Abstract
Purpose of review
We systematically review the literature on antibiotics approved by the Food and Drug Administration since 2015 or that are in development through phase III trials for the treatment of infections due to gram-negative organisms.
Recent findings
The crisis of antimicrobial resistance creates a dire need for the development of novel antimicrobials with enhanced activity against resistant bacteria. Of the agents that are currently in the pipeline or recently approved, few are from new classes and most represent modifications of preexisting agents. There continues to be a lack of treatment options especially for infections caused by organisms that produce metallo-β-lactamases. Furthermore, there is a paucity of data investigating the efficacy of these new antimicrobials for treatment of infections due to multidrug-resistant organisms.
Summary
This review outlines the antimicrobials in development for the treatment of infections due to gram-negative bacteria. There are various agents in development that seem promising, but more studies are needed to evaluate the efficacy of these agents in treating infections, especially those due to multidrug-resistant organisms. The development of new antimicrobials is critical to combat the crisis of antimicrobial resistance.
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Introduction
The development of antibiotics revolutionized the treatment of infectious diseases in the first half of the twentieth century. However, the subsequent emergence of antimicrobial resistance has raised the specter of a return to the pre-antibiotic era for many patients. Serious infections due to gram-negative organisms have been increasingly difficult to manage with the emergence of resistance via extended spectrum β-lactamases (ESBL) and the rise of carbapenem-resistant Enterobacteriaceae (CRE) and multidrug-resistant (MDR) organisms. There have been several initiatives calling for new antimicrobial development, including the Infectious Diseases Society of America’s 10 × ’20 campaign in 2010, followed by the Generating Antibiotic Incentives Now (GAIN) act in the USA and the Innovative Medicines Initiative New Drugs for Bad Bugs by the European Union [1]. Both the World Health Organization and the United States Centers for Disease Control global report described antimicrobial resistance as a global health emergency requiring an urgent need for the development for alternative antibacterial agents [2, 3]. Subsequently, there are various new antimicrobial agents in the pipeline for the treatment of gram-negative infections.
In this review, we summarize the available data for agents that were approved by the Food and Drug Administration (FDA) since 2015 or that are undergoing phase III clinical trials for the treatment of gram-negative infections.
Methods
Search strategy
A PubMed search was performed to identify clinical studies from January 1, 2000, through December 1, 2018 published in the English language. Antimicrobial agents that were FDA approved or undergoing phase III clinical trials from January 2015 through June 2018 were selected through the Pew Charitable Trust, FDA, and clinicaltrials.gov websites. These included cefiderocol, ceftazidime/avibactam (CZA), ceftobiprole medocaril, ceftolozane/tazobactam (C/T), delafloxacin, eravacycline, relebactam (REL) in combination with imipenem/cilastatin (IMI), lefamulin, meropenem-vaborbactam (M-V), plazomicin, and sulopenem. PubMed search included each antimicrobial in combination with MESH terms, publication types, and topics to encompass all types of clinical trials, randomized controlled trials, meta-analysis, and multicenter, longitudinal, follow-up, prospective, retrospective, cohort, case–control, comparative, and/or observational studies. This was supplemented by review of references and clinicaltrials.gov to identify additional articles.
Study review and selection
We included studies that focused on the clinical use of the selected antimicrobial agents for the treatment of gram-negative infections. Only primary studies were included. In vitro studies, animal studies, and pharmacokinetics (PK) were not systemically reviewed but pertinent current knowledge was also summarized. Only studies with infections due to gram-negative organisms were included.
Results
Literature search and study selection
Our literature search yielded 301 articles, of which 55 met inclusion criteria. The process of study selection is described in Fig. 1.
Articles included in the review.
Cefiderocol
Cefiderocol (S-649266) is a novel siderophore cephalosporin with a catechol side chain (Table 1). This allows ferric iron ion binding with a resulting complex that is transported into the bacteria and destroys cell wall synthesis [4]. It was studied at a dose of 2 g intravenously (IV) over 1 h every 8 h. It is predominantly renally excreted and therefore requires renal dose adjustment [4]. It has no significant drug interaction potential via drug transporters in vivo [5]. It is stable against hydrolysis from all β-lactamases including serine Klebsiella pneumoniae carbapenemases (KPC), oxacillinase (OXA), and metallo-β-lactamases (MBL), including New Delhi MBL (NDM), imipenemase (IMP), and Verona integron-encoded MBL (VIM). It has potent activity against gram-negative organisms including CRE and MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomomans maltophilia in vitro [6,7,8].
A double-blind phase II randomized controlled trial (RCT) by Portsmouth et al. determined cefiderocol to be noninferior to IMI for the treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis (Table 2—cefiderocol) [9•]. The subgroup analysis of patients with ESBL-producing organisms (n = 106) favored cefiderocol, although the types of β-lactamase were not distinguished [9•]. Phase III studies are in progress to evaluate the efficacy of cefiderocol for treatment of CRE infections (including healthcare-associated bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), cUTI, and bloodstream infections (BSI)) compared to best available therapy (BAT). It is also being studied in combination with linezolid compared to meropenem plus linezolid for the treatment of nosocomial pneumonia.
Ceftazidime/avibactam
CZA is a combination of a third-generation cephalosporin with a non-β-lactam, diazabicyclooctane β-lactamase inhibitor (Table 1). Avibactam extends activity to ceftazidime-resistant Enterobacteriaceae via potent inhibition of class A (ESBL, KPC), C (amp-C), and some class D β-lactamases, but it is not effective against class B β-lactamases (MBL) [64, 65]. CZA is most efficacious for MDR Enterobacteriaceae, particularly K. pneumoniae and Escherichia coli including those producing ESBL, KPC, and OXA-48 [12•, 19,20,21, 65]. In vitro studies suggest that coexistence of mixed populations of organisms can lead to reemergence of mutated blaKPC after treatment via plasmids that may restore meropenem susceptibility [25, 66].
CZA is currently approved at a dose of 2/0.5 g every 8 h IV and is rapidly bactericidal [67]. It demonstrates similar PK across genders and ages, as well as in patients with cystic fibrosis [68,69,70]. It requires renal adjustment with maintenance of a 4:1 ceftazidime to avibactam ratio and administration after hemodialysis [71]. Subgroup analysis of a phase III trial by Mazuski et al. favored meropenem over CZA in patients with moderate renal impairment [29••]. More studies will be needed to determine efficacy in patients with renal dysfunction. CZA is not associated with QTc prolongation [72, 73].
CZA was initially FDA approved for treatment of complicated intraabdominal infections (cIAI) in combination with metronidazole and cUTI including pyelonephritis (Table 2—ceftazidime/avibactam (CZA)) [22••, 28••, 29••, 74]. The RECLAIM trials demonstrated noninferiority to meropenem for the treatment of cIAI in combination with metronidazole [22••, 29••]. CZA maintained efficacy in patients with isolates that screened positive for ESBL in these trials [24•, 30]. The RECAPTURE trials determined noninferiority to doripenem for cUTI and acute pyelonephritis [28••]. Notably, 22% of the isolates recovered in these studies were ceftazidime nonsusceptible, and a limited number of critically ill patients were included. The REPRISE trial demonstrated the efficacy of CZA for treating cUTI and cIAI due to ceftazidime-non-susceptible isolates [27•]. The REPROVE trial by Torres et al. demonstrated noninferiority to meropenem in the treatment of HABP and VABP, prompting FDA approval for this indication [16••]. This study included about 25% critically ill patients and 100 ceftazidime nonsusceptible isolates [16••]. Studies investigating the efficacy of CZA in infections due to MDR organisms and CRE are limited by small sample size or observational study design. Observational studies demonstrate success in treating KPC K. pneumoniae, including a prospective study by Van Duin et al. that demonstrated superiority to colistin with 64% better outcomes overall [10, 17•, 20]. In small observational studies using CZA for the treatment of CRE infections, mostly due to KPC or OXA-48 producing K. pneumoniae, the clinical success ranges from 50 up to 86% with up to 30% mortality and significantly worse outcomes in patients requiring continuous renal replacement therapy or with higher severity of illness [10, 12•, 13, 20, 21, 23, 26]. It has poor activity against isolates expressing NDM-1, VIM-2, OXA-23, or PER-1 and about 50–70% success in the treatment of MDR or extensive drug-resistant (XDR) P. aeruginosa infections [13, 15, 19, 23, 28••, 29••, 30]. In pooled isolates from five RCTs, there were 89.7 and 66.1% sensitivity to MDR Enterobacter cloacae (n = 29) and P. aeruginosa (n = 56), respectively, and a minimal decrease in MICs compared to ceftazidime alone for P. aeruginosa [75]. Case reports note success in using CZA to treat other types of infections, including ventriculitis and hardware-associated osteomyelitis, due to KPC and MBL producing K. pneumoniae or P. aeruginosa [11, 14, 18]. There are ongoing phase II studies for the treatment of febrile neutropenia and in the pediatric population.
Ceftobiprole medocaril
Ceftobiprole medocaril is a water-soluble prodrug of ceftobiprole. This pyrrolidinone-3-ylidemethyl fifth-generation cephalosporin has activity against major gram-negative and gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-sensitive Enterococcus spp. (Table 1) [76]. It is rapidly bactericidal against MRSA through inhibition of penicillin binding protein-2 and is effective against resistant strains with reduced susceptibility to vancomycin or expression of the Enterococcal vancomycin resistance gene complex [77]. Ceftobiprole has excellent bactericidal activity against Streptococcus spp., including those that are penicillin and macrolide resistant, as well as Haemophilus influenzae, Neisseria gonorrhoeae, and Moraxella catarrhalis [78,79,80,81]. Even though it does not have good activity against Acinetobacter baumanni complex (70.7% resistant), it has more activity than ceftazidime and cefepime when blaADC-like gene is repressed [82]. It has good concentrations in soft tissue, skeletal muscle, and adipose tissue and is effective in treating MRSA mediastinitis in rat models [83, 84]. Ceftobiprole is studied at a dose of 500 mg IV, infused over 2 h every 8 h. It is 89% renally excreted and therefore requires dose reduction for renal impairment.
Ceftobiprole is not currently FDA approved in the USA but is approved in several countries for the treatment of acute bacterial skin and skin structure infections (ABSSSI) (Table 2—ceftobiprole medocaril). Initial RCTs investigated ceftobiprole for use of ABSSSI and demonstrated noninferiority to vancomycin plus ceftazidime for complicated ABSSSI including MRSA infections [33, 85]. There are several double-blind RCTs that evaluate the efficacy of ceftobiprole for the treatment of pneumonia [31,32,33]. Nicholson et al. found that ceftobiprole was noninferior to ceftriaxone plus linezolid for treatment of community-acquired bacterial pneumonia (CABP) [32]. However, when both groups were transitioned to oral therapy, eradications were better for the group receiving cefuroxime than ceftobiprole. A subsequent double-blind phase III RCT by Awad et al. included 781 patients and demonstrated noninferiority to ceftazidime plus linezolid for treatment of HABP, but not VABP, with comparable outcomes for Enterobacteriaceae and P. aeruginosa [31]. Notably, there were fewer patients in the VABP subgroup (96/781) and more studies are needed to determine its role in VABP. Current phase III studies have been initiated to evaluate efficacy in the treatment of bacteremia due to S. aureus.
Ceftolozane/tazobactam
C/T is a combination of an oxyimino-aminothiazolyl cephalosporin with a β-lactamase inhibitor that has enhanced activity against class A and C β-lactamases and some MBL (Table 1). C/T is FDA approved to be dosed at 1.5 g IV every 8 h for cUTI and cIAI and at a higher dose of 3 g IV every 8 h for nosocomial pneumonia [86]. C/T is more rapidly bactericidal than other cephalosporins [87]. It requires renal dose adjustment and 50–70% is removed with 3–4 h of hemodialysis [88]. Clearance is not significantly affected by weight, age, sex, ethnicity, or presence of infection [86]. Monogue et al. showed that patients with cystic fibrosis should receive over 90% probability of target attainment for 1.5 mg every 8 h and 3 g every 8 h for P. aeruginosa MIC ≤ 4 and 8, respectively [89].
C/T was FDA approved in 2015 for the treatment of cUTI and in combination with metronidazole for the treatment of cIAI [46••, 47••, 48]. The ASPECT trials demonstrated that C/T in combination with metronidazole was noninferior to meropenem for clinical cure of cIAI in 806 patients and superior to levofloxacin for composite and microbiological cures of cUTI in 1068 patients (Table 2—ceftolozane/tazobactam (C/T)) [46••, 47••]. In post hoc studies, efficacy was maintained in patients with ESBL-producing isolates (n = 150), P. aeruginosa (n = 72), and in levofloxacin-resistant isolates [43•, 44, 45]. Popejoy et al. showed that patients with diabetes mellitus in both treatment groups had lower cure rates and more adverse effects [39]. Moderate renal insufficiency was associated with higher rates of treatment failure for cIAI and cUTI regardless of treatment type [41]. Further investigation is necessary to determine the efficacy of treatment in these populations. Clinical trials are ongoing for the treatment of febrile infections due to MDR P. aeruginosa and VABP.
In observational studies, C/T demonstrates efficacy with over 70–80% clinical success in the treatment of infections due to MDR and XDR P. aeruginosa, including those expressing amp-C and OXA-48 [35, 38, 40, 42, 90,91,92]. These studies consisted of patients with predominantly respiratory tract infections and included critically ill and immunocompromised hosts. Case reports suggest efficacy as rescue treatment for meningitis, osteomyelitis, and hardware-associated infections due to XDR P. aeruginosa [34, 36, 37]. In vitro, the clinical success of C/T against MDR P. aeruginosa is attributed to its slow development of resistance, which requires multiple mutations in addition to amp-C production [93].
Delafloxacin
Delafloxacin is an anionic fluoroquinolone with increased activity against MRSA and gram-positive isolates (Table 1). It has a different structure than other quinolones that confers weak acidity, which allows it to be more active against S. aureus with improved intracellular and biofilm penetration [94]. Potency may be enhanced in the setting of a urinary tract infection in which urine is more acidic [95]. It has activity against gram-positive, anaerobe, and gram-negative organisms with better efficacy in vitro than levofloxacin for ciprofloxacin-resistant S. pneumoniae [96, 97]. It is predominantly renally excreted with 58.8% bioavailability. The approved dose is 300 mg every 12 h IV or 450 mg every 12 h orally [98, 99]. Unlike other fluoroquinolones, it does not induce cytochrome p3A, does not prolong the QTc, and does not require dose reduction for hepatic dysfunction [98, 100,101,102].
Delafloxacin was first investigated and approved for the treatment of ABSSSI in 2017. In a phase III double-blind RCT of 660 patients, Pullman et al. demonstrated noninferiority to vancomycin plus aztreonam for objective clinical response at 48 h and microbiological eradication, which persisted in the MRSA subgroup analysis (Table 2—delafloxacin) [49••]. Phase II studies demonstrated comparable efficacy to tigecycline and linezolid and higher cure rates compared to vancomycin alone, particularly in obese patients [50•, 51]. Phase III studies were recently completed to evaluate the efficacy of delafloxacin for community-acquired pneumonia and uncomplicated urogenital gonorrhea with results pending.
Eravacycline
Eravacycline is a novel synthetic fluorocycline tetracycline with enhanced activity against gram-positive and gram-negative organisms, including anaerobes, and without activity against Pseudomonas spp. (Table 1) [103]. In vitro, it has activity for ESBL, KPC, and MBL such as OXA and NDM [104, 105]. It is structurally similar to tigecycline and evades many resistance mechanisms of other tetracyclines, including ribosomal protection proteins and efflux pumps [106]. Eravacycline was studied at a dose of 1 mg/kg every 12 h IV. It has linear pharmacokinetics with 28% oral bioavailability. In phase I and II studies, the most common adverse effects were dose-related nausea and superficial phlebitis in 87.5% [107]. Phase I studies indicate that eravacycline can maintain high concentrations in epithelial lining fluid and alveolar macrophages, supporting its potential role in treating respiratory infections [108].
Eravacycline was FDA approved for cIAI in 2018. The IGNITE 1 trial by Solomkin et al. demonstrated noninferiority to ertapenem for clinical cure of cIAI (Table 2—eravacycline) [52••]. The majority of isolates were Enterobacteriaceae, especially E. coli, and few patients had Pseudomonas spp. [52••]. Notably, patients with renal insufficiency and hepatic dysfunction were excluded from this study. Prior phase II studies showed favorable response rates at both 1 and 1.5 mg/kg dosing compared to ertapenem [53]. A phase III trial for the treatment of cIAI compared to meropenem was completed with results pending. Two phase III trials for the treatment of cUTI were completed and failed to demonstrate noninferiority with results not currently published [109]. Phase I RCTs are recruiting patients to evaluate PK and safety in the pediatric population.
Imipenem/cilastatin + relebactam
Relebactam (MK7655) is a novel piperidine analogue diazabicyclooctane class A and C β-lactamase inhibitor (Table 1). It is currently being studied in combination with imipenem and cilastatin (IMI) in the treatment of gram-negative infections due to P. aeruginosa, E. coli, K. pneumoniae, and Enterobacter spp. In vitro, the addition of relebactam reduces MICs for KPC K. pneumoniae by 64-fold, but it has less impact on other ESBL and amp-C producers and is not active against class D β-lactamases [110, 111]. It is predominantly renally excreted and phase I studies show that coadministration does not significantly affect PK of the individual agents [54•].
A phase II multicenter double-blind RCT by Lucasti et al. demonstrated noninferiority of relebactam at both 250 and 125 mg doses in combination with IMI compared to IMI alone at discontinuation of IV therapy for treatment of cIAI (Table 2—imipenem/cilastatin (IMI) + relebactam (REL)) [54•]. However, only 36 isolates were IMI resistant [54•]. A phase III double-blind RCT comparing IMI/relebactam to IMI plus colistimethate for the treatment of IMI-resistant bacterial infections completed recruitment in 2017 with results pending. A phase II study evaluating efficacy for cUTI was initiated as well. Clinical trials are recruiting to study the efficacy of IMI/relebactam versus piperacillin/tazobactam for HABP/VABP, and phase I studies are underway in the pediatric population.
Lefamulin
Lefamulin is a semisynthetic pleuromutilin that has a similar mechanism of action to oxazolidinones by interfering with protein synthesis through binding to the 50S ribosome (Table 1) [112]. Lefamulin has rapid and high tissue penetration in the epithelial lining of the lungs, which suggests its potential role in the treatment of respiratory tract infections [113]. It also has rapid tissue penetration into plasma, skeletal muscle, and subcutaneous adipose, suggesting a potential role for the treatment of ABSSSI [113]. It is active against all aerobic gram-positive organisms except Enterococcus faecalis, including activity against MRSA, vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), penicillin-resistant S. pneumoniae, and vancomycin-resistant E. faecium [112, 114]. It also has activity against gram-negative organisms (except P. aeruginosa and A. baumannii), atypical organisms, some anaerobes, and drug-resistant Neisseria gonorrhoeae [112, 115].
Lefamulin is not currently FDA approved but is being studied for the treatment of CABP and ABSSSI. A phase II RCT by Prince et al. with 210 patients demonstrated comparable clinical success in the treatment of ABSSSI with 100 mg lefamulin, 150 mg lefamulin, and vancomycin (Table 2—lefamulin (BC-3781)) [116]. Two phase III double-blind RCTs (LEAP 1 and 2) demonstrated lefamulin to be noninferior to moxifloxacin with or without linezolid for treatment of CABP, but full results and publications are pending [55, 117].
Meropenem/vaborbactam
Vaborbactam (RPX7009) is a cyclic boronic acid β-lactamase inhibitor that inhibits class A and C as well as some class D β-lactamases, that is currently being studied in combination with meropenem (Table 1). The coadministration of these agents does not alter their individual PK [118]. It is predominantly renally excreted with over 80% recovered in the urine [119].
Meropenem/vaborbactam was FDA approved for the treatment of cUTI based on the results of the TANGO I and II trials. The TANGO I trial by Kaye et al. included 545 patients and demonstrated noninferiority and superiority of meropenem/vaborbactam to piperacillin/tazobactam for clinical and microbiologic cure of cUTI, although only a limited number of the isolates were carbapenem resistant (Table 2—meropenem/vaborbactam (M-V)) [58••]. The TANGO II trial by Wunderink et al. was a small study of 47 patients with CRE infections that demonstrated higher clinical and microbiological cure rates when treated with M-V compared to the best available therapy (polymixins, carbapenems, aminoglycosides, tigecycline, ceftazidime/avibactam) [56••]. This study included 22 patients with BSI, and infections mostly due to K. pneumoniae, including MBL-producing organisms. Cure rates remained higher in immunocompromised patients and those with prior antibiotic failure who received M-V; however, these subgroups had small sample sizes [56••]. A case report documents clinical and microbiologic success using M-V 40 mg/kg IV every 6 h over 3 h to treat KPC K. pneumoniae bacteremia in a pediatric patient with successful target attainment [57].
Plazomicin
Plazomicin (ACHN-490) is an aminoglycoside derivative of sisomicin that inhibits protein synthesis by binding to the ribosomal 30S subunit (Table 1). In phase I PK studies, it has predictable high peak and low troughs at 15 mg/kg once daily dosing, with achievable targets for E. coli and K. pneumoniae at 7 mg/kg [120]. Plazomicin has activity against typical aminoglycoside-resistant pathogens, including those with aminoglycoside-modifying enzymes (AME), ESBL, KPC, and MBL. In vitro, plazomicin has good activity against Enterobacteriaceae, including CRE and KPC, which is comparable to amikacin, carbapenems, and tigecycline, and better than gentamycin and tobramycin [121, 122]. In vitro, it inhibits 84.6% CRE, 92.9% KPC without MBL, and 87% OXA-48 and has improved activity against isolates with AME encoding genes (99% inhibited overall) compared to other aminoglycosides (gentamycin 31.3%, tobramycin 1.5%, amikacin 76.9%), meropenem (78.2%), and tigecycline (94.6%) [122]. Plazomicin has activity against Acinetobacter baumannii¸ Acinetobacter calcoaceticus, and P. aeruginosa; however, break points are higher for these organisms. It has limited activity against Enterococcus spp., S. pneumoniae, Providencia spp., Morganella spp., and Proteus mirabilis [121]. In vitro, it is the only aminoglycoside active against Brucella suis, but it is not consistently active against other Brucella spp. [123].
Plazomicin is currently FDA approved for treatment of cUTI. A phase II double-blind RCT by Connolly et al. demonstrated comparable clinical and microbiological cure for 10 mg/kg plazomicin, 15 mg/kg plazomicin, and levofloxacin for the treatment of cUTI and acute pyelonephritis (Table 2—plazomicin) [59•]. In this study, 2 of 74 patients at 15 mg/kg had vestibular or cochlear-related adverse effects and two patients discontinued therapy due to nephrotoxicity [59•]. Phase III RCTs that compare efficacy to meropenem for the treatment of cUTI and to colistin for CRE infections completed recruitment with results pending.
Solithromycin
Solithromycin is a fourth-generation macrolide fluoroketolide (Table 1). It has 67% bioavailability and is not affected by food. It is metabolized by cyp3A4p450 and is predominantly biliary excreted with only 10% renal clearance, but does not require dose adjustment for hepatic impairment [124]. It does not affect QTc and has similar safety for adolescents as adults [125, 126]. It has high concentrations in epithelial lining fluid and alveolar macrophages, suggesting a potential role in treating respiratory tract infections [127]. Its unique chemical structure allows greater intracellular accumulation than other macrolides, enabling it to treat both extra- and intracellular pathogens. Solithromycin has activity in vitro against both gram-positive and gram-negative organisms, including gram-positive anaerobes [128]. It has increased activity for Mycoplasma genitalium in vitro compared to other macrolides and 8- to 32-fold higher activity for Legionella pneumophila serotype 1 than azithromycin [129, 130].
Solithromycin is not currently FDA approved but is being studied for the treatment of CABP and urogenital gonorrhea. The SOLITAIRE-oral and SOLITAIRE-IV studies demonstrated that 5 days of treatment with solithromycin was noninferior to moxifloxacin for the treatment of CABP based on early clinical response, and clinical cure at short- and long-term follow-up (Table 2—solithromycin) [60••, 61••]. These studies used an initial dose of 800 mg orally or IV, followed by 400 mg PO daily for days 2 through 5 [60••, 61••]. Initial phase II studies compared solithromycin to levofloxacin with comparable efficacy [131]. Phase II studies were initiated to evaluate efficacy of a single 1200 mg PO dose for the treatment of N. gonorrhea [63]. A phase III study (SOLITAIR-J) to evaluate efficacy and safety of a single dose of 1200 mg PO solithromycin compared to intramuscular ceftriaxone and azithromycin for the treatment of uncomplicated urogenital gonorrhea with or without concomitant Chlamydia trachomatis completed enrollment with results pending.
Sulopenem
Solupenem is a carbapenem that is available orally and IV. It is active against gram-positive organisms and gram-negative organisms, including ESBL, but is not active against P. aeruginosa, Enterococcus spp., CRE, or MRSA (Table 1) [62]. It is dosed either at 1000 mg IV once daily or 500 mg PO twice daily with probenecid 500 mg PO twice daily.
Sulopenem is not FDA approved but being studied for CABP and cIAI. A phase II double-blind RCT was conducted to evaluate its efficacy for CABP requiring hospitalization with switch to oral therapy compared to ceftriaxone with transition to amoxicillin/clavulanic acid, with results pending. A phase III RCT is recruiting patients to compare solupenem to ertapenem for the treatment of cIAI.
Discussion
Given the antimicrobial resistance crisis, the development of new antimicrobials with enhanced activity against drug-resistant bacteria is critical; this is especially true for resistant gram-negative organisms. Of the agents that are currently in the pipeline or recently approved, most represent modifications of preexisting agents and the majority are administered intravenously. Each agent, except cefiderocol, targets only certain classes of β-lactamases and there continues to be a lack of treatment options for infections caused by metallo-β-lactamase-producing organisms. The use of ceftazidime/avibactam and ceftolozane/tazobactam for the treatment of resistant gram-negative infections is promising but studies looking specifically at patients with infections due to MDR organisms remain sparse and are limited to observational studies. The majority of RCTs for new antimicrobials have focused on cUTI and cIAI, and their effectiveness in other severe infections including BSI and nosocomial pneumonia is unclear. More studies are needed to determine the role of these agents in the treatment of resistant gram-negative infections.
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Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017;61.
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Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, et al. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother. American Society for Microbiology Journals. 2017;61:e02097–16.
Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections: Table 1. Clin Infect Dis. 2016;63:1615–8.
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Vissichelli, N.C., Stevens, M.P. Antibiotics in the Pipeline for Treatment of Infections due to Gram-Negative Organisms. Curr Treat Options Infect Dis 11, 115–144 (2019). https://doi.org/10.1007/s40506-019-00187-4
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DOI: https://doi.org/10.1007/s40506-019-00187-4