Secondary Logo

Share this article on:

New antibiotics and antimicrobial combination therapy for the treatment of gram-negative bacterial infections

Bassetti, Matteo; Righi, Elda

Current Opinion in Critical Care: October 2015 - Volume 21 - Issue 5 - p 402–411
doi: 10.1097/MCC.0000000000000235
INFECTIOUS DISEASES: Edited by Marin H. Kollef

Purpose of review Increasing rates of life-threatening infections due to multidrug-resistant (MDR) gram-negative bacteria, such as carbapenemase-producer strains, as well as pathogens that are resistant to all current therapeutic options, have been reported. The number of compounds that are currently being developed is still insufficient to control this global threat. We have reviewed the current available options for the treatment of MDR gram-negative infections, including combination regimens employing older antimicrobials and new compounds.

Recent findings A limited number of large trials have assessed the treatment options for commonly encountered resistant pathogens (e.g., Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa). Antimicrobials that were used in the past, such as colistin and fosfomycin, have been recently resumed and used in association with carbapenems, tigecycline, or aminoglycosides, showing a positive impact on clinical outcomes. New compounds belonging to various antimicrobial classes (e.g. beta-lactamase inhibitors, cephalosporins, glycyclines, aminoglycosides) have been investigated.

Summary Only few new molecules have an adequate activity against MDR gram-negative pathogens, especially carbapenemase-producer strains. Among these, ceftozolane/tazobactam has been recently approved for clinical use. Other compounds, such as avibactam combinations, plazomicin, and eravacycline, have shown promising activity in phase 2 and 3 clinical trials.

Infectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, Italy

Correspondence to Matteo Bassetti, MD, PhD, Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy. Tel: +39 0432 559355; fax: +39 0432 559360; e-mail: mattba@tin.it

Back to Top | Article Outline

INTRODUCTION

The incidence of infections due to resistant gram-negative pathogens has dramatically increased in the nosocomial setting [1,2]. Multidrug-resistant (MDR) gram-negative bacteria are defined as pathogens carrying resistance to one or more antimicrobials from at least three different classes. Recently, the spread of extended-spectrum beta-lactamase (ESBL)-producing bacteria has significantly increased the need for broad-spectrum antimicrobial use [3]. The overuse of molecules such as piperacillin/tazobactam, fluoroquinolones, and carbapenems has contributed to a further increase in antimicrobial resistance, thereby narrowing considerably the therapeutic options for MDR bacteria [4]. Carbapenem resistance is mainly due to the production of carbapenem-hydrolyzing beta-lactamases, or carbapenemases, that usually confer clinical resistance to most beta-lactams. Pathogens carrying carbapenemases that are commonly encountered in clinical practice include Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. Among these, bacteria producing K. pneumoniae carbapenemases (KPCs) are currently the most prevalent and widely distributed [5–7]. Other clinically important carbapenemases include metallo-beta-lactamases (MBLs; e.g. New Delhi metallo-beta-lactamases, Plasmid-mediated imipenem-type carbapenemases, Verona integron-encoded metallo-β-lactamases) and oxacillinase group of β-lactamases (OXA)-type carbapenemases (e.g. OXA-23 in A. baumannii and OXA-48 in K. pneumoniae) [7–10]. Table 1 summarizes the classification of beta-lactamases.

Table 1

Table 1

The widespread use of antimicrobials to overcome new resistant strains has led to the emergence of pathogens that are resistant to all current available molecules. In the past 10 years, the lack of new antibiotics to fight the emergence of MDR, extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria has been the main concern of professional agencies [11,12]. Although new molecules have been recently approved, very few antimicrobials have been developed to target MDR gram-negative resistant bacteria.

Box 1

Box 1

Back to Top | Article Outline

TEXT OF REVIEW

Old drugs and combination strategies

‘Polymyxins’ were initially used in the 1950s and then abandoned due to nephrotoxicity; recently, colistin (polymyxin E) has been resumed for the treatment of MDR strains of A. baumannii, KPC, P. aeruginosa, and Enterobacteriaceae [6]. Alarming data regarding colistin resistance, however, have been reported from Greek and Italian hospitals, where rates up to 36% were documented among KPC strains [13–15]. Suboptimal doses and the use of colistin monotherapy have been associated with emergence of resistance [16–18]. Since the previously used dose of 3 million international units (MIU) every 8 h has been linked to insufficient concentrations in critically ill patients, the current recommended dosage is 9 MIU loading dose followed by 4.5 MIU every 12 h [19,20]. Although colistin nephrotoxicity has not been confirmed by recent studies, a careful management of concomitant factors that can enhance toxicity (e.g. hypoalbuminemia and the use of nephrotoxic drugs) and dose adjustment based on patients’ renal function are warranted, especially in critically ill patients [21,22].

‘Tigecycline’ is the first representative of the tetracycline derivatives glycylcyclines. Tigecycline is active against methicillin resistant Staphylococcus aureus (MRSA), vancomcyin resistant enterococci (VRE), tetracycline-resistant E. coli, and several ESBL strains, whereas no clinical activity has been reported against P. aeruginosa, Proteus spp. and Providencia spp. [23]. In 2005, tigecycline was approved by the US Food and Drug Administration (FDA) for the treatment of complicated skin and skin structure infections (cSSSIs) and complicated intra-abdominal infections (cIAIs). Recent published data support tigecycline use at high doses (200 mg initially, and then 100 mg every 12 h) as part of the combination regimens against MDR pathogens [24,25]. Compared to the standard doses (100 mg loading dose followed by 50 mg every 12 h), higher tigecycline doses showed increased microbiological eradication among ICU patients and adequate lung levels in experimental pneumonia caused by metallo-beta-lactamase (NDM-1)-producing E. coli and K. pneumoniae [26,27]. Although no major issues of toxicity have been reported at high doses, the tolerability of these regimens in large trials still needs to be assessed.

‘Fosfomycin’ inhibits the early stages of the bacterial wall synthesis and was initially launched in the 1970s. Despite a large use for the treatment of urinary tract infections (UTIs) over the years, fosfomycin has maintained in-vitro activity against MDR gram-negative pathogens, especially KPC. Although fosfomycin lacks in-vitro activity towards Acinetobacter spp. and Pseudomonas spp., in-vivo synergy in combination regimens has been shown against these pathogens [28]. Fosfomycin use is limited among critically ill patients who can encounter either augmented or reduced renal clearance determining difficult-to-predict blood concentrations, potentially leading to suboptimal exposure or toxicity [29]. Promising results have been reported by a study encompassing 48 patients with XDR or PDR K. pneumoniae and P. aeruginosa treated with intravenous fosfomycin (24 g/day, in combination with colistin or tigecycline), reporting successful clinical outcomes in 54% and bacterial eradication in 56% [30].

Back to Top | Article Outline

Combination therapies

Previous studies conducted suggested that the benefit of combination therapy against MDR P. aeruginosa infections was mainly due to an increased likelihood of choosing an effective agent rather than an in-vitro synergy among antimicrobials or prevention of resistance [31,32]. Against other MDR gram-negative bacteria, however, several studies have shown higher efficacy and lower levels of resistance for combination treatment compared to monotherapy (Table 2) [33–35]. Colistin use was associated with increased survival rates if administered as part of combination regimens with tigecycline, an aminoglycoside, or meropenem (particularly for carbapenem MIC below 4 mg/l) [16,17]. Higher eradication rates were also demonstrated for the association of colistin with rifampin compared with colistin monotherapy against A. baumannii [36]. Similarly, fosfomycin synergy has been demonstrated with carbapenems (along with a reduction in the emergence of resistance), aminoglycosides, and quinolones [37]. Low mortality rates in KPC-associated infections were shown with the use of triple combination therapy including a carbapenem, tigecycline, and colistin [17]. A recent meta-analysis encompassing studies conducted in the USA, Greece, and Italy has compared the clinical outcome of combination therapy versus monotherapy to treat carbapenemase-producing Enterobacteriaceae infections, mainly KPC bloodstream infections (BSIs) [38]. Mortality rates in the two groups were 27.4 and 38.7%, respectively; a significant difference was also shown for carbapenem-sparing (30.7%) versus carbapenem-containing combination (18.8%) regimens, suggesting that the inclusion of a carbapenem may provide better survival benefit. Overall, current data support the use of combination therapy including colistin and/or tigecycline along with a carbapenem in the therapy of invasive infections due to carbapenem-resistant K. pneumoniae, especially in severe infections.

Table 2

Table 2

Back to Top | Article Outline

New compounds for the treatment of resistant gram-negative bacteria

Aminoglycosides

Aminoglycosides are bactericidal antibiotics that act through inhibition of protein synthesis. They are often administered in combination with beta-lactams or quinolones for the treatment of severe infections caused by aerobic gram-negative bacilli. Compared to other antimicrobials, this class has maintained sufficient levels of susceptibility against MDR-emerging pathogens. A new neoglycoside, plazomicin, has demonstrated promising activity towards MBL-producing strains.

‘Plazomicin’ (formerly ACHN-490) is characterized by a wide spectrum of activity including MRSA and MDR gram-negatives. Plazomicin is stable against most aminoglycoside-modifying enzymes that are found in NDM-1-producing Enterobacteriaceae, as well as other gram-negative pathogens [39]. In-vitro synergism has been reported with doripenem, imipenem, piperacillin/tazobactam, and cefepime against P. aeruginosa [40]. The pharmacokinetic properties of plazomicin were tested in two randomized clinical trials in healthy individuals, revealing a linear and dose-proportional profile and good penetration into the epithelial-lining fluid. Compared to other aminoglycosides, no evidence of side-effects on renal function or audiometry tests was observed [41]. A phase 2 study showed comparable efficacy to levofloxacin in patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (88 versus 81%, respectively) [42]. A phase 3 clinical trial for the treatment of patients with BSI or hospital acquired infections due to carbapenem-resistant Enterobacteriaceae comparing plazomicin to colistin (in association with tigecycline or meropenem) is currently ongoing [43].

Back to Top | Article Outline

Beta-lactamase inhibitor combinations

Beta-lactamase inhibitors (e.g. clavulanate, sulbactam, tazobactam) protect beta-lactams from enzymatic hydrolysis, enhancing their spectrum of activity against various ESBLs. Avibactam, relebactam, and RPX7009 are new investigational beta-lactamase inhibitors. Despite a wider spectrum of activity compared to conventional beta-lactamase inhibitors, however, their efficacy against class B carbapenemases remains limited.

‘Avibactam’ (NXL104) has high affinity with class A and class C beta-lactamases, and has been studied to address resistances caused by ESBLs, KPCs, OXA, and Ampicillin-type β-lactamases (AmpC)-producing organisms [44]. Avibactam has been mostly investigated in combination with ceftazidime, but it is also in clinical development in association with ceftaroline and aztreonam. Among these combinations, aztreonam/avibactam could be potentially used against NDM-1-producing bacteria and has shown promising results for the treatment of ESBL and KPC-producing strains [45].

‘Ceftazidime–avibactam’ combination has shown in-vitro activity against OXA-48, AmpC, and KPC strains, but not against MBL producers [24,46▪]. Noninferiority has been demonstrated using imipenem and meropenem as comparators in phase 2 trials for the treatment of cUTIs and cIAIs, respectively [47]. In the treatment of microbiologically documented abdominal infections, ceftazidime/avibactam showed success rates over 90%, with an efficacy against ESBL-producing isolates of 96% [48]. Phase 3 studies are ongoing to investigate the activity of avibactam/ceftazidime in respiratory infections including ventilator-associated pneumonia (VAP).

‘Ceftaroline–avibactam’ association has demonstrated in-vitro and in-vivo synergistic activity against ESBL and KPC-producing Klebsiella spp., and against ceftazidime-resistant Enterobacter cloacae strains, but not towards A. baumannii and P. aeruginosa [49]. This combination has completed a phase 2 trial in cUTIs versus doripenem, and a phase 1 trial in critically ill patients with augmented renal clearance [50].

‘Aztreonam–avibactam’ presents a large in-vitro spectrum against all carbapenemases due to the presence of aztreonam, a monobactam antibiotic that is stable against class B carbapenemases including MBL that are frequently produced by MDR strains of Klebsiella spp. and Pseudomonas spp. Nevertheless, aztreonam is hydrolyzed by class A ESBLs and class C beta-lactamases [51▪]. A phase 1 trial evaluating the safety of the combination has been completed [52].

‘Relebactam’ (MK-7655) is a novel beta-lactamase inhibitor under investigation in combination with imipenem/cilastatin. In-vitro activity has been shown against AmpC, ESBLs, and KPC, but not against MBL-producing strains [53]. Phase 2 trials are ongoing for the treatment of cIAIs and cUTIs [54,55].

‘RPX7009’ (RPX) is a serine beta-lactamase inhibitor that has been tested in association with meropenem. Against a large collection of KPC-producing Enterobacteriaceae, RPX was able to restore carbapenem activity from 2% to 70–98% [56]. Two phase 3 clinical trials are currently ongoing to evaluate the efficacy and safety of RPX/meropenem in cUTI and other severe infections including HAP, VAP, and BSI caused by carbapenem-resistant Enterobacteriaceae [57,58].

Back to Top | Article Outline

Carbapenems

Carbapenems are broad-spectrum beta-lactam antibiotics characterized by stability to hydrolysis by the majority of ESBLs. Carbapenems play a pivotal role in the antibiotic armamentarium as they possess the broadest spectrum of activity and greatest potency against gram-negative bacteria. Among carbapenems, meropenem, ertapenem, and imipenem/cilastatin are widely used for the treatment of severe infections including HAP, cIAIs, and BSI. New carbapenems can be classified according to their activity against nonfermenting resistant gram-negatives (e.g. P. aeruginosa and A. baumannii) and MRSA. Doripenem and biapenem are active towards P. aeruginosa and A. baumannii, but not MRSA, whereas tomopenem and razupenem display activity against MRSA, but not against nonfermenting bacilli. Panipenem and tebipenem, like ertapenem, do not have activity against nonfermenting pathogens and MRSA.

‘Biapenem’ has been approved for clinical use in Japan in 2002 and has completed phase 2 clinical studies in the USA. Biapenem is characterized by a high efficacy towards pathogens that are involved in both CAP and HAP (e.g. penicillin-resistant Streptococcus pneumoniae, A. baumannii, ESBL-producing Enterobacteriaceae, E. cloacae, Serratia marcescens, and Citrobacter freundii) and has an optimal penetration in the respiratory tissue. Its activity is scarce against P. aeruginosa [59]. Biapenem is administered at a dosage of 300 mg twice daily and requires dose adjustment in case of reduced renal function. A multicenter trial showed similar efficacy and tolerability profile for biapenem compared with imipenem/cilastatin in respiratory infections and UTIs [60]. The most commonly reported adverse effects with biapenem were nausea, skin eruption, vomiting, and diarrhea in 2–3% of patients [61].

Among new carbapenems, ‘doripenem’ is characterized by the broadest spectrum of activity against gram-negative pathogens. Its activity is similar to meropenem against E. coli, Citrobacter spp., and Burkholderia cepacia, although higher MICs have been displayed towards ESBL-producing K. pneumoniae, Proteus mirabilis, Serratia spp., Bacteroides fragilis, P. aeruginosa, and A. baumannii. Doripenem is effective against ESBL or AmpC, but reduced activity has been documented against MBC producers [62]. Combination regimens including doripenem seem promising for the treatment of MDR pathogens. Association of doripenem with colisitin showed in-vitro synergistic action against colistin-resistant, KPC strains. In vivo, doripenem has been successfully used in the so-called ‘dual carbapenem therapy’, in association with ertapenem against PDR KPC infections [63–65]. Two potential explanations have been related to the dual carbapenem effect: carbapenemases are thought to have a preferential affinity for ertapenem that is consumed by the enzymes, leaving higher concentrations of doripenem; alternatively, ertapenem initially may act by reducing the bacterial inoculum density, therefore allowing doripenem to exert its activity [66]. Doripenem at a dosage of 500 mg intravenous (i.v.) every 8 h has received US FDA approval for the treatment of cUTI and cIAIs, and European medical agency approval for the treatment of HAP and VAP [67]. Doripenem displays a favorable safety profile with mild gastrointestinal adverse effects and a lower incidence of seizures compared to other carbapenems [67].

Similarly to imipenem/cilastatin, ‘panipenem’ is marketed in association with ‘betamipron’ that inhibits its renal uptake. Panipenem presents excellent activity against E. coli, K. pneumoniae, Proteus spp., and Citrobacter spp., but has lower efficacy towards P. aeruginosa compared to meropenem, and is inactive against Stenotrophomonas maltophilia [68]. Panipenem is approved for clinical use in China, Korea, and Japan for the treatment of UTIs, lower respiratory tract infections, and surgical infections. Its efficacy and safety were demonstrated in three randomized phase 3 clinical trials in comparison with imipenem/cilastatin for the treatment of adults with respiratory and UTIs [68]. Panipenem/betamipron is administered as 500 mg every 12 h. Mild adverse effects have been associated with panipenem; the association with valproic acid is contraindicated due to possible occurrence of seizures [69].

‘Razupenem’ spectrum of activity includes MRSA, VRE, and some ESBL-producing bacteria [70–72]. Razupenem has reduced activity against AmpC enzymes and carbapenemases [70,71]. Its activity has been studied mainly in the treatment of cSSSI.

‘Tebipenem/pivoxil’ is a novel oral carbapenem developed for the treatment of upper respiratory tract infections, and its spectrum is mainly orientated on gram-positives, K. pneumonia, and E. coli [73]. Phase 2 clinical studies are ongoing in Japan.

‘Tomopenem’ is characterized by a spectrum of activity that includes both gram-positive and gram-negative bacteria. Among gram-negatives, tomopenem displays activity against ceftazidime-resistant P. aeruginosa and ESBL-producing Enterobacteriaceae [74–76]. Studies are ongoing for the treatment of cSSSI and HAP.

Back to Top | Article Outline

Cephalosporins

Cephalosporins are widely used in clinical practice and have been heavily affected by the emergence of resistance among gram-negative pathogens.

‘Ceftozolane/tazobactam’ represents the association of a novel cephalosporin, ceftozolane, and the beta-lactamase inhibitor tazobactam. This combination is characterized by enhanced antipseudomonal activity and efficacy against some ESBL and AmpC-producing bacteria. Ceftolozane chemical structure is similar to ceftazidime, except for the presence of side chain at the 3-position of the cephem nucleus that is responsible for its strong antipseudomonal activity. Due to the ability to escape P. aeruginosa resistance mechanisms (such as penicillin-binding protein mutations and efflux pumps), ceftolozane is active against MDR-resistant isolates [77,78]. Ceftozolane/tazobactam has also superior activity compared to piperacillin–tazobactam and ceftazidime against resistant strains of Enterobacteriaceae (e.g. E. coli, K. pneumoniae); its activity towards P. aeruginosa, with or without the addition of tazobactam, was at least eight-fold times greater than doripenem [78,79]. Ceftolozane also displays activity against TEM-betalactamase (TEM)-1 and sulphydril variable betalactamase (SHV)-1 producers [78]. Similar to other cephalosporins such as ceftazidime and ceftriaxone, however, ESBL and carbapenemases may compromise its activity. Tazobactam is an inhibitor of most class A beta-lactamases and some class C beta-lactamases, and protects ceftolozane from hydrolysis, expanding its spectrum against ESBL-producing bacteria [49,80]. Class B carbapenemases, however, are not hydrolyzed by this combination. In phase 3 trials, ceftozolane/tazobactam administered at 1.5 g every 8 h has shown superior efficacy compared to levofloxacin in cUTIs and comparable efficacy to meropenem in cIAI [81,82▪▪,83,84▪▪]. In December 2014, ceftozolane/tazobactam received US FDA approval for the treatment of cIAI and cUTIs.

Other new cephalosporins include ‘ceftobiprole medocaril’ and ‘ceftaroline fosamil’, characterized by a spectrum of activity towards resistant gram-negative pathogens that is similar to third-generation cephalosporins along with a distinctive activity against MRSA [85–89].

Back to Top | Article Outline

Quinolones

Fluoroquinolones are characterized by a large spectrum of activity that has been compromised by high levels of resistance towards beta-lactamase-producing pathogens. For this reason, new molecules in this class were developed to target MDR bacteria and to provide a low potential for resistance development. Nevertheless, new quinolones improved their spectrum mainly against gram-positive bacteria such as MRSA, with the exception of two compounds, delafloxacin and finafloxacin, that show a moderate activity also towards resistant gram-negatives.

‘Delafloxacin’ has been studied in the treatment of cSSSI. Towards gram-negatives, delafloxacin is active against few resistant K. pneumoniae and E. coli strains [90–92]. Its key characteristics are an unique chemical structure that allows an enhanced antibacterial effect in environments with reduced pH (e.g. the urinary tract during infections and phagolysosomes) and a low potential for the selection of resistances due to a dual mechanism of inhibition of DNA targets (i.e. gyrase and topoisomerase i.v.) [90,92,93]. Furthermore, delafloxacin can be administered both i.v. and orally, thus supporting its role in sequential therapy.

‘Finafloxacin’, also characterized by lower MIC at acidic pH, showed increased efficacy against E. coli, K. pneumoniae, and P. aeruginosa compared to levofloxacin and ciprofloxacin. Due to its characteristics, finafloxacin can be used to treat infections located within the urinary tract, gastric mucosa, or skin where the pH is lower [94]. Finafloxacin has also shown activity towards ciprofloxacin-resistant strains of A. baumannii [95]. A phase 2 study comparing finafloxacin administered 300 mg b.i.d. versus ciprofloxacin showed comparable efficacy in uncomplicated UTIs [96]. A phase 2 clinical trial is ongoing comparing i.v. and oral finafloxacin with ciprofloxacin in cUTI and acute pielonephritis [97].

Back to Top | Article Outline

Tetracyclines

Tetracyclines use in clinical practice has been largely limited by the development of bacterial resistance. Tigecycline, a relatively new molecule, presents a greatly improved spectrum of activity including tetracycline-resistant microorganisms and MDR gram-negatives.

‘Eravacycline’ is a novel fluorocycline that is not inhibited by the mechanisms that are responsible for tetracycline resistance, such as efflux pumps and ribosomal protection proteins [98]. Similarly to tigecycline, eravacycline is active against Enterobacteriaceae, expressing resistance genes from multiple classes of ESBL or carbapenemases [99,100]. Compared with tigecycline, eravacycline demonstrated lower MIC towards difficult-to-treat gram-negative pathogens. Similarly to tigecycline, potential activity was shown against A. baumannii, but not against P. aeruginosa [101]. Eravacycline has been studied for both i.v. and oral administration and is promising for the treatment of cIAI since it displays excellent activity against pathogens that frequently cause peritonitis and abdominal abscesses. A phase 2 study evaluating the safety and efficacy of eravacycline versus ertapenem in cIAI has been completed. Clinical cure rates were above 90% among infections caused by ESBL-producing levofloxacin and ertapenem-resistant organisms [101]. Phase 3 clinical trials are planned to further evaluate its efficacy for the treatment of cIAIs and cUTIs.

‘Omadacycline’ is a semisynthetic aminomethylcycline that presents activity against MSSA, MRSA, VRE, S. pneumonia, K. pneumoniae, Proteus spp., Providencia spp., Morganella morganii, and B. fragilis [102]. Overall, omadacycline had greater potency against gram-positive bacteria than against the enteric bacteria and has been studied mainly for the treatment of SSSI [103].

Table 3 summarizes the compounds that are active gram-negative pathogens along with their efficacy towards carbapenemase-producing bacteria and their clinical indications.

Table 3

Table 3

Back to Top | Article Outline

CONCLUSION

The optimal treatment for MDR, XDR, and PDR gram-negative infections is not well established due to the scarcity of new effective compounds and the paucity of robust clinical data supporting the use of current molecules. Colistin and tigecycline showed consistent in-vitro activity against carbapenemase-producing pathogens, and their use in association with other molecules seems promising. Overall, current data support that combination therapy with two or more in-vitro active drugs appears to be more effective than monotherapy for the treatment of resistant pathogens, especially Enterobacteriaceae and A. baumannii. Other new agents are currently under investigation or in late-stage development, although they present some limitations such as a lack of new mechanisms of action and consistent gaps in their spectrums against MBL-producing gram-negative pathogens. Among new compounds, ceftolozane–tazobactam, avibactam combinations, and plazomicin have shown the wider spectrum of activity.

Overall, careful use and tailored duration of currently available antibiotics along with adequate infection prevention procedures and antimicrobial stewardship remain mandatory to contain the infection burden caused by MDR gram-negative pathogens.

Back to Top | Article Outline

Acknowledgements

None.

Back to Top | Article Outline

Financial support and sponsorship

None.

Back to Top | Article Outline

Conflicts of interest

M.B. serves on scientific advisory boards for Astellas, Astra Zeneca, Bayer, Pfizer,MSD, Tetraphase; has received funding for travel or speaker honoraria from Pfizer, MSD, Gilead, Teva, Astellas AstraZeneca, Bayer, Basilea, Novartis, Shionogi, Vifor, Medicines company, Tetraphase. E.R. has no conflict of interest to disclose.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline

REFERENCES

1. Kallen AJ, Srinivasan A. Current epidemiology of multidrug-resistant gram-negative bacilli in the United States. Infect Control Hosp Epidemiol 2010; 31:S51–54.
2. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1–12.
3. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clinic Proceed Mayo Clinic 2011; 86:250–259.
4. Akova M, Daikos GL, Tzouvelekis L, Carmeli Y. Interventional strategies and current clinical experience with carbapenemase-producing Gram-negative bacteria. Clin Microbiol Infect 2012; 18:439–448.
5. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. J Am Med Assoc 2008; 300:2911–2913.
6. Lee CS, Doi Y. Therapy of infections due to carbapenem-resistant Gram-negative pathogens. Infect Chemother 2014; 46:149–164.
7. Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta-lactamases and its correlation with molecular structure. Antimicrob Ag Chemother 1995; 39:1211–1233.
8. Hammerum AM, Toleman MA, Hansen F, et al. Global spread of New Delhi metallo-beta-lactamase 1. Lancet Infect Dis 2010; 10:829–830.
9. Gupta N, Limbago BM, Patel JB, Kallen AJ. Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis 2011; 53:60–67.
10. Munoz-Price LS, Poirel L, Bonomo RA, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013; 13:785–796.
11. Piddock LJ. The crisis of no new antibiotics: what is the way forward? Lancet Infect Dis 2012; 12:249–253.
12. Infectious Diseases Society of A. The 10 x ’20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 2010; 50:1081–1083.
13. Capone A, Giannella M, Fortini D, et al. High rate of colistin resistance among patients with carbapenem-resistant Klebsiella pneumoniae infection accounts for an excess of mortality. Clin Microbiol Infect 2013; 19:E23–30.
14. Skiada A, Markogiannakis A, Plachouras D, Daikos GL. Adaptive resistance to cationic compounds in Pseudomonas aeruginosa. Int J Antimicrob Ag 2011; 37:187–193.15.16.
15. Kontopidou F, Giamarellou H, Katerelos P, et al. Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multicentre study on clinical outcome and therapeutic options. Clin Microbiol Infect 2014; 20:O117–123.
16. Qureshi ZA, Paterson DL, Peleg AY, et al. Clinical characteristics of bacteraemia caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in the era of CTX-M-type and KPC-type beta-lactamases. Clin Microbiol Infect 2012; 18:887–893.
17. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012; 55:943–950.
18. Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant gram-negative bacteremia. Clin Infect Dis 2013; 56:398–404.
19. Mohamed AF, Karaiskos I, Plachouras D, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Ag Chemother 2012; 56:4241–4249.
20. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Ag Chemother 2009; 53:3430–3436.
21. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 2011; 53:879–884.
22. Rocco M, Montini L, Alessandri E, et al. Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. Crit Care 2013; 17:R174.
23. Petersen PJ, Jacobus NV, Weiss WJ, et al. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob Ag Chemother 1999; 43:738–744.
24. Livermore DM, Mushtaq S, Warner M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Ag Chemother 2011; 55:390–394.
25. Poulakou G, Kontopidou FV, Paramythiotou E, et al. Tigecycline in the treatment of infections from multidrug resistant gram-negative pathogens. J Infect 2009; 58:273–284.
26. De Pascale G, Montini L, Spanu T, et al. High-dose tigecycline use in severe infections. Presented at: 33rd International Symposium on Intensive Care and Emergency Medicine. Brussels, Belgium, 19–22 March, 2013.
27. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009; 9:228–236.
28. Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Ag Chemother 2014; 58:5598–5601.
29. Parker S, Lipman J, Koulenti D, et al. What is the relevance of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill patients? A systematic review. Int J Antimicrob Ag 2013; 42:289–293.
30. Pontikis K, Karaiskos I, Bastani S, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Ag 2014; 43:52–59.
31. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 2012; 25:450–470.
32. Garnacho-Montero J, Sa-Borges M, Sole-Violan J, et al. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit Care Med 2007; 35:1888–1895.
33. Zarkotou O, Pournaras S, Tselioti P, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Inf Dis 2011; 17:1798–1803.
34. Batirel A, Balkan II, Karabay O, et al. Comparison of colistin-carbapenem, colistin-sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections. Eur J Clin Microbiol Inf Dis 2014; 33:1311–1322.
35. Daikos GL, Petrikkos P, Psichogiou M, et al. Prospective observational study of the impact of VIM-1 metallo-(-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother 2009; 53:1868–187322.
36. Durante-Mangoni E, Signoriello G, Andini R, et al. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis 2013; 57:349–358.
37. Samonis G, Maraki S, Karageorgopoulos DE, et al. Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates. Eur J Clin Microbiol Inf Dis 2012; 31:695–701.
38. Tzouvelekis LS, Markogiannakis A, Piperaki E, et al. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Inf 2014; 20:862–872.
39. Galani I, Souli M, Daikos GL, et al. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J Chemother 2012; 24:191–194.
40. Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Exp Rev Antiinfect Ther 2012; 10:459–473.
41. Cass RT, Brooks CD, Havrilla NA, et al. Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects. Antimicrob Ag Chemother 2011; 55:5874–5880.
42. Poulikakos P, Falagas ME. Aminoglycoside therapy in infectious diseases. Exp Opin Pharmacother 2013; 14:1585–1597.
43. ClinicalTrial.org. A study of plazomicin compared with colistin in patients with infection due to carbapenem-resistant Enterobacteriaceae (CRE). Identifier NCT01970371.
44. Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible, nonbeta-lactam beta-lactamase inhibitor. Proce Natl Acad Sci USA 2012; 109:11663–11668.
45. Crandon JL, Nicolau DP. Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-beta-lactamase producers. Antimicrob Ag Chemother 2013; 57:3299–3306.
46▪. Levasseur P, Girard AM, Miossec C, et al. In vitro antibacterial activity of the ceftazidime-avibactam combination against Enterobacteriaceae, including strains with well characterized beta-lactamases. Antimicrob Ag Chemother 2015; 59:1931–1934.

Reports the microbiological activity of ceftazidime–avibactam combination against resistant Enterobacteriaceae.

47. Vazquez JA, Gonzalez Patzan LD, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin 2012; 28:1921–1931.
48. Lucasti C, Popescu, I, Ramesh, M, et al. Efficacy and safety of ceftazidime/NXL104 plus metronidazole versus meropenem in the treatment of complicated intraabdominal infections in hospitalized adults. Presented at: European Congress of Clinical Microbiology and Infectious Diseases and International Congress of Chemotherapy. Milan, Italy, 7–10 May 2011.
49. Sader HS, Fritsche TR, Kaniga K, et al. Antimicrobial activity and spectrum of PPI-0903 M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob Ag Chemother 2005; 49:3501–3512.
50. ClinicalTrials.gov. Pharmacokinetic study of ceftaroline fosamil/avibactam in adults with augmented renal clearance. Identifier N. NCT01624246.
51▪. Wang X, Zhang F, Zhao C, et al. In vitro activities of ceftazidime-avibactam and aztreonam-avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. Antimicrob Ag Chemother 2014; 58:1774–1778.

Presents the microbiological activity of avibactam combinations.

52. ClinicalTrials.gov. To investigate the safety and tolerability of aztreonam-avibactam (ATM-AVI). Identifier N. NCT01689207.
53. Hirsch EB, Ledesma KR, Chang KT, et al. In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob Ag Chemother 2012; 56:3753–3757.
54. ClinicalTrials.gov. Study of the safety, tolerability, and efficacy of MK-7655 + imipenem/cilastatin versus imipenem/cilastatin alone for the treatment of complicated urinary tract infection (cUTI) (MK-7655-003). NCT01275170.
55. ClinicalTrials.gov. Study of the safety, tolerability, and efficacy of MK-7655 + imipenem/cilastatin versus imipenem/cilastatin alone to treat complicated intra-abdominal infection [cIAI] (MK-7655-004). NCT01506271.
56. Castanheira M, Becker HK, Rhomberg PR, Jones RN. Effect of the β-lactamase inhibitor RPX7009 combined with meropenem tested against a large collection of KPC-producing Enterobacteriaceae. Presented at 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, 5–9 September 2014, Washington, United States.
57. ClinicalTrials.gov. A phase 3, multi-center, randomized, open-label study of carbavance (Meropenem/RPX7009) versus best available therapy in subjects with selected serious infections due to carbapenem-resistant Enterobacteriaceae. Identifier N. NCT02168946.
58. ClinicaTrials.gov. A phase 3, multi-center, randomized, open-label study of carbavance (Meropenem/RPX7009) versus best available therapy in subjects with selected serious infections due to carbapenem-resistant Enterobacteriaceae. Identifier N. NCT02168946.
59. Chen HY, Livermore DM. In-vitro activity of biapenem, compared with imipenem and meropenem, against Pseudomonas aeruginosa strains and mutants with known resistance mechanisms. J Antimicrob Chemother 1994; 33:949–958.
60. Jia B, Lu P, Huang W, et al. A multicenter, randomized controlled clinical study on biapenem and imipenem/cilastatin injection in the treatment of respiratory and urinary tract infections. Chemother 2010; 56:285–290.
61. 2002; Perry CM, Ibbotson T. Biapenem Drugs. 62:2221–2234.[discussion 2235].
62. Queenan AM, Shang W, Flamm R, Bush K. Hydrolysis and inhibition profiles of beta-lactamases from molecular classes A to D with doripenem, imipenem, and meropenem. Antimicrob Ag Chemother 2010; 54:565–569.
63. Giamarellou H, Galani L, Baziaka F, Karaiskos I. Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae. Antimicrob Ag Chemother 2013; 57:2388–2390.
64. Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Ag Chemother 2011; 55:3002–3004.
65. Ceccarelli G, Falcone M, Giordano A, et al. Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Ag Chemother 2013; 57:2900–2901.
66. Thomson KS. Double-carbapenem therapy not proven to be more active than carbapenem monotherapy against KPC-positive Klebsiella pneumoniae. Antimicrob Ag Chemother 2012; 56:4037[author reply 4038].
67. Matthews SJ, Lancaster JW. Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Therapeut 2009; 31:42–63.
68. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: past, present, and future. Antimicrob Ag Chemother 2011; 55:4943–4960.
69. 2003; Goa KL, Noble S. Panipenem/betamipron drugs. 63:913–925.[discussion 926].
70. MacGowan AP, Noel A, Tomaselli S, et al. Pharmacodynamics of razupenem (PZ601) studied in an in vitro pharmacokinetic model of infection. Antimicrob Ag Chemother 2011; 55:1436–1442.
71. Livermore DM, Mushtaq S, Warner M. Activity of the anti-MRSA carbapenem razupenem (PTZ601) against Enterobacteriaceae with defined resistance mechanisms. J Antimicrob Chemother 2009; 64:330–335.
72. Tran CM, Tanaka K, Yamagishi Y, et al. In vitro antimicrobial activity of razupenem (SMP-601, PTZ601) against anaerobic bacteria. Antimicrob Ag Chemother 2011; 55:2398–2402.
73. Sato N, Kijima K, Koresawa T, et al. Population pharmacokinetics of tebipenem pivoxil (ME1211), a novel oral carbapenem antibiotic, in pediatric patients with otolaryngological infection or pneumonia. Drug Met Pharmacokin 2008; 23:434–446.
74. Koga T, Abe T, Inoue H, et al. In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem. Antimicrob Agents Chemother 2005; 49:3239–3250.
75. Sugihara K, Sugihara C, Matsushita Y, et al. In vivo pharmacodynamic activity of tomopenem (formerly CS-023) against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus in a murine thigh infection model. Antimicrob Agents Chemother 2010; 54:5298–5302.
76. Breilh D, Texier-Maugein J, Allaouchiche B, et al. Carbapenems. J Chemother 2013; 25:1–17.
77. Moya B, Zamorano L, Juan C, et al. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2010; 54:3933–3937.
78. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother 2011; 55:2390–2394.
79. Juan C, Zamorano L, Perez JL, et al. Spanish Network for Research in Infectious D: activity of a new antipseudomonal cephalosporin, CXA-101 (FR264205), against carbapenem-resistant and multidrug-resistant Pseudomonas aeruginosa clinical strains. Antimicrob Ag Chemother 2010; 54:846–851.
80. Jones RN, Sader HS, Flamm RK. Update of dalbavancin spectrum and potency in the USA: report from the SENTRY Antimicrobial Surveillance Program (2011). Diagn Microbiol Infect Dis 2013; 75:304–307.
81. Clinicaltrials.gov. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous levofloxacin in complicated urinary tract infection, including pyelonephritis. Identifier NCT01345929.
82▪▪. Wagenlehner F, Umeh O, Huntington J, et al. Efficacy and safety of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (CUTI)/pyelonephritis in hospitalised adults: results from the phase 3 aspect-CUTI trial. Presented at 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Barcelona, Spain, 10–13 May 2014.

Presents the results of the phase 3 trials in cUTIs comparing ceftolozane/tazobactam versus levofloxacin.

83. Clinicaltrials.gov. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous meropenem in complicated intraabdominal infections. Identifier NCT01445678.
84▪▪. Eckmann C, Hershberger E, Miller B, et al. Efficacy and safety of ceftolozane/tazobactam versus meropenem in the treatment of complicated intra-abdominal infections (cIAI) in hospitalised adults: results from the phase 3 aspect-cIAI trial. Presented at 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Barcelona, Spain, May 10–13, 2014

Presents the results of the phase 3 trials in cIAIs comparing ceftolozane/tazobactam versus meropenem.

85. Queenan AM, Shang W, Kania M, et al. Interactions of ceftobiprole with beta-lactamases from molecular classes A to D. Antimicrob Ag Chemother 2007; 51:3089–3095.
86. Walkty A, Adam HJ, Laverdiere M, et al. In vitro activity of ceftobiprole against frequently encountered aerobic and facultative Gram-positive and Gram-negative bacterial pathogens: results of the CANWARD 2007-2009 study. Diagn Microbiol Infect Dis 2011; 69:348–355.
87. Nicholson SC, Welte T, File TM Jr, et al. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int J Antimicrob Ag 2012; 39:240–246.
88. Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother 2010; 65 (Suppl 4):iv9–16.
89. Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010; 51:641–650.
90. Remy JM, Tow-Keogh CA, McConnell TS, et al. Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization. J Antimicrob Ther 2012; 67:2814–2820.
91. Nilius AM, Shen LL, Hensey-Rudloff D, et al. In vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. Antimicrob Ag Chemother 2003; 47:3260–3269.
92. Almer LS, Hoffrage JB, Keller EL, et al. In vitro and bactericidal activities of ABT-492, a novel fluoroquinolone, against Gram-positive and Gram-negative organisms. Antimicrob Agents Chemother 2004; 48:2771–2777.
93. Lemaire S, Tulkens PM, Van Bambeke F. Contrasting effects of acidic pH on the extracellular and intracellular activities of the antigram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus. Antimicrob Ag Chemother 2011; 55:649–658.
94. Stubbings W, Leow P, Yong GC, et al. In vitro spectrum of activity of finafloxacin, a novel, pH-activated fluoroquinolone, under standard and acidic conditions. Antimicrob Ag Chemother 2011; 55:4394–4397.
95. Higgins PG, Stubbings W, Wisplinghoff H, Seifert H. Activity of the investigational fluoroquinolone finafloxacin against ciprofloxacin-sensitive and -resistant Acinetobacter baumannii isolates. Antimicrob Ag Chemother 2010; 54:1613–1615.
96. ClinicalTrials.gov. Finafloxacin 300 mg twice a day (b.i.d.) versus ciprofloxacin 250 mg twice a day (b.i.d) in patients with lower uncomplicated UTI (uUTI) (FLUT). Identifier NCT00722735.
97. ClinicalTrials.gov. A multi-dose, double-blind, double-dummy, active-control, randomized clinical (phase II) study of two dosing regimens of finafloxacin for the treatment of cUTI and/or acute pyelonephritis requiring hospitalisation. Identifier NCT01928433.
98. Clark RB, Hunt DK, He M, et al. Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy. J Med Chem 2012; 55:606–622.
99. Sutcliffe JA, O’Brien W, Fyfe C, Grossman TH. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Ag Chemother 2013; 57:5548–5558.
100. Grossman TH, Starosta AL, Fyfe C, et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Ag Chemother 2012; 56:2559–2564.
101. Solomkin JS, Ramesh MK, Cesnauskas G, et al. Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections. Antimicrob Ag Chemother 2014; 58:1847–1854.
102. Macone AB, Caruso BK, Leahy RG, et al. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Ag Chemother 2014; 58:1127–1135.
103. Robert D, Arbeit DR, Roberts JA, et al. Safety and efficacy of PTK 0796: results of the phase 2 study in complicated skin and skin structure infections following IV and oral step down therapy. Presented at: 48th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC, USA, 2014.
Keywords:

combination regimens; gram-negative pathogens; multidrug resistance; new antibiotics

Copyright © 2015 YEAR Wolters Kluwer Health, Inc. All rights reserved.