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 . 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 . 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.
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.
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 . 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. . 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 . 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 . 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% .
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 . Similarly, fosfomycin synergy has been demonstrated with carbapenems (along with a reduction in the emergence of resistance), aminoglycosides, and quinolones . Low mortality rates in KPC-associated infections were shown with the use of triple combination therapy including a carbapenem, tigecycline, and colistin . 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) . 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.
New compounds for the treatment of resistant gram-negative bacteria
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 . In-vitro synergism has been reported with doripenem, imipenem, piperacillin/tazobactam, and cefepime against P. aeruginosa . 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 . A phase 2 study showed comparable efficacy to levofloxacin in patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (88 versus 81%, respectively) . 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 .
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 . 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 .
‘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 . In the treatment of microbiologically documented abdominal infections, ceftazidime/avibactam showed success rates over 90%, with an efficacy against ESBL-producing isolates of 96% . 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 . 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 .
‘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 .
‘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 . 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% . 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].
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 . 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 . The most commonly reported adverse effects with biapenem were nausea, skin eruption, vomiting, and diarrhea in 2–3% of patients .
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 . 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 . 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 . Doripenem displays a favorable safety profile with mild gastrointestinal adverse effects and a lower incidence of seizures compared to other carbapenems .
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 . 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 . 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 .
‘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 . 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.
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 . 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].
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 . Finafloxacin has also shown activity towards ciprofloxacin-resistant strains of A. baumannii . A phase 2 study comparing finafloxacin administered 300 mg b.i.d. versus ciprofloxacin showed comparable efficacy in uncomplicated UTIs . A phase 2 clinical trial is ongoing comparing i.v. and oral finafloxacin with ciprofloxacin in cUTI and acute pielonephritis .
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 . 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 . 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 . 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 . Overall, omadacycline had greater potency against gram-positive bacteria than against the enteric bacteria and has been studied mainly for the treatment of SSSI .
Table 3 summarizes the compounds that are active gram-negative pathogens along with their efficacy towards carbapenemase-producing bacteria and their clinical indications.
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.
Financial support and sponsorship
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.
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