant Strain MRSA, linezolid-nonsusceptible Strain (MIC ≥ 4 μg/mL), Clinical Isolate (MIC ≥ 8 μg/mL), ATCC 986537, NRS271 1.E+10 1.E+10 1.E+09 1.E+09 1.E+08 1.E+08 1.E+07 1.E+07 1.E+06 1.E+06 1.E+05 1.E+05 1.E+04 1.E+04 1.E+03 1.E+03 1.E+02 1.E+02 1.E+01 1.E+01 02 48 24 02 48 24 Hours Hours Growth control Iclaprim Vancomycin Linezolid Growth control Iclaprim Daptomycin Linezolid MRSA, vancomycin-resistant Strain (MIC ≥ 32 μg/mL), ATCC 1409053, vanA-positive 1.E+10 1.E+09 1.E+08 1.E+07 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 02 48 24 Hours Growth control Iclaprim Vancomycin Linezolid Figure 3. Iclaprim is rapidly bactericidal in time-kill curves, 2X MIC for all antibodies, against methicillin-resistant Staphylococcus aureus isolates, which were also not sus- ceptible to daptomycin, linezolid, or vancomycin. Abbreviations: CFU, colony-forming unit; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus. Table 3. Phase 2 and 3 Clinical Trials Studying Iclaprim Indication Phase Dosages Year Results Reference HABP 2 Iclaprim 0.8 mg/kg IV q12h; 2007–2008 Iclaprim comparable to vancomycin at clinical cure at  iclaprim1.2 mg/kg IV q8h; test of cure (iclaprim q12h 73.9% [17/23], iclaprim q8h vancomycin 1 g IV q12h 62.5% [15/24], vancomycin 1g 52.2% [12/23]. Iclaprim comparable to vancomycin at day 28 mortality (icl- aprim q12h 8.7% [2/23], iclaprim q8h 12.5% [3/24], vancomycin 1 g 21.7% [5/23]). cSSSI 2 Iclaprim 0.8 mg/kg IV q12h; 2006–2007 Iclaprim noninferior to vancomycin at primary FDA end  iclaprim 1.6 mg/kg IV q12h; point of clinical cure at test of cure (iclaprim 0.8 mg/ vancomycin 1 g IV q12h kg 92.9% [26/28], iclaprim 1.6 mg/kg 90.3% [28/31] compared with vancomycin 92.9% [26/28]). cSSSI 3 Iclaprim 0.8 mg/kg IV q12h; 2007–2008 In ASSIST-1, iclaprim clinical cure (iclaprim 83.1%  linezolid 600 mg IV q12h [207/249]) comparable to linezolid (88.7% [220/248]) at test of cure (treatment difference, –5.6%; 95% CI, –11.72% to 0.6%). cSSSI 3 Iclaprim 0.8 mg/kg IV q12h; 2007–2008 In ASSIST-2, iclaprim clinical cure (iclaprim 81.3%  linezolid 600 mg IV q12h [204/251]) noninferior to linezolid (81.9% [199/243]) at test of cure (treatment difference, –0.6%; 95% CI, –7.7% to 6.5%). ABSSSI 3 Iclaprim 80 mg IV q12h; van- 2016–2017 In REVIVE-1, iclaprim noninferior to vancomycin at pri-  comycin 15 mg/kg IV q12h mary FDA end point of early clinical response (iclaprim 80.9% [241/298] compared with vancomycin 81.0% [243/300]). ABSSSI 3 Iclaprim 80 mg IV q12h; van- 2016–2017 In REVIVE-2, iclaprim noninferior to vancomycin at pri- Unpublished comycin 15 mg/kg IV q12h mary FDA end point of early clinical response (iclaprim 78.3% [231/295] compared with vancomycin 76.7% [234/305]). Abbreviations: ABSSSI, acute bacterial skin and skin structure infection; cSSSI, complicated skin and skin structure infections; HABP, hospital-acquired pneumonia; IV, intravenous; VABP, ventilator-associated bacterial pneumonia. 6 • OFID • Huang et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Log CFU/mL Log CFU/mL Log CFU/mL patients with ABSSSI. The inclusion criteria for these 2 studies signs and symptoms: cough; new onset of purulent sputum were a bacterial infection of the skin (major cutaneous abscess, production or a change (worsening) in character of sputum; cellulitis/erysipelas, and/or wound infections) with a lesion size dyspnea, tachypnea, or hypoxemia with a partial pressure oxy- area of at least 75 cm and the presence of purulent or sero- gen <60 mm Hg and at least 2 signs and symptoms of systemic purulent drainage or at least 3 signs and symptoms of infec- infection such as fever or respiratory rate >30 breaths/min; tion (discharge, erythema, swelling, warmth, and/or pain). One pulse rate >120 beats/min; altered mental status; WBC count 3 3 study has completed (REVIVE-1) , and the second is await- >10 000/mm or <4500/mm ; and/or >15% immature neutro- ing completion of final analyses (REVIVE-2). In REVIVE-1, phils (bands). In addition, all patients had a new pulmonary 598 patients were randomized to receive 80 mg of iclaprim infiltration documented by chest radiograph, a suitable respira- or 15 mg/kg of vancomycin, each administered twice a day tory specimen for culture, a Gram stain with a Gram-positive for 5–14 days. The actual mean duration of treatment in each pathogen, and a clinical pulmonary infection score (CPIS) >6. group was 7 days for both iclaprim and vancomycin. For each Seventy patients were randomized to receive 0.8 mg/kg IV q12h patient, the unblinded pharmacist relayed the creatinine clear- (n = 23) or 1.2 mg/kg q8h (n = 24) of iclaprim or 1 g q12 h of ance or vancomycin trough levels (to which the investigator was vancomycin (n-23), all administered twice a day for 7–14 days. blinded) to adjust the vancomycin dosage to maintain a trough Aztreonam was permitted for patients whose pneumonia was of 10–15 mg/L for patients with an organism with an MIC that caused by mixed (gram-positive and aztreonam-susceptible was ≤1 mg/L, or 15–20 mg/L for those with an MIC >1 mg/L. gram-negative) pathogens. Patient demographics and microbi- Patient demographics recorded at baseline were similar in all ology recorded at baseline were similar in all treatment groups. treatment groups. The primary end point, which was FDA The most common isolated pathogen was S. aureus (71%), and approved on the basis of its clinical relevance, of this study 40% of these were MRSA. There were no ventilator associ- was a ≥20% reduction in lesion size (early clinical response ated pneumonia (VAP) patients in the study. The primary end [ECR]) compared with baseline among patients randomized to point was clinical cure, defined as complete resolution of all iclaprim or vancomycin at the early time point (ETP), 48 to 72 signs and symptoms of pneumonia (tachypnea, cough, rigors or hours after the start of administration of the study drug in the shaking chills, rales, pulmonary consolidation, hypoxia, pleu- ITT population. ritic chest pain, purulent sputum production, and respiratory In REVIVE-1, iclaprim achieved noninferiority compared secretions), improvement or lack of progression of all abnor- with vancomycin; 80.9% (241 of 298) of patients receiving malities on chest radiograph, and no further antibiotic treat- iclaprim demonstrated an ECR at the ETP compared with ment at the TOC visit. 81.0% (243 of 300) of patients receiving vancomycin (treat- Cure rates in the ITT population were 73.9% (17 of 23), 62.5% ment difference, –0.13%; 95% CI, –6.42% to 6.17%) . In (15 of 24), and 52.2% (12 of 23) in the iclaprim q12h, iclaprim REVIVE-2, the topline results showed that iclaprim achieved q8h, and vancomycin groups, respectively (iclaprim q12h vs noninferiorty compared with vancomycin; 78.3% (231 of vancomycin, P = .13; iclaprim q8h vs vancomycin, P = .47). 295) of patients receiving iclaprim demonstrated an ECR at the e m Th ortality rates within 28 days of the start of treatment ETP compared with 76.7% (234 of 305) of patients receiving were 8.7% (2 of 23), 12.5% (3 of 24), and 21.7% (5 of 23) for the vancomycin (treatment difference, 1.58%; 95% CI, –5.10% to iclaprim q12h, iclaprim q8h, and vancomycin groups, respect- 8.26%) (unpublished data). Iclaprim was well tolerated in both ively (no statistically significant differences). The adverse event studies, with most adverse events, such as headache, nausea, profile of both iclaprim dosing regimens was similar to that of vomiting, and fatigue, categorized as mild. In REVIVE-1, the vancomycin. The following treatment-emergent adverse events most common adverse effects (≥5%) for iclaprim- and van- were reported in 2 or more patients: thrombocythemia (vanco- comycin-treated patients were headache (10.2% and 2.4%), mycin 2, iclaprim 1), diarrhea (vancomycin 2, iclaprim 0), and nausea (9.9% and 5.7%), secondary ABSSSI (6.8% and 3.3%), prolonged QTc (vancomycin 0, iclaprim 2). fatigue (6.1% and 3.0%), and vomiting (4.8% and 5.1%), respec- REGULATORY tively. In REVIVE-2, the most common adverse event (>5%) for iclaprim- and vancomycin-treated patients was nausea (5.7% Iclaprim is being developed to treat ABSSSI, HABP including and 5.6%, respectively). VABP, and other infections attributed to Gram-positive patho- gens including multidrug-resistant pathogens. Phase 2 for the Treatment of HABP Two phase 3 clinical studies in cSSSI (ie, ASSIST-1 and -2), A randomized, double-blind phase 2 study compared the effi- statistically powered to demonstrate noninferiority to linezolid cacy and safety of iclaprim with those of vancomycin in patients with a prespecified margin of 12.5%, were completed in 2007. with nosocomial pneumonia suspected or confirmed to be In November 2008, an FDA Advisory Committee meeting was caused by Gram-positive pathogens . Patients were diag- held to discuss the efficacy data from these 2 phase 3 studies. The nosed with pneumonia by having at least 2 of the following Advisor y C ommittee recommended that iclaprim not be approved Iclaprim for Skin Infections and Nosocomial Pneumonia • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6. European Centre for Disease Prevention and Control. Antimicrobial resistance for the cSSSI indication based on these data because the nonin- surveillance in Europe. https://ecdc.europa.eu/sites/portal/files/media/en/pub- feriority margin of greater than 10% in ASSIST-2 (ie, –11.7%) lications/Publications/antimicrobial-resistance-europe-2015.pdf. Accessed 15 was considered unacceptable. A complete response letter from September 2017. 7. van Hal SJ, Jensen SO, Vaska VL, et al. Predictors of mortality in Staphylococcus the FDA stated, among other items, that “an additional study or aureus bacteremia. Clin Microbiol Rev 2012; 25:362–86. studies would be required to demonstrate the effectiveness of 8. Rehm SJ, Tice A. Staphylococcus aureus: methicillin-susceptible S. aureus to methicillin-resistant S. aureus and vancomycin-resistant S. aureus. Clin Infect Dis iclaprim.” In October 2009, the iclaprim marketing authoriza- 2010; 51(Suppl 2):S176–82. tion application for Europe was withdrawn. 9. Howden BP, Peleg AY, Stinear TP. The evolution of vancomycin intermediate Staphylococcus aureus (VISA) and heterogenous-VISA. Infect Genet Evol 2014; In 2015, the FDA granted QIDP status and Fast Track status 21:575–82. for iclaprim for ABSSSI and HABP. Motif has conducted 2 add- 10. Sánchez García M, De la Torre MA, Morales G, et al. Clinical outbreak of lin- ezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA 2010; itional phase 3 studies in patients with ABSSSI (ie, REVIVE-1 303:2260–4. and -2) to assess the noninferiority at –10% of iclaprim to van- 11. Hawser S, Lociuro S, Islam K. Dihydrofolate reductase inhibitors as antibacterial comycin. Both REVIVE-1 and -2 have met this end point. agents. Biochem Pharmacol 2006; 71:941–8. 12. Ho JM, Juurlink DN. Considerations when prescribing trimethoprim-sulfameth- oxazole. CMAJ 2011; 183:1851–8. SUMMARY 13. Oefner C, Bandera M, Haldimann A, et al. Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for Iclaprim is a diaminopyrimidine antibiotic that is administered the increase in affinity and antibacterial activity. J Antimicrob Chemother 2009; as a fixed intravenous dose and is potent, rapidly bactericidal, has 63:687–98. 14. Morgan A, Cofer C, Stevens DL. Iclaprim: a novel dihydrofolate reductase inhibi- good tissue penetration in skin and skin structures and in lung tor for skin and soft tissue infections. Future Microbiol 2009; 4:131–44. compartments, and it has completed 2 phase 3 studies for cSSSI. 15. Huang DB, O’Riordan W, Overcash JS, Heller B. A Phase 3, Randomized, dou- ble-blind, multicenter study to EValuate the safety and efficacy of intravenous In addition, iclaprim has completed 2 phase 3 studies for ABSSSI; Iclaprim versus Vancomycin for the trEatment of acute bacterial skin and skin REVIVE-1 and -2 demonstrated noninferiority to vancomycin for structure infections suspected or confirmed to be due to Gram-positive patho- gens: REVIVE-1. Clin Infect Dis. In press. the FDA-approved primary end point of early clinical response. 16. Hawser S. AR-100, a novel dimaniopyrimidine compound: bactericidal activ- Iclaprim has completed 1 phase 2 study for HABP including VABP, ity and post-antibiotic effect on gram-positive pathogens (F-2029). Abstracts of which showed comparable efficacy and safety for the primary end the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2002; San Diego, CA: September 27–30. points of TOC and day 28 mortality. Based on these data, iclaprim, 17. Andrews J, Honeybourne D, Ashby J, et al. Concentrations in plasma, epithelial if approved, has the potential to offer an alternative treatment lining fluid, alveolar macrophages and bronchial mucosa after a single intra- venous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men. J Antimicrob option for patients with ABSSSI or HABP, including VABP. Chemother 2007; 60:677–80. 18. Stevens D, Leighton A, Dankner WM, et al. Efficacy of iclaprim in complicated Acknowledgments skin and skin structure infections: Preliminary results of ASSIST-1. Poster 1079 presented at: The 45th Annual Meeting of the Infectious Diseases Society of Financial support. This work was supported by Motif Bio plc, New America; October 4–7, 2007; San Diego, CA. York, USA. 19. Dryden M, O’Hare MD, Sidarous E, Hadváry P, et al. Clinical efficacy of iclaprim Potential conifl cts of interest. D.B.H. is an employee of Motif in complicated skin and skin structure infection (cSSSI): Preliminary results from BioSciences. M.V., J.M., C.S., and R.P. are consultants for Motif BioSciences. the ASSIST-2 clinical trial. Poster P545 presented at: The 18th Annual European T.H. has received consultancy fees from Basliea Pharmaceutica, Genentech, Congress of Clinical Microbiology and Infectious Diseases Meeting; April 19–22, Medicines Company, and Motif Biosciences. All authors have submitted the 2008; Barcelona, Spain. ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that 20. Lodise T, Bosso J, Kelly C, et al. Use of pharmacokinetic and pharmacodynamic the editors consider relevant to the content of the manuscript have been analyses to determine the optimal fixed dosing regimen of iclaprim for treat- disclosed. ment of serious gram-positive infections. Antimicrob Agents Chemother. In press. 21. Sader HS, Fritsche TR, Jones RN. Potency and bactericidal activity of iclaprim References against recent clinical gram-positive isolates. Antimicrob Agents Chemother 1. World Health Organization. Antimicrobial resistance global report on surveil- 2009; 53:2171–5. lance. 2014. http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_ 22. Huang DB, Hawser S, Gemmell CG, Sahm DF. In vitro activity of iclaprim eng.pdf. Accessed 15 September 2017. against methicillin-resistant Staphylococcus aureus nonsusceptible to dapto- 2. US Centers for Disease Control and Prevention. Antibiotic resistance mycin, linezolid or vancomycin: a pilot study. Can J Infect Dis Med Microbiol. threats in the United States 2013. https://www.cdc.gov/drugresistance/pdf/ In Press. ar-threats-2013–508.pdf. Accessed 13 September 2017. 23. Krievins D, Brandt R, Hawser S, et al. Multicenter, randomized study of the effi- 3. Golkar Z, Bagasra O, Pace DG. Bacteriophage therapy: a potential solution for the cacy and safety of intravenous iclaprim in complicated skin and skin structure antibiotic resistance crisis. J Infect Dev Ctries 2014; 8:129–36. infections. Antimicrob Agents Chemother 2009; 53:2834–40. 4. Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P T 2015; 24. Huang DB, File TM Jr, Torres A, et al. A phase II randomized, double-blind, mul- 40:277–83. ticenter study to evaluate efficacy and safety of intravenous Iclaprim versus van- 5. Michael CA, Dominey-Howes D, Labbate M. The antimicrobial resistance crisis: comycin for the treatment of nosocomial pneumonia suspected or confirmed to causes, consequences, and management. Front Public Health 2014; 2:145. be due to gram-positive pathogens. Clin Ther 2017; 39:1706–18. 8 • OFID • Huang et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy003/4791932 by Ed 'DeepDyve' Gillespie user on 16 March 2018
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