Plazomicin: A step toward next generation aminoglycosides. Review
Surgycare Lifescience, Sendhwa (MP), India.
Aminoglycosides are selectively active against gram negative bacteria through inhibition of protein synthesis; moreover, those are given parenterally or topically because they are poorly absorbed from the gastrointestinal tract, therefore are given parenterally or topically. Nephrotoxicity and ototoxicity are the most common side effects associated with aminoglycosides therapy. As the resistance developed in most of the bacteria that open the door to use either most toxic combination therapy of present aminoglycosides with other antibiotics such as beta lactams or vancomycin with which they exert a synergistic effect or to discover next generation aminoglycosides, without toxicities. For the discovery of next generation aminoglycosides, a successful step passes through identification of one structure with molecular formula C25H48N6O10 and 592.68 molecular wight from 490 analogous of sisomicin with absence of 3’-OH and 4’-OH groups and named as “ACHN-490” or “Plazomicin” by Achaogen. Plazomicin showed activity against Enterobacteriaceae (EC), Multi drug resistant Enterobacteriaceae (MDR-EC), Aminoglycoside resistant Enterobacteriaceae (AR-EC), Carbapenem resistant Enterobacteriaceae (CR-EC), Colistin resistant (CR-CRE), Tigecycline resistant (TR-EC). Lack of nephrotoxicity or ototoxicity associated with plazomicin; make it drug of future in next generation aminoglycosides. In this review, I am trying to underlying discovery and development of plazomicin as newer antibiotic.
Gram-negative rods ranging length 1-3 μm was first characterized and named as Enterobacteriaceae by Rahn in 1937. Since, they are facultative anaerobes, oxidase-negative, catalase positive, grow on agar, and their natural hosts are human and animal intestines. These species live in the human body, but most are opportunistic in that they can cause severe diseases under certain conditions1.
The 48 genera, 219 species and 41 sub-species in Enterobacteriaceae family were identified in which arond 20 species are responsible for approximately 95% of the infections such as diarrhea and a variety of extra-intestinal infections (EII), bacteremia, respiratory tract infection (RTI) and urinary tract infections (UTI). Some of the more common genera of this family are Citrobacter, Edwardsiella, Enterobacter, Erwinia, Escherichia, Hafnia, Klebsiella, Morganella, Proteus, Providentia, Salmonella, Serratia, Shigella and Yersinia2, 3. Antimicrobial drugs have caused a dramatic change not only of the treatment of infectious diseases but of a fate of mankind. The use of antimicrobial agents was begun for the treatment of infectious diseases with discovery of quinine for malaria and emetine for amebiasis. In 1967, the therapeutic use of arsphenamines by Paul Ehrlich for the treatment of syphilis established relation between microbial pathogens and drugs. Since, the trend of antimicrobial chemotherapy against GPB, began in 1929 with the discovery of the penicillin by Alexander Fleming and sulphonamides by Gerhard Domagk in 1935 while in the late 1940s, Selman Waksman discovered streptomycin for the treatment of infection caused by GNB; moreover, provided a basic key in discovery of therapeutic agent. From this discovery, many new classes of antibiotic had been described by the 1960s. The semisynthetic penicillins introduced by Beecham in 1960s included methicillin, ampicillin and cloxacillin. Meanwhile, the cephalosporin C was established by Abraham and Newton4. The toxicity, especially to cells in the inner and middle ear and the kidney was reported in 1946 when the first randomized trial of streptomycin against pulmonary tuberculosis conducted. Furthermore, some strains of tuberculosis are resistant to treatment with streptomycin. Therefore, medical researchers have put considerable effort into identifying other antibiotics with streptomycin's efficacy, but without its toxicity. Thereafter marked by the successive introduction of a series of milestone compounds kanamycin, gentamicin, and tobramycin which definitively established the usefulness of this class of antibiotics for the treatment of gram-negative bacillary infections. In the 1970s, the semisynthetic aminoglycosides dibekacin, amikacin, and netilmicin demonstrated the possibility of obtaining compounds which were active against strains that had developed resistance mechanisms towards earlier aminoglycosides as well as displaying distinct toxicological profiles5-7. The systematic screening approach introduced by Paul Ehrlich became the cornerstone of drug search strategies in the pharmaceutical industry and resulted in thousands of drugs identified and translated into clinical practice, including, of course, a variety of antimicrobial drugs such as linezolide and tigecycline in 2005 and doripenem in 20078.
The term aminoglycoside is derived from the chemical structure of these compounds, which are made up of amino group attached to glycosides (derivatives of sugar). Aminoglycosides encompass a large group of aminocyclitol containing molecules that are structurally diverse, hydrophilic, and polycationic. Aminoglycosides categorized into three major groups on the basis of structure viz aminoglycosides contains a streptamine nucleus (streptomicin), aminoglycosides contains either a streptamine or a 2-deoxystreptamine nucleus (spectinomycin and hygromycin B) and aminoglycosides contains a 2-deoxystreptamine nucleus with amino sugar rings substituted at either positions 4 and 5 or positions 4 and 6 (paromomycin and gentamicin). The 6-amino hexose ring linked to position 4 of the 2-deoxystreptamine is designated as the prime (′) or A ring and the pentose or hexose ring linked to position 5 or 6 is labeled the double prime (″) or C ring; the central 2-deoxystreptamine ring is sometimes referred to as the B ring9. Aminoglycosides are selectively active against oxygen-dependent (aerobic), gram-negative bacterial cells, since these cells possess the chemical characteristics that attract aminoglycosides and the specific transport mechanisms that facilitate the uptake of the drugs into the cells. Once inside bacterial cells, aminoglycosides exert their effects by binding to 30s subunit of ribosome, organelles that are fundamental to protein synthesis. As a result, protein synthesis is inhibited, and the bacterial cell dies. The aminoglycosides are poorly absorbed from the gastrointestinal tract and therefore are given parenterally, via intramuscular or intravenous injection, or topically, via application to the skin. The toxicities associated with aminoglycosides are severe and are sometimes irreversible, and the margin of safety between a toxic and a therapeutic dose is narrow. Nephrotoxicity (impairment of kidney function) and ototoxicity (impairment of the organs of hearing and balance) are the most common side effects of aminoglycosides. Once-daily administration of aminoglycosides has limited the toxicity of these agents and enabled their reintroduction into clinical practice. Recent studies have shown no additional benefits of concomitant administration of aminoglycosides with current lactams, and the available evidence does not support the use of once-daily administration for all indications10, 11. The treatment of uncomplicated gonorrhoea infection (gram-negative diplococci on urethral smear described in various clinicl trials that upports sucessive use of aminoglycosides. The treatment with gentamicin was described by Hiera using Quasi-random (treatment assigned to alternate consecutive patients); moreover it established comparative effectiveness between single dose gentamicin 280 mg intramuscular injection (n = 302) and single dose kanamycin 2 g intramuscular injection (n = 113). The cure of gentamicin 98% was (216/220) whereas kanamycin 95% (85/89) with no serious toxicity or other adverse reactions was noticed in both the group12. Yoon et al. also conducted RCT with same clinical condtion, using single dose gentamicin 240 mg intramuscular injection (n = 137) and single dose kanamycin 2 g intramuscular injection (n = 137). The reported cure arate gentamicin was 62.4% (78/125) and kanamycin 98.3% (86/126) because 23 patients did not attend follow-up and were excluded. There was no side effect of using kanamycin and gentamicin13. Pareek and Chowdhury reported super cure rate 95% (19/20) with single-dose gentamicin 160 mg intramuscular injection (n = 20) compared to single-dose spectinomycin 2 g intramuscular injection (n = 20), 80% (16/20) of spectinomycin. There were no obvious side effects with either of these drugs14. Iskandar et al. conducted RCT (randomly allocated to 3 groups of 30 patients) using single dose gentamicin 240 mg intramuscular injection (n = 30). He reported gentamicin cure rate was 19/22 (86.4%) instead of 91% (27/30) with no adverse or side effects, because in the final reporting he included only those attended day 7 of the study15. Lule et al. studies RCT by computerised randomisation on men presenting with urethral discharge and Gram-negative intracellular diplococci using single dose gentamicin 240 mg intramuscular injection (n = 40) and found 95% (38/40) cure rate with no adverse or side effect16. Abbruzzese et al. reported randomized, double-blind trial that include 33 patients with urinary tract infection that received tobramycin 1.0 mg/kg of tobramycin every eight hours for seven days. The cure rate was 70% (23/33) with no nephrotoxicity17. Barza et al examined 21 randomised trials reported between year 1966 to 1995, which include 3091 patients with bacterial infection and tried to describe nephrotoxicity and ototoxicity associated specific aminoglycoside (amikacin, gentamicin, netilmicin, sisomicin, and tobramycin). The overall rate of nephrotoxicity (weighted by study size) was 5.5% for the single daily dose regimen and 7.7% in the multiple dose regimens. No evidence found for risk of ototoxicity18 but Farzal et al described systematic review which supports a recommendation for clinicians to perform routine hearing screening in children during and after aminoglycoside therapy19.
Aminoglycoside resistance and combination therapy:
In general definition, the ability adapts as well developed in microorganism against multiple antimicrobial agents that enables some bacteria to oppose the action of certain antibiotics, rendering the antibiotics ineffective known as multi drug resistance (MDR). A standardized international terminology was described by a group of international experts of European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) for acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp. Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA) also prescribed epidemiologically significant antimicrobial categories with new definition, “MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories”20. Several mechanisms has been demonstrated for aminoglycoside resistance, which include ribosomal alterations (modification of the target by mutation of the 16S rRNA or ribosomal protein, methylation of 16S rRNA), loss of permeability (reduced permeability by modification of outer membrane’s permeability or diminished inner membrane transport, export outside the cell by active efflux pumps, active swarming) and enzymatic modification (the modification at −OH or −NH2 groups of the 2-deoxystreptamine nucleus or the sugar moiety by acetyltransferases, nucleotidyltranferases, or phosphotransferases21, 22. In 1980, the development of resistance toward monotherapy with present antimicrobial drugs insisted researcher to use combination antimicrobial therapy for the management of a variety of infectious diseases. The combination therapy may act synergistically and allow the use of smaller doses of each of the combined drugs. The rationale of using aminoglycoside and beta lactam combinations to delay or prevent the emergence of antimicrobial resistance was developed from data from animal studies in this year23, 24. Meta-analysis on the effect of aminoglycoside and beta lactam combination therapy versus beta lactam monotherapy on the emergence of resistance was published in 2005 by Bliziotis and coworkers. It included total 8 RCTs in the analysis and finally concluded “the aminoglycoside and beta lactam combination was not associated with a beneficial effect on the development of antimicrobial resistance among initially antimicrobial susceptible Isolates”25. A detailed survey of aminoglycoside related toxicity was published in 1986 by Kahlmeter y et al which include 10, 000 in clinical trials published between 1975 and 1982. The survey concluded on the basis of 144 published trials for evaluation of side effects viz 139 (Renal), 63 (Colchear) and 34 trials (Vestibular) with the average daily dosages of gentamicin, tobramycin, netilmicin and amikacin were 3.9, 3.8, 5.2 and 15.4 mg/kg, respectively. The average frequencies of nephrotoxicity were found as 14.0% gentamicin, 12.9% tobramycin, 8.7% netilmicin and 9.4% with amikacin whereas reported cochlear toxicity was 13.9% amikacin, 8.3 gentamicin, 6.1% tobramycin and 2.4% for netilmicin. However, some inconsistencies go unexplained: for example, the frequency of gentamicin nephrotoxicity was markedly higher in trials where it was compared to tobramycin (20 trials) when it was compared to netilmicin (16 trials)26. Wong KM et al compare the safety and efficacy of cefepime monotherapy (group A) against the potentially more toxic combination of vancomycin and netilmicin (group B) on 81 patients from 1998 to 2000. There were no significant differences in primary response rates and cure rates (no relapse >28 days after completion of antibiotic therapy) between both groups of patients (group A versus group B, 82% (32/39) versus 85% (29/34) and 72% (28/39) versus 76% (26/34) even no significant side effect was encountered in either group. It was conclude that once-daily 1gm cefepime monotherapy is a simple, safe and cost-effective alternative to vancomycin and netilmicin therapy in the treatment of bacterial peritonitis27. Vidal et al reported significant data by systematic review and metaanlysis of mostly used aminoglycosides. Literature review performed from 1966 to 2006. They described 1% difference in treatment failure (intension to treat analysis) between aminogycosides 29% (258/892) and control 28% (275/998). They reported detailed failure rate of intension to treat analysis covered aminoglycoside 34% (187/557), control 32% (40/650) in urinary tract infection; aminoglycosides 40% (26/63), control 26% (16/61) in Abdominal infection; aminoglycosides 40% (2/5), control 50% (4/8), aminoglycosides 27% (6/22), control 37% (7/19) in respiratory tract infection and aminogycosies 15% (37/245), control 15% (40/260) undefined and other conditions. They also described comaprative study between aminoglycosides and other antibiotics for microbial failure at the end of therapy. The data include failure rate of aminoglycosides was 24% (189/790) as compared to other antibiotics (beta lactam, quinolones and macrolides) 17% (151/878). In the detailed data analysis they found failure rate with aminoglycosides 25% (158/637) versus beta lactam 18% (132/724), aminoglycosides 24% (22/90) versus 5% (14/93) quinolones and aminoglycoside 6% (4/63) versus macrolides 8% (5/61). Total event of adeverse reaction reported was 5% (42/788) with aminoglcoside while 13% (109/866) with other antibiotics. Comparable data showed adverse effect associated with aminoglycosides 5% (28/561) versus 14% (90/624) beta lactam and aminoglycoside 6% (14/227) versus 8% (19/227)28. Abrams B et al demonstrate advantage of monotherapy with beta lactam antibiotics over combination therapy with aminoglycosides. They randomly treated 25 episodes of S. aureus endocarditis in intravenous drug abusers with either single or combination antibiotic regimens. There were no bacteriologic failures or relapses in either group29.
Discovery and development of plazomicin:
Netilmicin and dibekacin are currently available semisynthetic aminoglycosides derived from sisomicin, which is a naturally occurring aminoglycoside antibiotic, produced by Micromonospora inyoensis. Dibekacin is 3', 4’-dideoxykanamycin B and netilmicin is 1-N-ethyl sisomicin. Antibacterial spectrum shows bactericidal activity against a wide range of Gram-negative bacteria (including E. coli, Enterobacter, Klebsiella and Proteus spp. and Ps. aeruginosa) and also against staphylococci. Streptococci are usually resistant for aminoglycoside monotherapy; hence treatment involved combination therapy with beta lactam. According to structure activity relationship it is proposed that structural features made both the agents insusceptible to some of the enzymes found in resistant strains of bacteria which inactivate the parent compounds. Thus, structural similarities between sisomicin, gentamicin and tobramycin make them clinically active with some degree of different antibacterial spectrum include, superior activity of sisomicin compared with gentamicin against Ps. Aeruginosa while closely paralleling activity with tobramycin. However, sisomicin is inactivated by virtually all bacterial enzymes which inactivate gentamicin and tobramycin. Nevertheless, it retains useful activity against a number of gentamicin resistant strains of Ps. aeruginosa which are resistant by non-enzymatic (possibly permeability barrier) mechanisms; in this respect, it closely resembles tobramycin. Netilmicin has a generally broader antibacterial spectrum than gentamicin, tobramycin, amikacin, sisomicin or debekacin and is resistant to inactivation by phosphorylating and adenylylating enzymes hence make it challenging to treat drug resistant bacteria world-wide by application of new approaches to the use of existing antibiotics or their combination as well as also by the introduction of novel drugs30, 31.
Plazomicin is a next-generation semisynthetic aminoglycoside selected from 490 analogous of sisomicin by the team of Achaogen scientists and named “ACHN-490” has molecular formula C25H48N6O10 and 592.68 molecular wight. Plazomicin synthesized from sisomicin by two synthetic routes 1) selective N-protection of sisomicin, 2) N-Acylation of sisomicin, that involve modification of 2 amino acids in 8 step process. Although absence of 3’- and 4’-OH groups provide potent antibacterial and broad-spectrum of activity because Aminoglycoside modifying enzymes (AMEs) espcially O-phosphotransferas-3’ (APH-3’) and Oadenyltransferase-4’ (ANT-4’) cannot generate resistance. Since, ACHN-490 is the first semisynthetic next-generation aminoglycoside derived from sisomicin and specially designed to target key pathogens, particularly gram-negative organisms and those resistant to older antibiotics, while retaining the favorable bactericidal and synergistic properties of the aminoglycoside class. Structural features of plazomicin also reveal that substitution of hydroxy-aminobutyric acid at N1 gives protection from the AAC (3), ANT (2’’) and APH (2’’) while the hydroxyethyl substitute at the 6’ position blocks the multitude of AAC(6’) AMEs. Although plazomicin demonstrates activity against both Gram negative bacteria (GNB) and selected Gram-positive bacteria (GPB) as well as also proved its efficacy against clinically relevant AMEs. Plazomicin showed activity against Enterobacteriaceae (EC), Multi drug resistant Enterobacteriaceae (MDR-EC), Aminoglycoside resistant Enterobacteriaceae (AR-EC), Carbapenem resistant Enterobacteriaceae (CR-EC), Colistin resistant CRE, Tigecycline resistant TR-EC. Lack of nephrotoxicity or ototoxicity associated with plazomicin; make it drug of future in next generation aminoglycosides32-35. The in vitro activity suggested that plazomicin actively inhibited wide variety of single or multiple aminoglycoside resistance mechanisms including members of the EC family, Acinetobacter, Pseudomonas and Staphylococcus strains. In the path of discovery of next generation of aminoglycosides, MIC90 values of <2 μg/ml against E. coli, serine carbapenemase-producing K. pneumoniae, MDR-EC with metallo-β-lactamases, S. aureus (including MRSA), and Acinetobacter spp. that bore a variety of aminoglycoside resistance determinants, make plazomicin futuristic drug as first choice between all available aminoglycosides. Plazomicin inhibited the growth of AR-EC (MIC-90), ≤4 μg/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC-90), 8 μg/ml and 16 μg/ml, respectively)36, 37. ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AGEs than against those with altered permeability or efflux. All known transferable AMGEs were unable to inactive plazomicin, although plasmid carried armA and rmtC encoding ribosomal methyltransferases, such as those found in NDM-1 metallo-β-lactamase (MBL)-producing pathogens, conferred resistance to plazomicin with MICs ranging from 64 to >256 μg/ml38. ACHN-490 was active at ≤2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12–0.5 mg/L; isepamicin was active against 63/65 at ≤8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs ≥64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behaviour was associated with ArmA and RmtC 16S rRNA methylases. ACHN-490 has potent activity versus carbapenem-resistant isolates, except those also harbouring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-49039. Activity of plazomicin was examined against clinical isolates of A. baumannii and P. aeruginosa and found that ACHN-490 possessed superior activity against these isolates, with an MIC50 value of 8 mg/L. In P. aeruginosa, the activity of ACHN-490 was similar to that of amikacin (MIC50 value of 8 mg/L for both agents). For both A. baumannii and P. aeruginosa, the MICs of ACHN-490 did not correlate with the presence of commonly encountered aminoglycoside-modifying enzymes40. Cristina and coworkers evaluated the activity of plazomicin against a collection of carbapenem-resistant A. baumannii isolates. Plazomicin demonstrated more potent in vitro activity versus carbapenem- resistant A. baumannii isolates than the other aminoglycosides. The MICs for plazomicin and amikacin (the most active of the legacy aminoglycosides) ranged from 0.5μg/ml to 64μg/ml and from 0.5μg/ml to 512μg/ml, respectively, for carbapenem-resistant isolates and ranged from 0.5μg/ml to 16μg/ml and from 8μg/ml to 16μg/ml, respectively, for carbapenem-susceptible isolates. A.baumannii isolates that had high MICs to amikacin (MIC, 256 to 512μg/ml), the plazomicin MIC values were 16 μg/ml. However, it should be noted that there were eight isolates with plazomicin MICs higher than the amikacin MICs41. The in Vitro activity of ACHN-490 was evaluated against 493 meticillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2009–2010 from 23 US hospitals. The MIC50 and MIC90 values for ACHN-490 were 1 and 2 μg/mL compared with 8 and 32 μg/mL for amikacin, 0.5 and 1 μg/mL for gentamicin and 2 and >16 μg/mL for tobramycin. The gene encoding the AMGEs, APH(2″)-Ia/AAC(6′)-Ie was present in 12% of the subset of 84 isolates examined by polymerase chain reaction (PCR), whilst the gene encoding ANT(4′)-Ia was present in 89% of isolates42. Plazomicin demonstrates high activity against the Enterobacteriaceae including extended spectrum beta lactamase and most carbapenemase producers, as well as several of the non-fermenters. When compared to levofloxacin, the in vivo activity of plazomicin in complicated urinary tract infections (cUTIs) and in acute pyelonephritis in humans was very promising. Furthermore, regarding safety, no clinically significant effects on renal, vestibular, or cochlear function have been observed both at Phase I and II studies in humans, with mild to moderate adverse events being dose related43. The in vivo efficacy of ACHN-490 was assed against a variety of common pathogens in two murine models: the septicemia and neutropenic thigh models. When its activity against a gentamicin-susceptible strain of Escherichia coli was tested in the septicemia model, ACHN-490 improved 7-day survival with a dose-response profile similar to that of gentamicin, with 100% survival seen at doses of 1.6 mg/kg of body weight and above. In animals infected with a gentamicin-susceptible strain of Pseudomonas aeruginosa, treatment with either ACHN-490 or gentamicin led to 100% survival at doses of 16 mg/kg and above in the septicemia model. ACHN-490 was also effective in the neutropenic thigh model; reducing multidrug-resistant Enterobacteriaceae family and methicillin-resistant Staphylococcus aureus strains, as well as broadly susceptible strains, to static levels with dose-dependent activity. Against gentamicin-sensitive EC and methicillin resistant S. aureus, the efficacy of ACHN-490 was comparable to that of gentamicin. However, gentamicin resistant EC strains and those harboring the Klebsiella pneumoniae carbapenemase responded to ACHN-490 but not gentamicin, with static doses ranging from 12 mg/kg to 64 mg/kg for ACHN-490. These results suggest that ACHN-490 has the potential to become a clinically useful agent against drug resistant pathogens, including EC, P. aeruginosa, and methicillin-resistant S. aureus, and support further development of this promising novel aminoglycoside44. Synergy time kill studies of 47 methicillin-resistant Staphylococcus aureus strains with differing resistance phenotypes showed that combinations of sub-inhibitory concentrations of ACHN-490 and daptomycin yielded synergy against 43/47 strains at 24 h, while the combination was indifferent against the remaining 4 strains. ACHN-490 and ceftobiprole showed synergy in 17/47 strains tested at 24 h, while 6/47 strains showed synergy for sub-inhibitory combinations of ACHN-490 and linezolide45. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (±standard deviation) area under the concentration-time curve from 0 to 24 h (AUC0-24), maximum concentration of drug in serum (Cmax), half-life (t1/2), clearance, and volume of distribution at steady state for the 15-mg/kg, day 5 dose were 239±45h· mg/liter, 113±17h mg/liter, 3±0.3h, 1.1±0.1 ml/min/kg, and 0.24±0.04 liters/kg, respectively. AGMEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed46. For the application as a New Drug Application (NDA) in the United States and a Marketing Authorization Application (MAA) in Europe, Achaogen conducted three EPIC (Evaluating Plazomicin In cUTI) by enrolling 609 patients and CARE (Combating Antibiotic Resistant Enterobacteriaceae) involved 69 patients while reported positive top line data in December 2016. The EPIC trial was a multinational, randomized, and controlled, double-blind clinical trial in adult patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP) as a multinational, randomized, and controlled, double-blind clinical trial in adult patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP) to study plazomicin vs. meropenem, while CARE was a multinational, open label, Phase 3 clinical trial evaluating the efficacy and safety of plazomicin in patients with serious bacterial infections due to CRE. The study included two cohorts of patients which was a randomized, comparator-controlled cohort to compare plazomicin with colistin (either in combination with meropenem or tigecycline) for the treatment of bloodstream infection (BSI), hospital acquired bacterial pneumonia (HABP) or ventilator associated bacterial pneumonia (VABP) due to CRE, The reported data showed non-inferiority of plazomicin from comparator at the primary efficacy endpoints as specified by FDA, whereas found superior at the primary efficacy endpoints specified by EMA. The detailed EPIC study included plazomicin 15 mg/kg as a once daily 30-minute intravenous (IV) infusion or meropenem 1.0 gram every 8 hours as a 30-minute IV infusion in 1:1 patients for a minimum of 4 days. The patients who met protocol defined criteria for improvement were allowed to step-down to oral levofloxacin to complete a total of 7 to 10 days of therapy (IV plus oral). Achaogen submitted result to FDA pre-specified composite endpoint of clinical cure and microbiological eradication in the microbiological modified intent-to-treat (mMITT) as summarized on day 5 of therapy was 88.0% plazomicin vs. 91.4% meropenem (difference -3.4%, 95% CI: -10.0, 3.1%), while Test-of-Cure was 81.7% plazomicin vs. 70.1% meropenem (difference 11.6%, 95% CI: 2.7, 20.3. Results for EMA-specified endpoints of microbiological eradication at the test-of-cure visit was declared by Achaogen as mMITT was 87.4% plazomicin vs. 72.1% meropenem (difference 15.4%, 95% CI: 7.5, 23.2%) and ME was 90.5% plazomicin vs. 76.6% meropenem (difference 13.9%, 95% CI: 6.3, 21.7%). Total treatment emergent adverse events (TEAEs) related to renal function was reported in 3.6% and 1.3% of patients in the plazomicin and meropenem groups, respectively. In the CARE study Cohort 1 enrolled 30 patients with BSI and 9 patients with HABP/VABP. Cohort 2 (N=30) which was a single-arm expanded access cohort to evaluate plazomicin-based therapy in patients with BSI, HABP/VABP or cUTI due to CRE who were not eligible for enrollment in Cohort 1. Results from the CARE trial was submitted as primary endpoint at day 28 were 23.5% plazomicin vs. 50.0% colistin (difference 26.5%, 90% CI: -0.7, 51.2%) to describe all cause mortality or significant disease related complications while 11.8% plazomicin vs. 40.0% colistin (difference 28.2%, 90% CI: 0.7, 52.5% for all cause mortality.
The key attributes to support plazomicin that released by Achaogen are:
(i) Potent in vitro and in vivo activity in nonclinical studies against MDR Enterobacteriaceae, including CRE.
(ii) Demonstration of non-inferiority to meropenem at day 5 and statistical superiority to meropenem at the test-of-cure (day~17) in patients with cUTI/acute pyelonephritis (AP) infections due to Enterobacteriaceae, including fluoroquinolone-resistant and extended spectrum beta-lactamase (ESBL) producing isolates.
(iii) Demonstration of lower 28 Day all cause mortality and improved safety compared to colistin in patients with serious bacterial infections due to Potential to improve dosing strategy, which includes individualized patient dosing using our in vitro drug-monitoring assay.
(iv) Potential for more convenient administration as a once daily, 30-minute IV therapy compared to other IV antibiotics administered multiple times per day with infusion times up to two hours.
The rate of infection caused by multidrug resistant bacteria as well as safety profile of present used monotherapy or combination therapy, again catch the focus toward next generation aminoglycoside as first line treatment option with comparable safety benefits. Plazomicin sucessfully not only meet the pre-specified specification, also prooved superior clinical efficac with safety over the current availae aminoglycosides even reported combition therapy. The results of EPIC and CARE studies served as a milestone in the development of plazomicin in next generation aminoglycoside.
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Received on 22.06.2017 Accepted on 11.08.2017
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