THE EUROPEAN MEDICINES AGENCY APPROVED THE NEW ANTIBACTERIAL DRUGS – RESPONSE TO THE 2017 WHO REPORT ON THE GLOBAL PROBLEM OF MULTI-DRUG RESISTANCE

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VOLUME 60 , ISSUE 4 (December 2021) > List of articles

THE EUROPEAN MEDICINES AGENCY APPROVED THE NEW ANTIBACTERIAL DRUGS – RESPONSE TO THE 2017 WHO REPORT ON THE GLOBAL PROBLEM OF MULTI-DRUG RESISTANCE

Joanna Krajewska / Agnieszka Ewa Laudy *

Keywords : delafloxacin, eravacycline, β-lactamases inhibitors, siderophores, vaborbactam

Citation Information : Postępy Mikrobiologii - Advancements of Microbiology. Volume 60, Issue 4, Pages 249-264, DOI: https://doi.org/10.21307/PM-2021.60.4.20

License : (CC-BY-NC-ND 4.0)

Received Date : July-2021 / Accepted: September-2021 / Published Online: 12-January-2022

ARTICLE

ABSTRACT

The growing problem of antimicrobial resistance has been classified by the World Health Organization (WHO) as one of the top ten threats to mankind. In a special report published in 2017, the WHO presented a list of microorganisms for which the search for new therapeutic options is a priority. The highest (critical) priority was given to the search for new antibiotics active against carbapenem-resistant strains of Acinetobacter baumannii and Pseudomonas aeruginosa as well as against carbapenem- and third-generation-cephalosporin-resistant Enterobacterales strains (so-called critical priority pathogens). Whereas the second (high) priority was given among others to the search for new antibiotics active against methicillin- and vancomycin-resistant strains of Staphylococcus aureus (MRSA and VRSA) and vancomycin-resistant strains of Enterococcus faecium (VRE). Since the publication of the WHO report the European Medicines Agency has approved 6 novel, broad-spectrum antibiotics, from 6 different groups, addressing the priority pathogens to a different extent. Two of them are new combinations of carbapenems with non-β-lactam inhibitors of β-lactamases (active also against carbapenemases), belonging to two novel groups of inhibitors: diazabicyclooctanes (relebactam, combined with imipenem) and boronates (vaborbactam, combined with meropenem). The third new drug is a siderophore cephalosporin (cefiderocol) with an innovative mechanism of penetration into the bacterial cell. The next two antibiotics are the new fluoroquinolone (delafloxacin) and the new tetracycline (eravacycline), designed and synthesized to be more active than older members of these groups. The last innovative antibiotic is lefamulin – the first pleuromutilin approved for systemic use in humans. New approvals have expanded the number of available therapeutic options in the treatment of complicated urinary tract infections (meropenem/vaborbactam, cefiderocol), complicated intra-abdominal infections (meropenem/vaborbactam, eravacycline), nosocomial pneumonia (meropenem/vaborbactam, imipenem/relebactam), acute bacterial skin and skin structure infections (delafloxacin) and community-acquired pneumonia (lefamulin).

Problem narastającej oporności drobnoustrojów został zakwalifikowany przez Światową Organizację Zdrowia (WHO) jako jedno z dziesięciu największych zagrożeń dla ludzkości. W specjalnym raporcie z 2017 roku WHO przedstawiła listę bakterii, dla których poszukiwanie nowych opcji terapeutycznych jest priorytetowe. Za najpilniejsze działanie uznano poszukiwanie nowych antybiotyków skutecznych wobec opornych na karbapenemy szczepów Acinetobacter baumannii i Pseudomonas aeruginosa oraz opornych na karbapenemy i cefalosporyny III generacji szczepów Enterobacterales (tzw. patogeny o krytycznym priorytecie). Wysoki priorytet przypisano również poszukiwaniu leków aktywnych m.in. wobec szczepów Staphylococcus aureus opornych na metycylinę (MRSA) i wankomycynę (VRSA) oraz Enterococcus faecium opornych na wankomycynę (VRE). Od czasu publikacji raportu WHO, Europejska Agencja Leków (EMA) dopuściła do obrotu w sumie 6 nowych antybiotyków szerokospektralnych, z 6 różnych grup, skierowanych w różnym stopniu wobec szczepów priorytetowych wg WHO. Dwa spośród nich to nowe połączenia karbapenemów z nie-β-laktamowymi inhibitorami β-laktamaz (o aktywności także wobec karbapenemaz), należącymi do dwóch nowych grup inhibitorów: diazabicyklooktanowych (relebaktam, skojarzony z imipenemem) oraz boronowych (waborbaktam, skojarzony z meropenemem). Trzeci nowy lek to cefalosporyna sideroforowa (cefiderokol) o innowacyjnym mechanizmie wnikania do komórki bakteryjnej. Kolejne dwa antybiotyki to nowy fluorochinolon (delafloksacyna) i nowa tetracyklina (erawacyklina), zaprojektowane i zsyntezowane z myślą o zwiększonej skuteczności w stosunku do starszych przedstawicieli tych grup. Ostatni, innowacyjny antybiotyk to lefamulina – pierwsza pleuromutylina zarejestrowana do stosowania ogólnego u ludzi. Nowe rejestracje poszerzyły liczbę dostępnych opcji terapeutycznych w leczeniu m.in. powikłanych zakażeń dróg moczowych (meropenem/waborbaktam, cefiderokol), powikłanych zakażeń wewnątrzbrzusznych (meropenem/waborbaktam, erawacyklina), szpitalnych zapaleń płuc (meropenem/waborbaktam, imipenem/relebaktam), ostrych bakteryjnych zakażeń skóry i tkanek podskórnych (delafloksacyna) oraz pozaszpitalnych zakażeń płuc (lefamulina).

Graphical ABSTRACT

1. Introduction

According to the World Health Organization (WHO), the growing drug resistance of microorganisms is one of the top ten threats to humanity. In 2017, the WHO published a special report containing a list of pathogens for which the search for new therapeutic options is a priority, due to the increasingly limited range of antibiotics that can be used to treat infections caused by them [121]. Twelve pathogens were entered on the list, divided into 3 categories according to the urgency of searching for new therapeutic options active against them. The first group of pathogens with the highest critical priority included carbapenem-resistant Gram-negative bacilli. Carbapenem-resistant Acinetobacter baumannii (CRAB) strains were considered to be the most dangerous, followed by carbapenem-resistant Pseudomonas aeruginosa strains CRPA) and, in third place, carbapenem-resistant Enterobacterales (CRE). This group also includes Enterobacterales strains resistant to third-generation cephalosporins, as well as Mycobacterium tuberculosis and other acid-fast mycobacteria. Whereas, multidrug-resistant strains of Gram-positive cocci have been classified by the WHO into the second group of pathogens with a high priority of search for new drugs against them. This group includes Staphylococcus aureus strains resistant to methicillin (methicillin-resistant S. aureus – MRSA) and vancomycin (vancomycin-resistant S. aureus – VRSA); vancomycin-resistant Enterococcus faecium, as well as clarithromycin-resistant Helicobacter pylori; Campylobacter spp., and Salmonella spp. resistant to fluoroquinolones; and Neisseria gonorrhoeae resistant to fluoroquinolones and third-generation cephalosporins [121].

The most important problem among the critical priority pathogens is their resistance to carbapenems, associated with the production of hydrolyzing them enzymes (carbapenemases), or with non-specific mechanisms such as decreasing the outer membrane permeability and overexpression of genes encoding efflux pumps [26, 37, 60]. According to Ambler classification [4], carbapenemases occurring among the strains of Gram-negative bacilli belong mainly to classes A, B and D. So far, only a few class C carbapenemases have been described, e.g., the enzyme ADC-68 in A. baumannii. Among the class A enzymes, the KPC plasmid carbapenemases (Klebsiella pneumoniae carbapenemase), mainly the variants KPC-2 and KPC-3, are of the highest clinical significance [37]. They are widespread in Enterobacterales strains, primarily in K. pneumoniae strains and increasingly in E. coli strains. The ability to produce them has also been demonstrated in Gram-negative strains of non-fermenting bacilli, i.e., P. aeruginosa, and recently in A. baumannii. The genes encoding them are located in transposons in large conjugative plasmids, which creates the possibility of their easy horizontal transfer. In the therapy of infections caused by KPC-positive strains only colistin, tigecycline and sometimes aminoglycosides can be administered. The strains producing carbapenemases of the family GES (Guiana extended-spectrum β-lactamase) are of much lower clinical importance. It is relatively rare for GES enzymes to be detected in both P. aeruginosa strains and in the bacilli of Enterobacterales, and the genes encoding them are most often located in class 1 integrons [37].

Out of the class B enzymes of the Ambler classification system (metallo-β-lactamases – MBL) [37], the enzymes of the NDM (New Delhi metallo-β-lactamase) family occur the most frequently in Gram-negative bacilli strains worldwide. Originally, enzymes of MBL type posed a therapeutic problem mainly in P. aeruginosa strains. The predominant enzymes in Europe, also in Poland, were the ones from the VIM (Verona integrated-encoded metallo-β-lactamase) family, and in the Far East, IMP (imipenemase) enzymes. The first case of the production of the NDM-1 enzyme in Enterobacterales was described in 2009, and in the following years the ability to produce NDM enzymes became widely spread, mainly in K. pneumoniae, E. coli, P. aeruginosa and other bacilli. A wide substrate range of MBL enzymes (they hydrolize all β-lactams except monobactams) in combination with the easy horizontal transfer of the genes encoding them (located in plasmids, integrons or transposons) and the lack of an inhibitor that can be utilized in therapy (they are inhibited, among others, by EDTA) make these enzymes a significant clinical problem. It is considered that the greatest threat are NDM-positive strains, whose genomes also contain genes encoding other β-lactamases (AmpC, OXA-48, VIM, KPC) and genes determining resistance to other antibiotics (aminoglycosides and fluoroquinolones). The strains producing MBL enzymes usually remain sensitive to colistin, tigecycline and fosfomycin [37].

D class carbapenemases, according to the Ambler classification system, are oxacillinases of the OXA family, the substrate range of which has been expanded, giving them the capability of hydrolysing also carbapenems. The greatest clinical importance is possessed by the enzymes of the CHDL group (carbapenem-hydrolysing class D β-lactamases) and OXA-48 β-lactamase. CHDL enzymes are the dominant mechanism responsible for carbapenem resistance in A. baumannii strains [79, 102]. In A. baumannii strains, in addition to the naturally occurring chromosomal OXA-51-like enzyme, also OXA-23-like and OXA-24-like CHDL carbapenemases are most commonly detected. In turn, the carbapenemase of OXA-48 is commonly found in the bacilli of the order Enterobacterales. The hydrolytic activity of class D carbapenemases towards carbapenems and cephalosporins is lower compared to MBL and KPC-type enzymes. However, the presence of insertion sequences (ISAba) preceding the blaCHDL genes significantly increases the resistance of A. baumannii strains to carbapenems. A. baumannii CRAB strains, owing to the variety of other resistance mechanisms simultaneously occurring in them, are considered to be among the most dangerous pathogens, against which WHO recommends priority search for new therapeutic options.

Resistance to carbapenems has also been described among Enterobacterales strains as well as Gram-negative non-fermenting bacilli which do not produce carbapenemases. The cause of the insensitivity of the strains to carbapenems may lie in the reduction of the outer membrane permeability, due to a reduction in the abundance or changes in the conformation of the porins through which carbapenems penetrate into the cell, the so-called influx mechanism [26]. The reduced abundance or absence of OprD porins was the first reported mechanism of the resistance of P. aeruginosa to imipenem. This mechanism of resistance to carbapenems has also been described in K. pneumoniae strains (associated with OmpK35 and OmpK36 porins), E. coli (associated with OmpC and OmpF porins) and in A. baumannii (primarily CarO). Active removal of antibiotics from bacterial cells by the efflux pump systems, the so-called efflux mechanism plays an important role – in CRE strains, RND family pumps are the most important (e.g., AcrAB-TolC systems in E. coli as well as in K. pneumoniae) in CRPA strains, the MexAB-OprM and MexXY systems and the AdeABC system in CRAB strains [60]. It is often found that the resistance of Gram-negative bacilli to carbapenems includes simultaneous participation of two or three mechanisms, such as production of two different carbapenemases and/or disruption of antibiotic penetration into cells and/or active removal of drugs with the participation of efflux pump systems.

Among the pathogens from the second group according to WHO classification, the high priority kind, resistance of staphylococcal strains to methicillin and glycopeptides and resistance of enterococci to glycopeptides are the dominant problems [121]. The resistance to methicillin in staphylococci is linked to the presence of the mecA gene or its homologues, i.e., mecB, mecC or mecD, which determine the synthesis of the altered PBP-2a protein, having no affinity for β-lactam antibiotics (except for ceftaroline and ceftobiprole) [28]. The mec genes are located within a large mobile DNA fragment, i.e., SCCmec (staphylococcal cassette chromosome mec). In addition to being resistant to β-lactam, MRSA strains also typically exhibit resistance to aminoglycosides, fluoroquinolones, macrolides and lincosamins. On the other hand, they often remain sensitive to ceftaroline, ceftobiprole, linezolid, tigecycline, daptomycin, dalbavancin and rifampicin. Following the emergence of methicillin-resistant staphylococci, vancomycin became the drug of choice for the treatment of infections caused by them. Soon, however, strains with reduced susceptibility to this antibiotic (vancomycin intermediate-resistant Staphylococcus aureus – VISA), and (less frequently) vancomycin resistant strains appeared (vancomycin resistant Staphylococcus aureus – VRSA) [28]. The reasons for the reduced sensitivity of the VISA phenotype to vancomycin are not yet fully understood. Most likely, it is related to a change in the cell wall structure and a decrease in its permeability to vancomycin. In turn, the complete resistance to vancomycin, a VRSA phenotype, is conditioned by the presence of an operon containing the vanA gene. It has been demonstrated that this operon was located in the Tn1546 transposon, derived from the enterococcal conjugative plasmid. The resistance to vancomycin was first observed in enterococci. Among the VRE (vancomycin-resistant enterococci) strains responsible for hospital infections, E. faecium isolates display resistance to vancomycin significantly more often than E. faecalis [95]. The vanA gene, as well as other previously detected van genes (vanB, vanC, vanD, vanE, vanG, vanL, vanM, vanN), which determine resistance or reduced sensitivity of enterococci to vancomycin, are the ones responsible for the synthesis of the altered D-alanyl-D-alanine peptide fragment in the cell wall precursor, forming the D-alanyl-D-lactate or D-alanyl-D-serine. Thus, the target site of glycopeptide action changes, which is expressed through different levels of isolate resistance. In addition to VRE and MRSA strains, also the strains simultaneously resistant to linezolid are isolated, which may pose a serious clinical problem. The resistance of priority pathogens to fluoroquinolones results mainly from mutations in the genes encoding topoisomerase II, i.e., gyrase (in the gyrA genes) and topoisomerase IV (in the genes parC in E. coli and grlA in staphylococci), which results in the synthesis of altered subunits of these enzymes, with reduced affinity for fluoroquinolones [42]. Additionally, fluoroquinolones are substrates for many MDR pumps in priority pathogens, e.g., AdeABC in A. baumannii, MexAB-OprM in P. aeruginosa, AcrAB-TolC in Enterobacterales, NorA in S. aureus, CmeABC in Campylobacter spp. or NorM in N. gonorrhoeae [42].

Since the publication of the 2017 WHO report sounding alarm on the issue of searching for new effective drugs against dangerous pathogens, six new antibiotics from six different groups, addressing WHO priorities to various degree have been approved on the European market by the European Medicines Agency (EMA). Two of them are a new combination of carbapenems with non-β-lactam inhibitors of β-lactamases (also active against carbapenemases), from two new groups: diazabicyclooctane inhibitors (relebactam, combined with imipenem) and boronate ones (vaborbactam, combined with meropenem). The success of approving after many years new β-lactamase inhibitors from two unused before chemical groups resulted in extending the scope of the search for new inhibitors [12, 19, 39]. In turn, the search for new ways to overcome the barrier posed by the outer membrane of Gram-negative bacteria, resulted in the market authorisation of cefiderocol – siderophore cephalosporin. The use of siderophores in drug design is a novel approach to the concept of modern medication [80, 119]. Both the new combination of carbapenems with β-lactamase inhibitors and cefiderocol are active towards critical WHO pathogens to a varying degree. The next two original antibiotics comprise a novel fluoroquinolone (delafloxacin) and a new tetracycline (eravacycline), the molecules of which were designed and synthesized in order to increase efficacy and minimize the susceptibility to bacterial resistance mechanisms, typical of the older representatives of these groups. Both antibiotics are active against many WHO high priority pathogens. The last of the new antibiotics is lefamulin, the first representative of the pleuromutilin group registered for systemic use in humans. A distinctive feature of this group of antibiotics is its unique structure (meeting the WHO innovation criteria), rare occurrence of resistance and activity against pathogens of high priority according to the WHO. In turn, the strains of Gram-negative bacilli, i.e., P. aeruginosa, A. baumannii and Enterobacterales are naturally resistant to lefamulin. This article provides a review of new, wide-spectrum antibiotics active against the WHO priority pathogens, authorized for use in the European Union since 2018 (Figure 1).

Figure 1.

Structures of new antimicrobial compounds

Compounds are active against priority pathogens according to WHO, approved in the European Union since 2018: A) vaborbactam – a boron inhibitor of β-lactamases (combined with meropenem); B) relebactam – a diazabicyclooctane β-lactamase inhibitor (in combination with imipenem / cilastatin); C) cefiderocol – siderophore cephalosporin; D) delafloxacin – the fourth generation fluoroquinolones; E) eravacycline – the first fully synthetic tetracycline; F) lefamulin – the first pleuromutilin for systemic use in humans.

10.21307_PM-2021.60.4.20-f001.jpg

2. Boronate inhibitors of β-lactamases

Boronate β-lactamase inhibitors are a relatively new class of compounds with cyclic boronic acid as a pharmacophore. Vaborbactam (previously RPX7009) was dicovered under a program aimed at developing an inhibitor of serine β-lactamases, especially of the KPC type [39]. It is a monocyclic, reversible competitive inhibitor of class A enzymes according to the Ambler system (CTX-M, KPC, BKC, FRI, SME, TEM, SHV) and class C (AmpC) with which it creates covalent bonds between the boronate moiety and the catalytic serine centre. The inhibition of KPC by vaborbactam does not trigger its inactivation and is characterized by extremely slow reversibility. At the same time, vaborbactam is not active against class B enzymes (e.g., NDM, VIM) and class D (e.g., OXA-48), does not inhibit human serine enzymes and does not exhibit direct antimicrobial activity in therapeutic concentrations [15, 39, 111]. In vitro research has demonstrated that vaborbactam reduces the MIC values of carbapenems more vigorously than of the other β-lactams, hence the meropenem-vaborbactam combination was selected for further research [66].

In trials conducted on clinical isolates of Gram-negative strains of (E. coli, Enterobacter spp., K. pneumoniae, A. baumannii and P. aeruginosa), it was confirmed that vaborbactam increases the activity of meropenem against carbapenem-resistant strains of Enterobacterales but not against P. aeruginosa and A. baumannii strains [59, 97]. In large-scale surveillance programmes, the overall percentage of meropenem/vaborbactam among Enterobacterales was 99.3% and was higher than for meropenem (96.9%). In contrast, among Enterobacterales resistant to carbapenem, vaborbactam restored meropenem activity in 73.9% of the strains, and among the strains producing KPC in as much as 99.5%. Vaborbactam did not restore sensitivity to meropenem in strains producing metallo-β-lactamases and OXA-48 enzymes [88] as well as in the strains of A. baumannii, P. aeruginosa and Stenotrophomonas maltophilia [14]. Similar results were obtained by analysing the sensitivity of the collection of clinical E. coli strains resistant to carbapenems isolated around the world, in which the overall proportion of meropenem/vaborbactam-sensitive strains was 66% and was only lower than the percentage of strains sensitive to tigecycline (100%) and amikacin (74%). Sensitivity was greater among the strains of Latin American origin (88%) and lower among strains isolated in Europe (75%) and Asia (51%) [52]. Also, in the study by Zhou et al. [129], it was concluded that the proportion of K. pneumoniae strains with increased MIC values of meropenem and vaborbactam in China is higher than in other geographical areas, possibly due to the dissemination in this area of strains with defects in both major porins (OmpK35 and OmpK36) involved in the entry of carbapenems into a bacterial cell.

The growing problem of infections caused by the strains producing metallo-β-lactamases (and therefore resistant to all β-lactams, except aztreonam), combined with the absence of an effective inhibitor of these enzymes, has also resulted in attempts to combined meropenem/vaborbactam with aztreonam – a monobactam resistant to carbapenemases but destroyed by a number of serine enzymes. So far, in vitro research has demonstrated that meropenem/vaborbactam acts synergistically with aztreonam against multidrug-resistant K. pneumoniae and E. coli strains producing both NDM-type enzymes and serine β-lactamases [11, 70]. However, the effectiveness of this combination requires further research.

The hitherto observed resistance of strains to meropenem/vaborbactam was most likely associated with the production of metallo-β-lactamases [15], mutations in genes encoding porins (OmpK35, OmpK36) [24, 66, 108] responsible for drug influx and/or overexpression of AcrAB-TolC pump systems [15] involved in the efflux mechanism, less often resistance was associated with an overproduction of KPC, associated with an increase in the number of blaKPC gene copies [108]. So far, no case of resistance associated with a mutation in the blaKPC genes has been described.

In clinical trials it was demonstrated that meropenem/vaborbactam (administered 2 g/2 g every 8 h) is non-inferior to piperacillin/tazobactam (4 g/0.5 g every 8 h) in patients with complicated urinary tract infection (cUTI) [55]. The results of the latest clinical trial (TANGO II) further indicate that meropenem-vaborbactam is superior to the best available therapy (BAT) in patients with a confirmed or suspected infection with Enterobacterales resistant to carbapenems and with multiple comorbidities such as renal failure, immunodeficiency, or prior antibiotic therapy [9, 10]. Increased cure rate, decreased mortality, and lower nephrotoxicity were observed in the patients group treated with meropenem/vaborbactam [9].

A preparation containing meropenem with vaborbactam powder for concentrate for solution for infusion (1 g/1 g) under the trade name of Vaborem has been approved on the European market since 20.11.2018 [20]. Its therapeutic indications include the treatment of complicated urinary tract infections (including pyelonephritis), complicated intra-abdominal infections, nosocomial pneumonia (including ventilator-associated pneumonia) and infections caused by Gram-negative aerobic organisms in adult patients with limited treatment options.

3. Diazabicyclooctane inhibitors of β-lactamases

Relebactam (formerly MK-7655) is the second, after avibactam, non-β-lactam inhibitor of β-lactamases from the group of diazabicyclooctane derivatives, approved for treatment [20]. Relebactam is structurally similar to avibactam, however, it contains an additional piperidine ring which ensures a positive charge at physiological pH for the molecule, crucial for reducing its susceptibility to active removal by pump systems in the phenomenon of efflux. Biochemical analyses have demonstrated that relebactam is an inhibitor of class A (of KPC type) and class C enzymes (AmpC type, e.g., AmpC Pseudomonas-derived cephalosporinase-3, PDC-3) and in addition (similarly to imipenem), it is not a substrate for the MDR pump systems in P. aeruginosa [7, 12, 124]. The lack of susceptibility of the imipenem/relebactam combination to being removed from bacterial cells by the P. aeruginosa MDR pump systems and the activity of relebactam against AmpC enzymes resulted in this combination being selected for further research. In vitro research has confirmed that relebactam actually increases the activity of imipenem against Enterobacterales strains, whose carbapenem resistance was associated with the production of KPC enzymes or in which the production of AmpC or ESBL β-lactamases was observed combined with the reduced permeability of the outer membrane (mutations in OmpK36). As was also observed in the P. aeruginosa OprD-deficient strains and (at higher concentrations of the drug) against P. aeruginosa MDR strains. Similarly to vaborbactam, relebactam is not an inhibitor of metallo-β-lactamases (NDM, IMP, VIM) or class D enzymes (OXA), neither does it display direct antibacterial activity [36, 40, 63]. The synergistic interaction of imipenem/relebactam with amikacin and colistin against imipenem-resistant P. aeruginosa strains has also been described under in vitro conditions [6].

In many large surveillance studies, the susceptibility to imipenem/relebactam of clinical strains isolated from patients with lower respiratory tract infections, urinary tracts infections and intra-abdominal infections has been tested [53, 54, 64, 65]. It has been demonstrated that in the presence of relebactam, imipenem concentrations able to prevent the growth of most clinical Enterobacterales strains (including carbapenem-resistant strains) were reduced, although the MIC values of imipenem for Serratia marcescens strains are usually higher than for other species. The percentage of imipenem/relebactam-sensitive strains of E. coli, Klebsiella spp., Citrobacter spp., and Enterobacter spp. reached over 95%. However, among S. marcescens the percentage of susceptible strains was lower. Imipenem/relebactam is also effective against P. aeruginosa strains (the percentage of susceptible strains reaching over 90%), with the exception of strains producing β-lactamases of class B or D. Among the strains resistant to carbapenems, 42–66% of Enterobacterales strains and 74–78% of P. aeruginosa strains remain sensitive to imipenem/relebactam. Relebactam, however, does not increase the activity of imipenem against Acinetobacter spp. [53, 54, 64, 65, 115].

The observed resistance of Gram-negative bacilli to imipenem/relebactam stems mainly from the production of metalloenzymes. In P. aeruginosa strains, it may also be due to the ability to produce class A carbapenemases from the GES family and overexpression of genes encoding PDC enzymes in combination with the loss of the OprD porin proteins [65, 124]. In Enterobacterales, in turn, resistance may be caused by the production of oxacillinases with carbapenemase activity, e.g., OXA-48, as well as mutations in the genes encoding porin proteins and a decrease in the abundance of these porins (OmpK35, OmpK36, OmpC and OmpF), thereby limiting imipenem/relebactam penetration into bacterial cells [30, 51].

Clinical studies have demonstrated that imipenem (administered at a dose of 500 mg every 6 hours) in combination with relebactam (125 mg or 250 mg every 6 hours) is a well-tolerated treatment and is non-inferior than imipenem used alone in the group of patients with complicated intra-abdominal infections and complicated urinary tract infections [67, 101]. Imipenem/relebactam was also characterized by comparable efficacy and lower nephrotoxicity than the use of imipenem and colistin in the combination therapy of infections caused by imipenem-resistant Gram-negative bacilli [78]. On the basis of the obtained results, a preparation containing imipenem/cilastatin (where cilastatin is an inhibitor of dehydrogenase I, a kidney enzyme which inactivates imipenem) with relebactam (Recarbrio 500 mg/500 mg + 250 mg, powder for solution for infusion) was approved by EMA on 13.02.2020 for the treatment of nosocomial pneumonia (also associated with mechanical ventilation) and in the treatment of Gram-negative bacterial infections in adults with limited therapeutic options [20].

4. Siderophore cephalosporins

Cefiderocol is a representative of a new group of antibiotics – siderophore cephalosporins [80]. Siderophores are a structurally diverse group of small molecules (150–2000 Da) with chelating properties and high iron affinity [119]. Iron is an essential element for the functioning of many enzymes, and therefore also for microorganisms. However, its acquisition by bacteria is hampered due to the low solubility of iron at physiological pH under aerobic conditions, in which easily bioavailable Fe (II) ions are oxidized to Fe (III), causing the formation of insoluble ferric oxyhydroxides. In addition, host defence mechanisms cause further reduction in iron accessibility at the infection site due to the secretion of their own iron-binding proteins, such as lipocalin 2, also called siderocalin, or neutrophil gelatinase associated lipocalin (NGAL). In order to obtain the sufficient amount of iron, the bacteria produce and secrete siderophores into the extracellular environment, whose task is to bind its ions and transport them inside the cell. More than 500 different siderophores have been identified so far. Characteristic structural elements in their molecules are iron chelating functional groups (hydroxamates, catechols, carboxylates, phenolate moieties or combinations thereof) attached to a linear or cyclic scaffold forming a hexadentate structure. After binding an iron ion, the resulting complex (ferrisiderophore) is absorbed in the mode of active transport. In Gram-negative bacteria, the entire complex crosses both the outer and inner membranes, and the bounded iron is released in the cytoplasm. Alternatively, iron may be released in the periplasmic space [119].

The first attempts to use siderophores to transport antibiotics inside the cell were made already in the 1970s. In the 20th century, this strategy was called the “trojan horse approach” [80]. Cefiderocol (formerly S-649266, GSK2696266) is the first antibiotic of this type introduced into healthcare. It is used in the form of cefiderocol sulphate tosylate. It is a catechol siderophore cephalosporin, which was selected from other derivatives of a similar structure, in the course of a program aimed at finding a new antibiotic active against carbapenem-resistant strains [5]. Cefiderocol has a structural similarity to cefepime, such as the presence of a pyrrolidinium group on the C-3 side chain, increasing antimicrobial activity and stability against β-lactamases, and a carboxypropanoxyimino group on the C-7 side chain, which improves the transport of cefiderocol across the outer membrane. Additionally, cefiderocol also has a chlorocatechol group at the end of the C-3 side chain, which is responsible for siderophoric activity [96].

The principal mechanism of action of cefiderocol is the inhibition of cell wall synthesis by binding to PBPs (mainly PBP-3). Cefiderocol, after binding iron, reaches the periplasmic space through active transport, in which, inter alia, CirA and Fiu transporters in E. coli and PiuA in P. aeruginosa are involved. This transport mechanism eliminates the problem of resistance associated with reducing the number of porins in the outer membrane or the overexpression of the MDR pumps, which are responsible for the phenomenon of efflux [96]. Furthermore, a cefiderocol molecule is resistant to a wide range of β-lactamases, both serine (KPC-3, OXA-23, AmpC) and metallo-β-lactamases (IMP-1, VIM-2) [46, 47]. However, this resistance may arise due to mutations within the genes encoding either PBPs, or a protein related to the regulation of iron ion uptake or siderophores transport protein, as well as the production of β-lactamases capable of hydrolysing cefiderocol (NDM, PER type) and overexpression of native bacterial siderophores [58, 69, 96].

Cefiderocol is highly active against a broad spectrum of Gram-negative bacteria, both representatives of Enterobacterales (Enterobacter spp., Klebsiella spp., Proteus spp., S. marcescens, Shigella flexneri, Salmonella spp., Yersinia spp.) as well as non-fermenting bacilli (Acinetobacter spp., Pseudomonas spp., Burkholderia spp., S. maltophilia) and Vibrio spp. [48]. However, it displays no activity against aerobic Gram-positive bacteria (Staphylococcus spp., Enterococcus spp.) as well as anaerobic bacteria. Cefiderocol is also active against strains producing various β-lactamases, such as the KPC, VIM, NDM and OXA-48 types in Enterobacterales, or the VIM, IMP, NDM and GES types in P. aeruginosa or CHDL enzymes from the OXA-23, OXA-24/40 and OXA-58 groups in A. baumannii [48]. The sensitivity of the clinical strains of Enterobacterales and non-fermenting bacilli has been analysed in several international surveillance studies [27, 35, 106]. So far, the percentages of cefiderocol-sensitive strains isolated from patients suffering from, e.g., nosocomial pneumonia, bloodstream infection, complicated intra-abdominal infections and complicated urinary tract infections are at a level > 95%, irrespective of the geographic region. A lower percentage was observed only in the case of K. pneumoniae strains (88%).

In clinical studies it has been demonstrated that cefiderocol (administered 2 g every 8 hours) is non-inferior to imipenem (1 g every 8 hours) in the treatment of complicated urinary tract infections (cUTI) (APEKS-cUTI study) [89], and non-inferior to meropenem (2 g every 8 hours) in the treatment of nosocomial pneumonia (also linked to mechanical ventilation) (APEKS-NP) [122]. It has also been demonstrated that cefiderocol has similar clinical and microbiological efficacy in the treatment of critically ill patients infected with carbapenem-resistant Gram-negative bacilli, compared to the best available therapy (BAT), although in the group treated with cefiderocol, higher mortality has also been reported, mainly in patients with infections caused by Acinetobacter spp. [8]. Cefiderocol was approved by EMA on 23.04.2020 under the name of Fetcroja 1 g, powder for concentrate for solution for infusion. Its current therapeutic indications include the treatment of infections caused by aerobic Gram-negative bacteria in adults, with limited therapeutic options [20].

5. New fluoroquinolones

Delafloxacin (formerly WQ-3034, ABT-492) is a new 4 th generation fluoroquinolone and the first anionic compound in this group [57, 112]. Its molecule is distinguished primarily by the absence of the basic group in the C7 position (which ensures acidic properties), the presence of chlorine in the C8 position, which serves as an electron-withdrawing group on the aromatic ring (which increases the polarity of the compound and improves its activity and stability) and the presence of a voluminous heteroaromatic substituent in the N1 position, whereby the surface area of delafloxacin is much larger than that of other fluoroquinolones. As a result, delafloxacin exists in an anionic form at neutral pH and in a neutral form in an acidic medium. This contributes to its increased activity under low pH conditions, while the activity of other fluoroquinolones decreases as the pH drops.

The mechanism of action of delafloxacin, like all fluoroquinolones, consists in inhibiting gyrase and topoisomerase IV [81]. However, it has been shown to act with comparable potency on both of these topoisomerases in both E. coli and S. aureus. Whereas the remaining fluoroquinolones are more active against topoisomerase IV in Gram-positive bacteria and against gyrase in Gram-negative bacteria. The inhibition of gyrase activity is a more effective way of inhibiting DNA replication due to the involvement of this enzyme at an earlier stage (removal of positive supercoils before the replication forks) than in the case of topoisomerase IV, which operates behind the replication forks (DNA decatenation and chromosomal separation). Thus, the stronger interaction of delafloxacin with gyrase in Gram-positive bacteria (in comparison to the remaining fluoroquinolones) contributes to the increased activity of this new fluoroquinolone against these bacteria.

Additionally, the similar affinity to both topoisomerases suggested that delafloxacin, compared to other fluoroquinolones, should predispose strains to developing resistance to a lesser degree due to the necessity to create mutations simultaneously in both genes encoding these topoisomerases. In vitro studies have demonstrated a lower potential for the selection of resistant, spontaneous mutants of S. aureus MRSA strains than in the case of other fluoroquinolones [92]. The mutant prevention concentration (MPC) values of delafloxacin were 8 to 32 times lower than the MPC values of moxifloxacin, levofloxacin and ciprofloxacin, and additionally, in the obtained mutants, compared to the parent strain, a decrease in viability was observed. The sensitivity analysis of the strains isolated from patients treated with delafloxacin during clinical examinations confirmed that delafloxacin retained high activity also against the strains with mutations in quinolone resistance-determining regions (QRDR) [72]. Delafloxacin MIC values were not significantly increased (i.e., MIC > 0.5 mg/l) until there were simultaneous double mutations in both gyrA and parC genes.

As anticipated, in in vitro studies, delafloxacin demonstrated more significant activity than trovafloxacin, levofloxacin and ciprofloxacin against sensitive and quinolone-resistant strains of Gram-positive bacteria (Staphylococcus spp., Enterococcus spp., Streptococcus spp., Listeria monocytogenes), fastidious Gram-negative bacteria (H. influenzae, Moraxella catarrhalis, N. gonorrhoeae, Legionella pneumophila) and H. pylori. Its effectiveness against Enterobacterales and P. aeruginosa strains was comparable with other fluoroquinolones, and its effectiveness against Chlamydia spp. was comparable with trovafloxacin and higher than levofloxacin [3, 29, 81]. Under in vitro conditions, delafloxacin is also effective against Mycoplasma pneumoniae, Mycoplasma fermentans, Mycoplasma hominis and Ureaplasma spp. [113]. It also shows activity against the biofilm formed by S. aureus MSSA and MRSA, with the ability to penetrate into its interior reaching 52% (depending on the proportion of polysaccharides in the matrix) and increased effectiveness against biofilms of lower pH [100]. It has been demonstrated that delafloxacin usually has a bactericidal effect against Streptococcus pneumoniae, H. influenzae and M. catarrhalis strains [34].

The high activity of delafloxacin against staphylococci (also MRSA) and streptococci, the strains most often causing acute bacterial skin and skin structure infections (ABSSSI), combined with its high activity in the acidic environment (typical for the skin), directed further research on the application of delafloxacin to this disease. The recently published results of the surveillance studies of the sensitivity of 11,866 strains isolated over the years 2014–2019 in the USA and Europe from patients with ABSSSI confirmed the high activity of delafloxacin [99]. The most frequently isolated strains were S. aureus MSSA (~ 30.6%), E. coli (11%), Streptococcus spp. (10%) and S. aureus MRSA (7.2%). The susceptibility to this antibiotic was confirmed for 98.7% of MSSA strains, 98.4% of Streptococcus spp. strains, 58% of E. coli strains and 65.6% of MRSA strains.

In clinical trials, delafloxacin turned out to be a drug with linear pharmacokinetics, minimal accumulation and was well-tolerated – gastrointestinal side effects were observed only at single oral doses > 1200 mg or multiple doses > 800 mg [44]. An oral dose of 450 mg and an intravenous dose of 300 mg proved to have comparable effects, providing an option of changing the route of administration during the therapy [43].

In randomized clinical trials in patients with complicated infections of the skin and subcutaneous tissue (abscesses and wound infections after surgery, trauma, burns and bites) intravenous delafloxacin (300 mg twice daily) was as effective as tigecycline (50 mg twice daily) [83], vancomycin with aztreonam (15 mg/kg+ 2 g twice daily) [91] and linezolid (600 mg twice daily) [56] and more effective than vancomycin (15 mg/kg of body mass twice daily) [56]. Efficacy not worse than that of vancomycin with aztreonam has also been demonstrated for delafloxacin with the dosage pattern of 300 mg intravenously (twice daily) for 2 days and then 450 mg orally [82]. The same dosage pattern for delafloxacin was non-inferior than moxifloxacin (400 mg intravenously followed by 400 mg orally once daily) in the treatment of community-acquired bacterial pneumonia (CABP), also pneumonia caused by atypical pathogens (M. pneumoniae, Chlamydia pneumoniae, L. pneumophila) [45]. Delafloxacin showed at least 16-fold greater activity than moxifloxacin against Gram-positive bacteria and fastidious Gram-negative bacilli, and also retained activity against resistant strains, e.g., S. pneumoniae MDR, Haemophilus spp. producing β-lactamases and macrolide-resistant strains, as well as S. aureus MRSA and fluoroquinolone-resistant strains [71, 73].

However, a single 900 mg dose of delafloxacin turned out to be an ineffective form of treating uncomplicated gonorrhoea – many treatments for N. gonorrhoeae infections with MIC values below 0.008 mg/l were unsuccessful, indicating the need to modify the dosing regimen [41].

In the European Union, delafloxacin was approved on 16.12.2019 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community acquired pneumonia (CABP) in adults, when the application of other antibacterial agents commonly recommended for the initial treatment of these infections is considered to be inappropriate. Both the oral (450 mg tablets) and intravenous (300 mg) forms were registered under the trade name Quofenix [20].

6. New tetracyclines

Tetracyclines are natural or semi-synthetic compounds with amphoteric properties, containing four fused carbocyclic rings (including an aromatic one) in their molecule [31]. Their mechanism of action consists in inhibiting protein synthesis by binding to the 30S ribosome subunit. All compounds from this group are characterized by a broad spectrum of activity, both against Gram-positive and Gram-negative bacteria, mycoplasmas, chlamydia, rickettsiae and some protozoa. The differences between individual representatives concern the pharmacokinetic properties and potency. The first tetracycline antibiotics (produced by various species of actinomycetes – Streptomyces) were introduced into medicine at the turn of the 1940s and 1950s. Unfortunately, their intensive use in medicine led to the rapid emergence and spread of resistance associated with the presence of tet genes, encoding membrane pump proteins involved in the phenomenon of the so-called efflux (e.g., tet(A), tet(B), tet(K), tet(L) genes), ribosome protective proteins (e.g., tet(M), tet(O), tet(P), tet(S)) or tetracycline-inactivating enzymes, i.e., the tet(X) gene.

However, the growing drug resistance of microorganisms to antibiotics from other groups contributed to the renewed interest in tetracyclines. Determining the structure of the tetracycline-30S ribosome co-crystal demonstrated that the binding to the ribosome does not involve only the region around the C5-C9 carbon atoms [13]. Therefore, attempts were made to introduce structural modifications at C7 and C9 atoms, which resulted in the market launch of semi-synthetic tetracyclines (minocycline, tigecycline, omadacycline). The new tetracyclines are characterized by increased antibacterial activity and lower susceptibility to bacterial resistance mechanisms [31]. However, the number of the chemical modifications of natural tetracyclines and thus the possibility of obtaining new, semi-synthetic derivatives is limited. It was only the de novo synthesis of subsequent compounds containing the tetracycline skeleton that significantly increased the number of new compounds from this group [107].

Eravacycline (formerly TP-434) is the first fully synthetic tetracycline introduced into medicine [20]. Its molecule is characterized by the presence of fluorine at the C7 carbon atom and the pyrrolidinoacetamido group at the C9 carbon of the tetracycline core and is also active against tetracycline-resistant strains with the tet(M) and tet(Q) genes (responsible for blocking the tetracycline binding site to the ribosome) and the genes tet(A), tet(B) and tet(K) (responsible for the synthesis of membrane proteins of MDR pumps) [33, 123]. The spectrum of eravacycline activity includes strains of S. aureus (also linezolid resistant MRSA and MRSA), Streptococcus spp., Enterococcus spp. (also VRE), E. coli, K. pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, S. marcescens, Salmonella spp., Shigella spp., A. baumannii, Acinetobacter lwoffii, S. maltophilia, Legionella pneumophila, H. influenzae, M. catarrhalis, N. gonorrhoeae, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides ovatus, Prevotella spp., Clostridioides difficile, and Clostridium perfringens. Eravacycline maintains its effectiveness also against strains resistant to fluoroquinolones, aminoglycosides, third-generation cephalosporins, carbapenems, polymyxins and MDR strains, and its effectiveness is usually 2–4 times higher than or equal to tigecycline, both against Gram-positive and Gram-negative bacteria [1, 23, 50, 62, 103, 110, 125, 127]. It has also been shown that under in vitro conditions eravacycline acts synergistically with colistin against A. baumannii strains, also against strains resistant to carbapenems and colistin [84]. Nevertheless, the strains of P. aeruginosa and Burkholderia cenocepacia are resistant to eravacycline [110].

Moreover, it has been demonstrated that eravacycline is effective against the biofilm of the uropathogenic E. coli strain to a degree comparable to that of gentamicin and levofloxacin, and to a greater degree than in the case of colistin and meropenem [32]. However, eravacycline has not been shown to be effective against the biofilm formed by S. aureus strains isolated from periprosthetic-joint infections [130].

Recently published results of large surveillance studies have confirmed the high effectiveness of eravacycline against a wide spectrum of clinical strains [76, 77]. The percentage shares of susceptible strains were respectively: 97.6% for S. aureus (95.5% for MRSA and 99.8% for MSSA), 84.6% for S. epidermidis, 89.9% for S. haemolyticus, 99.4% for E. faecalis (98.3% for VR strains, 99.5% for VS), 97.7% for E. faecium (96.1% for VR strains and 98.9% for VS) and 92.6% for Enterobacterales (82% for MDR strains). In turn, for A. baumannii strains for which no MIC breakpoints have been defined, the MIC50/MIC90 values reached 0.5 mg/l and 1 mg/l, respectively (for MDR strains the MIC90 reached 2 mg/l).

However, the clinical effectiveness of eravacycline may be threatened in the future by the increasing resistance arising from the antibiotic-removal mechanism (efflux), enzymatic degradation of this antibiotic and modification of its binding site in the ribosome. So far, it has been demonstrated that in S. aureus (both MRSA and MSSA), E. faecalis and S. agalactiae strains, the MIC values of eravacycline (similar to tigecyclines) showed significant decreases in the presence of MDR pump inhibitors such as carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and L-phenylalanine-L-arginine-β-naphthylamide (PAβN) [61, 118, 127]. Additionally, research describes clinical strains of A. baumannii resistant to eravacycline with overexpression of the AdeABC pump system [98], K. pneumoniae with overexpression of OqxAB and MacAB-TolC pumps [128] as well as K. pneumoniae PDR (pan-drug resistant) strains isolated from farm animals in China with the expression of a new RND efflux pump, of the MexCD-OprJ type, called TMexCD1-TOprJ1, responsible for the resistance, among others to all tetracycline antibiotics [68]. Since the genes encoding it are located in the plasmid, their spread among zoonotic strains of K. pneumoniae may pose a serious clinical threat in the future. Another, equally important threat to the effectiveness of applying eravacycline in therapy is the spread of tet(X) genes located in plasmids and transposons. Several variants of these genes have recently been described in China in A. baumannii strains (environmental and clinical) [16, 116] and in Enterobacterales strains isolated from the stool samples of healthy adults in Singapore [18]. They are also widespread among E. coli strains isolated from animals (pigs, chickens, migratory birds) and soil [17, 109], and recently the presence of these genes has also been confirmed in Proteus sp. isolated from retail pork [38]. Resistance to eravacycline may also result from mutations in the genes encoding the proteins of the 30S ribosome subunit, as already described in S. aureus and S. agalactiae strains [61, 117].

Clinical studies have shown that when it comes to the treatment of complicated intra-abdominal infections, eravacycline (administered 1 mg/kg every 12 hours) is well tolerated and safe, as well as non-inferior to meropenem (administered 1 g every 8 hours) and non-inferior to ertapenem (1 g every 24 hours) [104, 105]. Based on the results obtained, eravacycline was approved by the EMA for use against this nosological unit on 20.09.2018 and registered under the trade name Xerava 50 mg, powder for concentrate for solution for infusion [20].

7. Pleuromutilins

Lefamulin is a new antibiotic from the group of pleuromutilins – derivatives of naturally occurring pleuromutilin, isolated in the 1950s from the fungus Pleurotus mutilus (presently, Clitophilus scyphoides) [86]. The first semi-synthetic derivatives of pleuromutilin (tiamulin and valnemulin) were approved for veterinary use in 1979 and 1999, respectively. However, these drugs were used only in the treatment of pulmonary and intestinal infections in animals but not in the production of food of animal origin as growth promoters or for enhancement of feed efficiency (unlike, among others, tetracyclines, streptogramins or sulphonamides). This may explain the low prevalence of bacterial resistance to pleuromutilins. Retapamulin was the first antibiotic of this class approved for human use, but it was only available as an ointment for topical application for a short-term treatment of superficial skin infections (impetigo, minor lacerations, abrasions, or sutured wounds). Lefamulin (formerly BC-3781) is the second pleuromutilin approved for human use, but the first to be approved for systemic use, both in the intravenous and oral forms [86].

Chemically, pleuromutilins are diterpenoids containing in their molecule a 14-carbon tricyclic scaffold (essential for antimicrobial activity) and a glycolic ester moiety forming a side chain at the C14 position, various modifications of which correspond, among others, to different pharmacodynamic properties of derivatives [126]. The mechanism of action of this group of antibiotics consists in inhibiting protein synthesis by binding to the 50S ribosome subunit at the peptidyl transferase centre (PTC), in the middle of the domain V of the 23S rRNA molecule. A tricyclic core that forms hydrogen bonds with the nucleotides in the pocket near the A-site of the ribosome is responsible for the attachment of pleuromutilins to the ribosome, while the side chain at position C14 extendes towards the P-site, hindering the movement of the 3’ tRNA end towards the P site. A lefamulin molecule features a stronger bond to the ribosome than other pleuromutilins due to the presence of the 2-(4-amino-2-hydroxycyclohexyl) sulfanylacetate side chain at the C14 position, the amino group of which allows the formation of another hydrogen bond. Additionally, the presence of hydroxyl and primary amine groups in this chain increases the solubility of lefamulin in water [21].

Under in vitro conditions, lefamulin is effective against most Gram-positive cocci (S. aureus MSSA and MRSA, S. epidermidis, vancomycin-resistant E. faecium, S. pneumoniae (also resistant to penicillin, macrolides and MDR strains), S. pyogenes, S. agalactiae, Streptococcus spp. groups C and G), and some Gram-negative bacteria (H. influenzae, Haemophilus parainfluenzae, L. pneumophila, M. catarrhalis, N. gonorrhoeae) and atypical pathogens (M. pneumoniae, Ch. pneumoniae). However, it is not active against Gram-negative non-fermenting bacilli and Enterobacterales [49, 74, 85, 93, 94, 114].

Surveillance studies have confirmed that lefamulin is exceedingly active against pathogens causing community-acquired pneumonia, isolated from patients worldwide (SENTRY Antimicrobial Surveillance Program) [85, 87]. The overall percentage share of strains with the MIC values for lefamulin below 1 mg/l (breakpoint for S. pneumoniae) was 99.2%, including 100% for S. pneumoniae and M. catarrhalis strains, 99.8% for S. aureus, 93.8% for H. influenzae and 88.1% for E. faecium. Simultaneously, no cross-resistance was detected between lefamulin and β-lactams, fluoroquinolones and macrolides.

Resistance to lefamulin in the strains of usually sensitive bacterial species may be a result of mutations in the V domain 23S rRNA, e.g., due to the nucleotide methylation at position 2503 influenced by Cfr methyltransferase [75]. The Cfr enzyme provides cross resistance to oxazolidinones, lincosamides, phenicols and streptogramins. Furthermore, the acquisition of resistance may result from mutations in the genes encoding the ribosomal protein L3 (rplC) and L4 (rplD), which modifies the structure of PTC and disturbs lefamulin attachment to it. It has been demonstrated that the resistance may also be related to the protection of the lefamulin target binding site by membrane pump proteins of the ABC-F subfamily encoded by the vga(A), vga(B), vga(E) and Isa(E) genes. ABC-F proteins may induce cross-resistance to lincosamides and streptogramins A [75]. It has also been demonstrated that the inactivation of the MtrCDE pump (but not MacAB and NorM) in N. gonorrhoeae reduces significantly (at least 4-fold) the MIC values of lefamulin [49].

In clinical trials it has been demonstrated that lefamulin (administered 150 mg intravenously every 12 hours for 3 days, followed by 600 mg orally every 12 hours) is non-inferior as moxifloxacin (400 mg administered intravenously every 24 hours for 3 days, followed by 400 mg orally every 24 hours) in the treatment of community-acquired pneumonia [22]. Comparable results were obtained when lefamulin and moxifloxacin were administered orally exclusively [2]. At the same time, in the treatment of acute bacterial skin and skin structure infections caused by Gram-positive pathogens, in the group of patients treated with lefamulin (100 or 150 mg intravenously every 12 hours), the percentage of clinical successes was comparable to the group of patients treated with vancomycin (1 g intravenously every 12 hours) [90]. Currently, the intravenous (150 mg injections every 12 hours) and oral (600 mg tablets) forms of lefamulin, under the trade name Xenleta, were approved for use on 27.07.2020 only in the treatment of community-acquired pneumonia in adults [20].

8. Summary

Six new, broad-spectrum antibacterial drugs have been registered on the European market since 2018, which are, according to WHO, active against the strains classified as pathogens with a critical and high priority need of search for new drugs. Two of them are new combinations of β-lactams with non-β-lactam inhibitors of β-lactamases (meropenem with vaborbactam and imipenem/cilastatin with relebactam), one is a representative of a new group of siderophore antibiotics (cefiderocol), the next two are new derivatives of known groups of antibiotics: fluoroquinolones (delafloxacin) and tetracyclines (eravacycline). Moreover, EMA approved lefamulin as the last of the new drugs in July 2020, i.e., the first representative of a new group of drugs – pleuromutilin, intended for systemic use in humans. Lefamulin, unlike the aforementioned new drugs, is not active against Gram-negative non-fermenting bacilli and Enterobacterales, which are naturally resistant to it. According to the criteria adopted by the WHO, two of the 6 new antibacterial drugs (delafloxacin and lefamulin) were registered as effective against high priority pathogens (vancomycin-resistant enterococci, MRSA), and the remaining four (meropenem/vaborbactam, imipenem/cilastatin/relebactam, eravacycline and cefiderocol) as active against critical pathogens (carbapenem-resistant Enterobacterales), while only one (cefiderocol) displays high effectiveness also against carbapenem-resistant strains of P. aeruginosa and A. baumannii. The WHO innovation criterion is fully met only by meropenem/vaborbactam (in the new chemical class category) and partially by lefamulin, with the reservation that the representatives of this group (pleuromutilins) have already been used in veterinary medicine and for topical treatment in humans. On the other hand, the innovation criterion in the category of the lack of cross-resistance is potentially met by meropenem/vaborbactam and cefiderocol.

Two of the approved drugs are available in both intravenous and oral formulations (delafloxacin and lefamulin). Owing to new registrations, there has been an increase in the number of therapeutic options in the treatment of complicated urinary tract infections (meropenem/vaborbactam, cefiderocol), complicated intra-abdominal infections (meropenem/vaborbactam, eravacycline), nosocomial pneumonia, including those associated with mechanical ventilation (meropenem/vaborbactam, cilastatin/relebactam), acute bacterial skin and skin structure infections (delafloxacin) and community-acquired pneumonia (lefamulin). According to the recent WHO report on new antibiotics, the number of new therapeutic options available for the treatment of infections caused by high and critical priority pathogens, as well as PDR (pan-drug resistant) and XDR (extensively drug resistant) pathogens is still insufficient [120]. Recently, however, a case of therapeutic success has been reported in the treatment of Achromobacter sp. PDR infection in a 10-year-old female patient with cystic fibrosis after applying the combination of cefiderocol, meropenem with vaborbactam and phage therapy (Ax2CJ45ϕ2). The treatment was well tolerated and led to the eradication of Achromobacter sp. [25]. It is thus possible that, owing to the combination therapy, the new antibiotics will also prove effective against PDR and XDR pathogens, which will enhance the prospects of their application in healthcare.

1. Wstęp

Narastająca lekooporność drobnoustrojów to według| Światowej Organizacji Zdrowia (World Health Organization – WHO) jedno z dziesięciu największych zagrożeń dla ludzkości. W 2017 roku WHO opublikowała specjalny raport, zawierający listę patogenów, dla których poszukiwanie nowych opcji terapeutycznych jest priorytetowe, ze względu na coraz bardziej ograniczoną pulę antybiotyków możliwych do wykorzystania w leczeniu wywoływanych przez nie infekcji [121]. Na liście znalazło się w sumie 12 patogenów, podzielonych na 3 kategorie pod względem pilności w poszukiwaniu nowych, aktywnych wobec nich opcji terapeutycznych. W pierwszej grupie patogenów o najwyższym, krytycznym priorytecie znalazły się oporne na karbapenemy pałeczki Gram-ujemne. Jako najgroźniejsze uznano oporne na karbapenemy szczepy Acinetobacter baumannii (carbapenem-resistant Acinetobacter baumannii – CRAB), następnie szczepy Pseudomonas aeruginosa (carbapenem-resistant Pseudomonas aeruginosa – CRPA) i na trzecim miejscu szczepy z rzędu Enterobacterales (carbapenem-resistant Enterobacterales – CRE). Do grupy tej należą także szczepy Enterobacterales oporne na cefalosporyny III generacji oraz Mycobacterium tuberculosis i inne prątki kwasooporne. Natomiast wielolekooporne szczepy ziarenkowców Gram-dodatnich zostały zaklasyfikowane przez WHO do drugiej grupy patogenów o wysokim priorytecie konieczności poszukiwania dla nich nowych leków. Do grupy tej włączono szczepy Staphylococcus aureus oporne na metycylinę (methicillin-resistant S. aureus – MRSA) i wankomycynę (vancomycin-resistant S. aureus – VRSA), Enterococcus faecium oporne na wankomycynę, a ponadto Helicobacter pylori oporne na klarytromycynę, Campylobacter spp. i Salmonella spp. oporne na fluorochinolony oraz Neisseria gonorrhoeae oporne na fluorochinolony i cefalosporyny III generacji [121].

Najpoważniejszym problemem wśród krytycznie priorytetowych patogenów jest ich oporność na karbapenemy, związana z wytwarzaniem rozkładających je enzymów (karbapenemaz), bądź z niespecyficznymi mechanizmami, takimi jak zmniejszenie przepuszczalności błony zewnętrznej oraz nadekspresja genów kodujących pompy błonowe (efflux pumps) [26, 37, 60]. Karbapenemazy występujące wśród szczepów pałeczek Gram-ujemnych należą głównie do klas A, B i D wg klasyfikacji Amblera [4]. Dotychczas opisano jedynie nieliczne karbapenemazy z klasy C np. enzym ADC-68 u A. baumannii. Spośród enzymów klasy A największe znaczenie kliniczne mają plazmidowe karbapenemazy typu KPC (Klebsiella pneumoniae carbapenemase), przede wszystkim warianty KPC-2 oraz KPC-3 [37]. Są one szeroko rozpowszechnione u szczepów Enterobacterales, a głównie u szczepów K. pneumoniae i coraz częściej u szczepów E. coli. Zdolność do ich wytwarzania wykazano także u szczepów Gram-ujemnych pałeczek niefermentujących tj. P. aeruginosa, a ostatnio u A. baumannii. Kodujące je geny zlokalizowane są w transpozonach w dużych plazmidach koniugacyjnych, co stwarza możliwość łatwego ich horyzontalnego transferu. W terapii zakażeń wywołanych przez szczepy KPC-dodatnie można jedynie stosować kolistynę, tygecyklinę i niekiedy aminoglikozydy. O wiele mniejsze znaczenie kliniczne mają szczepy wytwarzające karbapenemazy z rodziny GES (Guiana extended-spectrum β-lactamase). Enzymy GES wykrywane są stosunkowo rzadko zarówno u szczepów P. aeruginosa jak i pałeczek Enterobacterales, a geny je kodujące zlokalizowane są najczęściej w integronach klasy 1 [37].

Spośród enzymów klasy B wg Amblera (metalo-β-laktamaz – MBL) najczęściej u szczepów pałeczek Gram-ujemnych na całym świecie występują obecnie enzymy rodziny NDM (New Delhi metallo-β-lactamase) [37]. Pierwotnie enzymy typu MBL stwarzały problem terapeutyczny głównie u szczepów P. aeruginosa. W Europie, także w Polsce, dominowały enzymy z rodziny VIM (Verona integrated-encoded metallo-β-lactamase), a na Dalekim Wschodzie enzymy IMP (imipenemase). W 2009 roku opisano pierwszy przypadek wytwarzania enzymu NDM-1 u Enterobacterales, a w kolejnych latach doszło do szerokiego rozpowszechnienia zdolności wytwarzania enzymów NDM głównie u K. pneumoniae, E. coli, P. aeruginosa oraz innych pałeczek. Szeroki zakres substratowy enzymów MBL (rozkładają wszystkie β-laktamy oprócz monobaktamów) w połączeniu z łatwym transferem horyzontalnym kodujących je genów (zlokalizowanych w plazmidach, integronach lub transpozonach) oraz brakiem możliwego do zastosowania w lecznictwie inhibitora (są hamowane m.in. przez EDTA) sprawiają, że enzymy te stanowią istotny problem kliniczny. Za największe zagrożenie uważa się szczepy NDM-dodatnie, które jednocześnie zawierają w swoich genomach także geny kodujące inne β-laktamazy (AmpC, OXA-48, VIM, KPC) oraz geny warunkujące oporność na inne antybiotyki (aminoglikozydy i fluorochinolony). Szczepy wytwarzające enzymy MBL pozostają zazwyczaj wrażliwe na kolistynę, tygecyklinę i fosfomycynę [37].

Karbapenemazy z klasy D wg Amblera to oksacylinazy z rodziny OXA, których zakres substratowy został rozszerzony i mają zdolność hydrolizy także karbapenamów. Największe znaczenie kliniczne mają enzymy grupy CHDL (carbapenem-hydrolyzing class D β-lactamases) oraz β-laktamaza OXA-48. Enzymy CHDL są dominującym mechanizmem oporności na karbapenemy u szczepów A. baumannii [79, 102]. Oprócz naturalnie występującego chromosomalnego enzymu OXA-51-like u szczepów A. baumannii wykrywane są najczęściej karbapenemazy CHDL z grupy OXA-23-like oraz OXA-24-like. Natomiast karbapenemaza OXA-48 występuje powszechnie u pałeczek z rzędu Enterobacterales. Aktywność hydrolityczna karbapenemaz klasy D wobec karbapenemów i cefalosporyn jest mniejsza w porównaniu do enzymów typu MBL oraz KPC. Jednakże obecność sekwencji insercyjnych (ISAba) poprzedzających geny blaCHDL znacznie zwiększa oporność szczepów A. baumannii na karbapenemy. Szczepy A. baumannii CRAB ze względu na wielorakość innych mechanizmów oporności jakie u nich jednocześnie występują zaliczane są do najgroźniejszych patogenów, wobec których WHO zaleca priorytetowe poszukiwanie nowych opcji terapeutycznych.

Oporność na karbapenemy opisano również wśród szczepów Enterobacterales jak i Gram-ujemnych pałeczek niefermentujących, które nie wytwarzają karbapenemaz. Przyczyną braku wrażliwości szczepów na karbapenemy może być ograniczenie przepuszczalności błony zewnętrznej, wskutek obniżenia liczebności lub zmiany w konformacji poryn, przez które karbapenemy wnikają do wnętrza komórki, tzw. mechanizm influx [26]. Obniżenie liczebności lub brak poryn OprD był pierwszym opisanym mechanizmem oporności P. aeruginosa na imipenem. Ten mechanizm oporności na karbapenemy opisano także u szczepów K. pneumoniae (związany z porynami OmpK35 i OmpK36), E. coli (związany z porynami OmpC i OmpF) oraz u A. baumannii (przede wszystkim CarO). Ważną rolę odgrywa również mechanizm aktywnego usuwania antybiotyków z komórek bakteryjnych przez systemy pomp błonowych tzw. mechanizm efflux – u szczepów CRE największe znaczenie mają pompy z rodziny RND (np. systemy AcrAB-TolC u E. coli jak i u K. pneumoniae) u szczepów CRPA systemy MexAB-OprM i MexXY, a u szczepów CRAB system AdeABC [60]. Bardzo często w oporności pałeczek Gram-ujemnych na karbapenemy biorą udział jednocześnie dwa lub trzy mechanizmy, takie jak wytwarzanie dwóch różnych karbapenemaz i/lub zaburzenie wnikania antybiotyku do wnętrza komórek i/lub aktywne usuwanie leków przy udziale systemów pomp błonowych.

Wśród patogenów z drugiej grupy wg WHO, o wysokim priorytecie, dominującymi problemami jest oporność szczepów gronkowców na metycylinę i glikopeptydy oraz oporność enterokoków na glikopeptydy [121]. Metycylinooporność gronkowców związana jest z obecnością genu mecA lub jego homologów tj. mecB, mecC lub mecD warunkujących syntezę zmienionego białka PBP-2a, nieposiadającego powinowactwa do antybiotyków β-laktamowych (oprócz ceftaroliny i ceftobiprolu) [28]. Geny mec zlokalizowane są w obrębie dużego mobilnego fragmentu DNA tj. SCCmec (ang. staphylococcal cassette chromosome mec). Oprócz oporności na β-laktamy, szczepy MRSA są również zazwyczaj oporne na aminoglikozydy, fluorochinolony, makrolidy i linkozaminy. Często pozostają natomiast wrażliwe na ceftarolinę, ceftobiprol, linezolid, tygecyklinę, daptomycynę, dalbawancynę i ryfampicynę. Po pojawieniu się opornych na metycylinę gronkowców, lekiem z wyboru w leczeniu wywoływanych przez nie infekcji stała się wankomycyna. Wkrótce jednak pojawiły się również szczepy o obniżonej wrażliwości na ten antybiotyk (vancomycin intermediate-resistant Staphylococcus aureus – VISA), a także (rzadziej) szczepy oporne na wankomycynę (vancomycin-resistant Staphylococcus aureus – VRSA) [28]. Przyczyny obniżonej wrażliwości fenotypu VISA na wankomycynę wciąż nie są do końca wyjaśnione. Najprawdopodobniej związane jest to ze zmianą struktury ściany komórkowej i zmniejszeniem jej przepuszczalności dla wankomycyny. Natomiast całkowita oporność na wankomycynę, fenotyp VRSA, warunkowana jest obecnością operonu zawierającego gen vanA. Wykazano iż operon ten zlokalizowany był w transpozonie Tn1546, pochodzącym z plazmidu koniugacyjnego enterokoków. To właśnie u enterokoków po raz pierwszy zaobserwowano oporność na wankomycynę. Wśród szczepów VRE (vancomycin-resistant enterococci) wywołujących zakażenia szpitalne znacznie częściej oporność na wankomycynę wykazują izolaty E. faecium niż E. faecalis [95]. Gen vanA jak i inne wykryte dotychczas geny van (vanB, vanC, vanD, vanE, vanG, vanL, vanM, vanN) warunkujące oporność lub obniżoną wrażliwość enterokoków na wankomycynę odpowiadają za syntezę zmienionego fragmentu peptydowego D-alanylo-D-alaniny w prekursorze ściany komórkowej, powstaje D-alanylo-D-mleczan lub D-alanylo-D-seryna. Następuje więc zmiana miejsca docelowego działania glikopeptydów co wyraża się w różnych poziomach oporności izolatów. Oprócz szczepów VRE i MRSA izolowane są także szczepy oporne jednocześnie na linezolid, co może stanowić poważny problem kliniczny. Oporność patogenów priorytetowych na fluorochinolony wynika natomiast przede wszystkim z mutacji w genach kodujących topoizomerazę II czyli gyrazę (w genach gyrA) i topoizomerazę IV (w genach parC u E. coli oraz grlA u gronkowców), co skutkuje syntezą zmienionych podjednostek tych enzymów, o zmniejszonym powinowactwie do fluorochinolonów [42]. Dodatkowo, fluorochinolony są substratami dla wielu pomp MDR u patogenów priorytetowych, np. AdeABC u A. baumannii, MexAB-OprM u P. aeruginosa, AcrAB--TolC u Enterobacterales, NorA u S. aureus, CmeABC u Campylobacter spp. czy NorM u N. gonorrhoeae [42].

Od czasu publikacji raportu WHO z 2017 roku alarmującego w sprawie poszukiwania nowych skutecznych leków przeciwko groźnym patogenom, na rynku europejskim zostało zarejestrowanych przez Europejską Agencję Leków (European Medicines Agency – EMA) sześć nowych antybiotyków z 6 różnych grup, adresujących w różnym stopniu priorytety WHO. Dwa spośród nich to nowe połączenie karbapenemów z nie-β-laktamowymi inhibitorami β-laktamaz (o aktywności także wobec karbapenemaz), z dwóch nowych grup: inhibitorów diazabicyklooktanowych (relebaktam, sko jarzony z imipenemem) oraz boronowych (waborbaktam, skojarzony z meropenemem). Sukces jakim było dopuszczenie po wielu latach do obrotu nowych inhibitorów β-laktamaz z dwóch dotychczas nie stosowanych grup chemicznych spowodowało rozszerzenie zakresu poszukiwań nowych inhibitorów [12, 19, 39]. Poszukiwanie nowych sposobów na pokonanie bariery jaką jest błona zewnętrzna bakterii Gram-ujemnych zaowocowały natomiast wprowadzeniem na rynek cefiderokolu – cefalosporyny sideroforowej. Wykorzystanie sideroforów w projektowaniu leków jest nowatorskim podejściem do koncepcji współczesnego leku [80, 119]. Zarówno nowe połączenie karbapenemów z inhibitorami β-laktamaz jak i cefiderokol są w różnym stopniu aktywne wobec krytycznych patogenów WHO. Dwa kolejne oryginalne antybiotyki to nowy fluorochinolon (delafloksacyna) oraz nowa tetracyklina (erawacyklina), których cząsteczki zostały zaprojektowane i zsyntezowane z myślą o zwiększonej skuteczności oraz zminimalizowanej podatności na bakteryjne mechanizmy oporności, typowe dla starszych przedstawicieli tych grup. Oba antybiotyki są aktywne wobec wielu patogenów o wysokim priorytecie wg WHO. Ostatni z nowych antybiotyków to lefamulina – pierwszy przedstawiciel grupy pleuromutylin zarejestrowany do stosowania ogólnego u ludzi. Charakterystyczną cechą tej grupy antybiotyków jest unikatowa struktura (spełniająca kryteria innowacyjności WHO), rzadkie występowanie oporności oraz aktywność wobec patogenów o wysokim priorytecie wg WHO. Natomiast szczepy pałeczek Gram-ujemnych tj. P. aeruginosa, A. baumannii oraz Enterobacterales są na lefamulinę naturalnie oporne. Niniejszy artykuł zawiera przegląd nowych, szerokospektralnych antybiotyków, aktywnych wobec priorytetowych patogenów wg WHO, dopuszczonych do obrotu na terenie Unii Europejskiej od 2018 roku (Rycina 1).

Rycina 1.

Wzory strukturalne nowych związków przeciwbakteryjnych

Struktury nowych zwiąków aktywnych wobec priorytetowych patogenów wg WHO, dopuszczonych do obrotu na terenie Unii Europejskiej od 2018 roku: A) waborbaktam – boronowy inhibitor β-laktamaz (skojarzony z meropenemem); B) relebaktam – diazabicyklooktanowy inhibitor β-laktamaz (skojarzony z imipenemem/cilastatyną); C) cefiderokol – cefalosporyna sideroforowa; D) delafloksacyna – fluorochinolon IV generacji; E) erawacyklina – pierwsza w pełni syntetyczna tetracyklina; F) lefamulina – pierwsza pleuromutylina do stosowania ogólnego u ludzi.

10.21307_PM-2021.60.4.20-f003.jpg

2. Boronowe inhibitory β-laktamaz

Boronowe inhibitory β-laktamaz to stosunkowo nowa klasa związków, z cyklicznym kwasem boronowym jako farmakoforem. Waborbaktam (wcześniej RPX7009) został otrzymany w ramach programu ukierunkowanego na poszukiwanie inhibitora β-laktamaz serynowych, szczególnie typu KPC [39]. Waborbaktam jest monocyklicznym, odwracalnym inhibitorem kompetycyjnym enzymów z klasy A wg Amblera (z rodzin CTX-M, KPC, BKC, FRI, SME, TEM, SHV) oraz C (AmpC), z którymi tworzy kowalencyjne wiązania między ugrupowaniem boronowym a katalitycznym centrum serynowym. Inhibicja KPC przez waborbaktam nie powoduje jego inaktywacji oraz charakteryzuje się ekstremalnie wolną odwracalnością. Jednocześnie, waborbaktam nie działa na enzymy klasy B (np. NDM, VIM) oraz D (np. OXA-48), nie hamuje ludzkich proteaz serynowych ani nie wykazuje bezpośredniej aktywności przeciwbakteryjnej w stężeniach terapeutycznych [15, 39, 111]. W badaniach in vitro wykazano, że waborbaktam silniej obniża wartości MIC karbapenemów niż pozostałych β-laktamów, stąd do dalszych badań wytypowano kombinację meropenem-waborbaktam [66].

W testach przeprowadzonych z udziałem klinicznych izolatów pałeczek Gram-ujemnych (E. coli, Enterobacter spp., K. pneumoniae, A. baumannii oraz P. aeruginosa) potwierdzono, że waborbaktam zwiększa aktywność meropenemu wobec opornych na karbapenemy szczepów Enterobacterales ale nie wobec szczepów P. aeruginosa oraz A. baumannii [59, 97]. W dużych badaniach przeglądowych ogólny odsetek szczepów wrażliwych na meropenem/waborbaktam wśród Enterobacterales wynosił 99,3% i był wyższy niż dla meropenemu (96,9%). Natomiast wśród Enterobacterales opornych na karbapenemy waborbaktam przywracał aktywność meropenemu u 73,9% szczepów, a wśród szczepów wytwarzających KPC aż u 99,5%. Waborbaktam nie przywracał wrażliwości na meropenem szczepom wytwarzającym metalo-β-laktamazy oraz enzymy typu OXA-48 [88], a także szczepom A. baumannii, P. aeruginosa i Stenotrophomonas maltophilia [14]. Podobne wyniki uzyskano analizując wrażliwość kolekcji szczepów klinicznych E. coli opornych na karbapenemy, pochodzących z całego świata, w której ogólny odsetek szczepów wrażliwych na meropenem/waborbaktam wynosił 6% i był niższy tylko od odsetka szczepów wrażliwych na tygecyklinę (100%) i amikacynę (74%). Wrażliwość była większa wśród szczepów pochodzących z Ameryki Łacińskiej (88%) a mniejsza wśród szczepów izolowanych w Europie (75%) i w Azji (51%) [52]. Również w pracy Zhou i wsp. [129] stwierdzono, że odsetek szczepów K. pneumoniae z podwyższonymi wartościami MIC meropenemu z waborbaktamem w Chinach jest wyższy niż w innych rejonach geograficznych, prawdopodobnie wskutek rozpowszechnienia w tym rejonie szczepów z defektami w obu głównych porynach (OmpK35 oraz OmpK36) zaangażowanych we wnikanie karbapenemów do komórki bakteryjnej.

Narastający problem zakażeń szczepami wytwarzającymi metalo-β-laktamazy (i w związku z tym opornymi na wszystkie β-laktamy oprócz aztreonamu) w połączeniu z brakiem skutecznego inhibitora tych enzymów, spowodował, że podjęte zostały również próby skojarzenia meropenemu/waborbaktamu z aztreonanem – monobaktamem opornym na działanie karbapenemaz ale rozkładanym przez szereg enzymów serynowych. Jak dotąd w badaniach in vitro wykazano, że meropenem/waborbaktam działa synergistycznie z aztreonamem wobec wielolekoopornych szczepów K. pneumoniae oraz E. coli wytwarzających zarówno enzymy typu NDM jak i β-laktamazy serynowe [11, 70]. Skuteczność tej kombinacji wymaga jednak dalszych badań.

Obserwowana jak dotąd oporność szczepów na meropenem/waborbaktam była najczęściej związana z wytwarzaniem metalo-β-laktamaz [15], mutacjami w genach kodujących białka poryn (OmpK35, OmpK36) [24, 66, 108] odpowiedzialnych za wnikanie leku czyli influx i/lub nadekspresją systemów pompy AcrAB-TolC [15] biorących udział w mechanizmie wyrzutowym (tzw. efflux), rzadziej w efekcie nadprodukcji KPC związanej ze zwiększeniem liczby kopii genów blaKPC [108]. Jak dotąd, nie opisano przypadku oporności związanego z mutacją w genach blaKPC.

W badaniach klinicznych wykazano, że meropenem/waborbaktam (podawany 2 g/2 g co 8 h) jest nie gorszy niż piperacylina/tazobaktam (4 g/0,5 g co 8 h) u pacjentów z powikłanym zakażeniem układu moczowego (complicated urinary tract infection – cUTI) [55]. Wyniki ostatniego z badań klinicznych (TANGO II) wskazują ponadto, że meropenem-waborbaktam jest skuteczniejszy od najlepszej dostępnej terapii (best available treatment – BAT) u pacjentów z potwierdzonym lub podejrzeniem zakażenia opornymi na karbapenemy Enterobacterales oraz dodatkowymi obciążeniami, takimi jak: niewydolność nerek, deficyty odporności czy wcześniejsza antybiotykoterapia [9, 10]. W grupie chorych leczonych meropenemem/waborbaktamem obserwowano lepszą wyleczalność, niższą śmiertelność oraz niższą nefrotoksyczność [9].

Na rynku europejskim od 20.11.2018 roku zarejestrowany jest preparat zawierający meropenem z waborbaktamem w postaci proszku do sporządzania infuzji (1 g/1 g) pod nazwą handlową Vaborem [20]. Jego wskazania rejestracyjne obejmują leczenie powikłanych zakażeń układu moczowego (w tym odmiedniczkowego zapalenia nerek), powikłanych zakażeń w obrębie jamy brzusznej, szpitalnych zapaleń płuc (także respiratorowych) oraz zakażeń wywołanych tlenowymi drobnoustrojami Gram-ujemnymi u pacjentów dorosłych, z ograniczonymi możliwościami leczenia.

3. Diazabicyklooktanowe inhibitory β-laktamaz

Relebaktam (wcześniej MK-7655) jest drugim po awibaktamie, nie-β-laktamowym inhibitorem β-laktamaz z grupy pochodnych diazabicyklooktanowych, dopuszczonym do stosowania w lecznictwie [20]. Relebaktam jest strukturalnie podobny do awibaktamu, zawiera jednak dodatkowy pierścień piperydynowy, zapewniający cząsteczce dodatni ładunek w fizjologicznym pH, kluczowy dla obniżenia jej podatności na aktywne usuwanie przez systemy pomp w zjawisku efflux. W badaniach biochemicznych wykazano, że relebaktam jest inhibitorem enzymów klasy A (typu KPC) oraz klasy C (typu AmpC, m.in. AmpC Pseudomonas-derived cephalosporinase-3, PDC-3), a dodatkowo (podobnie jak imipenem) nie jest on substratem dla systemów pomp MDR u P. aeruginosa [7, 12, 124]. Brak podatności połączenia imipenem/relebaktam na usuwanie go z komórek bakteryjnych przez systemy pomp MDR P. aeruginosa oraz aktywność relebaktamu wobec enzymów AmpC sprawiły, że do dalszych badań wytypowano tę właśnie kombinację. W badaniach in vitro potwierdzono, że relebaktam faktycznie zwiększa aktywność imipenemu wobec szczepów Enterobacterales, których oporność na karbapenemy związana była z wytwarzaniem enzymów typu KPC lub u których obserwowano wytwarzanie β-laktamaz typu AmpC bądź ESBL przy jednoczesnym zmniejszeniu przepuszczalności błony zewnętrznej (mutacje w OmpK36). Jak również obserwowano to zjawisko u szczepów P. aeruginosa z defektem wytwarzania poryn OprD oraz (w wyższych stężeniach preparatu) wobec szczepów P. aeruginosa MDR. Podobnie jak waborbaktam, relebaktam nie jest jednak inhibitorem metalo-β-laktamaz (NDM, IMP, VIM) ani enzymów klasy D (OXA), nie wykazuje również bezpośredniej aktywności przeciwbakteryjnej [36, 40, 63]. W warunkach in vitro opisano również synergistyczne oddziaływanie imipenemu/relebaktamu z amikacyną oraz kolistyną wobec szczepów P. aeruginosa opornych na imipenem [6].

W wielu dużych badaniach przeglądowych testowano wrażliwość na imipenem/relebaktam szczepów klinicznych izolowanych od pacjentów z zakażeniami m.in. dolnych dróg oddechowych, dróg moczowych i zakażeniami wewnątrzbrzusznymi [53, 54, 64, 65]. Wykazano, że w obecności relebaktamu następuje obniżenie stężenia imipenemu, które powoduje zahamowanie wzrostu większości klinicznych szczepów Enterobacterales (także opronych na karbapenemy), chociaż wartości MIC imipenemu dla szczepów Serratia marcescens są z reguły wyższe niż dla pozostałych gatunków. Odsetki wrażliwych na imipenem/relebaktam szczepów E. coli, Klebsiella spp., Citrobacter spp., i Enterobacter spp. kształtowały się na poziomie ponad 95%. Natomiast wśród S. marcescens odsetek szczepów wrażliwych był niższy. Imipenem/relebaktam jest również skuteczny wobec szczepów P. aeruginosa (odsetki szczepów wrażliwych powyżej 90%), za wyjątkiem szczepów produkujących β-laktamazy klas B lub D. Wśród szczepów opornych na karbapenemy wrażliwe na imipenem/relebaktam pozostaje od 42 do 66% szczepów Enterobacterales oraz od 74 do 78% szczepów P. aeruginosa. Relebaktam nie zwiększa jednak aktywności imipenemu wobec szczepów Acinetobacter spp. [53, 54, 64, 65, 115].

Zaobserwowana oporność pałeczek Gram-ujemnych na imipenem/relebaktam wynika głównie z wytwarzania metaloenzymów. U szczepów P. aeruginosa może również wynikać ze zdolności do wytwarzania karbapenemaz klasy A z rodziny GES oraz nadekspresji genów kodujących enzymy PDC w połączeniu z utratą białka porynowego OprD [65, 124]. Natomiast u Enterobacterales przyczyną oporności może być wytwarzanie oksacy linaz o aktywności karbapenemaz np. OXA-48, a także mutacje w genach kodujących białka poryn oraz spadek liczebności tych poryn (OmpK35, OmpK36, OmpC i OmpF) i tym samym ograniczenie wnikania imipenemu/relebaktamu do komórek bakteryjnych [30, 51].

W badaniach klinicznych wykazano, że imipenem (podawany 500 mg co 6 h) w skojarzeniu z relebaktamem (125 mg lub 250 mg co 6 h) jest kuracją dobrze tolerowaną i nie gorszą niż samodzielnie zastosowany imipenem w grupie pacjentów z powikłanymi zakażeniami wewnątrzbrzusznymi oraz z powikłanymi zakażeniami dróg moczowych [67, 101]. Imipenem/relebaktam charakteryzował się również porównywalną skutecznością oraz mniejszą nefrotoksycznością niż zastosowanie imipenemu i kolistyny w leczeniu skojarzonym zakażeń wywołanych przez pałeczki Gram-ujemne oporne na imipenem [78]. Na podstawie uzyskanych wyników preparat zawierający imipenem/cylastatynę (gdzie cylastatyna jest inhibitorem dehydrogenazy I, enzymu nerkowego, który unieczynnia imipenem) z relebaktamem (Recarbrio 500 mg/500 mg + 250 mg, proszek do sporządzania roztworu do infuzji) został 13.02.2020 roku dopuszczony przez EMA do stosowania w leczeniu szpitalnych zapaleń płuc (także związanych z wentylacją mechaniczną) oraz w leczeniu zakażeń bakteriami Gram-ujemnymi u osób dorosłych z ograniczonymi możliwościami terapeutycznymi [20].

4. Cefalosporyny sideroforowe

Cefiderokol jest przedstawicielem nowej grupy antybiotyków – cefalosporyn sideroforowych [80]. Siderofory to zróżnicowana strukturalnie grupa cząsteczek o niskiej masie (150–2000 Da), o właściwościach chelatujących z dużym powinowactwem do żelaza [119]. Żelazo jest pierwiastkiem niezbędnym do funkcjonowania wielu enzymów, a w związku z tym także dla mikroorganizmów. Jego pozyskiwanie przez bakterie jest jednak utrudnione ze względu na niską rozpuszczalność żelaza przy fizjologicznym pH w warunkach tlenowych, w których dochodzi do utleniania łatwo przyswajalnych jonów Fe(II) do Fe(III) i powstawania nierozpuszczalnych tlenowodorotlenków. Ponadto, mechanizmy obronne pacjenta powodują dalsze ograniczanie dostępności żelaza w miejscu infekcji w związku z wydzielaniem własnych białek wiążących jony żelaza, takich jak lipokalina 2, nazywana również siderokaliną lub lipokaliną neutrofilową związaną z żelatynazą (neutrophil gelatinase associated lipocalin – NGAL). W celu pozyskania odpowiedniej ilości żelaza bakterie wytwarzają i wydzielają do środowiska zewnątrzkomórkowego siderofory, których zadaniem jest związanie jonów żelaza i ich przetransportowanie do wnętrza komórki. Jak dotąd zidentyfikowano ponad 500 różnych sideroforów. Charakterystycznymi elementami strukturalnymi w ich cząsteczkach są chelatujące żelazo grupy funkcyjne (hydroksamiany, katechole, karboksylany, ugrupowania fenolanowe lub ich kombinacje) przyłączone do liniowego lub cyklicznego szkieletu tworzącego heksadentatową strukturę. Po związaniu jonu żelaza, powstały kompleks (ferrosiderofor) jest wchłaniany na zasadzie transportu aktywnego. U bakterii Gram-ujemnych cały kompleks przekracza zarówno błonę zewnętrzną jak i błonę wewnętrzną, a związane żelazo jest uwalniane w cytoplazmie. Alternatywnie, żelazo może być uwalniane w przestrzeni periplazmatycznej [119].

Pierwsze próby wykorzystania sideroforów do transportu antybiotyków do wnętrza komórki podjęto już w latach 70. XX wieku, a strategię tę nazwano „metodą konia trojańskiego” (trojan horse approach) [80]. Cefiderokol (wcześniej S-649266, GSK2696266) jest pierwszym tego typu antybiotykiem wprowadzonym do lecznictwa. Jest stosowany w postaci tosylanu siarczanu cefiderokolu. Jest to katecholowa cefalosporyna sideroforowa, wyselekcjonowana spośród innych pochodnych o podobnej strukturze, w trakcie programu ukierunkowanego na znalezienie nowego antybiotyku aktywnego wobec szczepów opornych na karbapenemy [5]. Cefiderokol wykazuje podobieństwo strukturalne do cefepimu, takie jak obecność grupy pirolidyniowej przy łańcuchu bocznym C-3 zwiększającej aktywność przeciwbakteryjną i stabilność wobec β-laktamaz, oraz grupy karboksypropanoksyiminonowej przy łańcuchu C-7 ułatwiającej transport cefiderokolu przez błonę zewnętrzną. Dodatkowo, cefiderokol posiada również grupę chlorokatecholową na końcu łańcucha C-3, odpowiadającą za aktywność sideroforową [96].

Zasadniczy mechanizm działania cefiderokolu polega na hamowaniu syntezy ściany komórkowej poprzez wiązanie z białkami PBP (głównie PBP-3). Cefiderokol, po związaniu żelaza, dociera do przestrzeni periplazmatycznej w drodze transportu aktywnego, w który zaangażowane są m. in. transportery CirA i Fiu u E. coli oraz PiuA u P. aeruginosa. Ten mechanizm transportu eliminuje problem oporności związanej z obniżeniem liczby poryn w błonie zewnętrznej lub nadekspresji pomp MDR odpowiedzialnych za zjawisko efflux [96]. Dodatkowo, cząsteczka cefiderokolu jest oporna na szeroki wachlarz β-laktamaz, zarówno serynowych (KPC-3, OXA-23, AmpC) jak i metalo-β-laktamaz (IMP-1, VIM-2) [46, 47]. Oporność może jednak być wynikiem mutacji w obrębie genów kodujących białka PBP, białka związanego z regulacją wychwytu jonów żelaza lub białka transportującego siderofory, a także wytwarzaniem β-laktamaz zdolnych do hydrolizy cefiderokolu (typu NDM, PER) oraz nadekspresją natywnych sideroforów bakteryjnych [58, 69, 96].

Cefiderokol wykazuje wysoką aktywność wobec szerokiego spektrum bakterii Gram-ujemnych, zarówno przedstawicieli Enterobacterales (Enterobacter spp., Klebsiella spp., Proteus spp., S. marcescens, Shigella flexneri, Salmonella spp., Yersinia spp.) jak i pałeczek niefermentujących (Acinetobacter spp., Pseudomonas spp., Burkholderia spp., S. maltophilia) oraz Vibrio spp. [48]. Nie wykazuje natomiast aktywności wobec tlenowych bakterii Gram-dodatnich (Staphylococcus spp., Enterococcus spp.) oraz bakterii beztlenowych. Cefiderokol jest również aktywny wobec szczepów wytwarzających różne β-laktamazy, takie jak typu KPC, VIM, NDM i OXA-48 u Enterobacterales, czy typu VIM, IMP, NDM i GES u P. aeruginosa lub enzymy CHDL z grup OXA-23, OXA-24/40 i OXA-58 u A. baumannii [48]. Wrażliwość klinicznych szczepów Enterobacterales oraz pałeczek niefermentujących była badana w kilku międzynarodowych badaniach przeglądowych [27, 35, 106]. Jak dotąd, odsetki wrażliwych na cefiderokol szczepów izolowanych od pacjentów m.in. ze szpitalnym zapaleniem płuc, zakażeniem krwi, powikłanymi zakażeniami wewnątrzbrzusznymi oraz powikłanymi zakażeniami dróg moczowych kształtują się na poziomach > 95%, niezależnie od regionu geograficznego. Niższy odsetek obserwowano jedynie w przypadku szczepów K. pneumoniae (88%).

W badaniach klinicznych wykazano, że cefiderokol (podawany w dawce 2 g co 8 h) jest nie mniej skuteczny w leczeniu powikłanych zakażeń dróg moczowych (cUTI) niż imipenem (w dawce 1 g co 8 h) w badaniu APEKS-cUTI [89] oraz nie mniej skuteczny w leczeniu szpitalnych zapaleń płuc (także związanych z wentylacją mechaniczną) niż meropenem (w dawce 2 g co 8 h) w badaniu APEKS-NP [122]. Wykazano również, że cefiderokol posiada podobną kliniczną oraz mikrobiologiczną skuteczność w leczeniu ciężko chorych pacjentów zakażonych opornymi na karbapenemy szczepami pałeczek Gram-ujemnych w porównaniu do najlepszej dostępnej terapii (best available therapy – BAT), chociaż w grupie osób leczonych cefiderokolem odnotowano również wyższą śmiertelność, głównie wśród pacjentów z zakażeniami wywoływanymi przez Acinetobacter spp. [8]. Cefiderokol został zarejestrowany przez EMA 23.04.2020 roku pod nazwą Fetcroja 1 g, proszek do sporządzania koncentratu roztworu do infuzji. Jego aktualne wskazania rejestracyjne obejmują leczenie zakażeń wywoływanych przez tlenowe bakterie Gram-ujemne u osób dorosłych, z ograniczonymi opcjami terapeutycznymi [20].

5. Nowe fluorochinolony

Delafloksacyna (wcześniej WQ-3034, ABT-492) jest nowym fluorochinolonem IV generacji i pierwszym anionowym związkiem w tej grupie [57, 112]. Jej cząsteczka wyróżnia się przede wszystkim brakiem zasadowej grupy w pozycji C7 (co zapewnia kwasowe właściwości), obecnością chloru w pozycji C8 przyciągającego elektrony z pierścienia aromatycznego (co zwiększa polarność związku oraz podnosi jego aktywność i stabilność) oraz obecnością dużego podstawnika heteroaromatycznego w pozycji N1, przez co powierzchnia cząsteczki delafloksacyny jest zdecydowanie większa niż innych fluorochinolonów. W rezultacie, delafloksacyna występuje w postaci anionowej w pH obojętnym oraz w postaci neutralnej w środowisku kwaśnym. Przyczynia się to do jej zwiększonej aktywności w warunkach niskiego pH, podczas gdy aktywność innych fluorochinolonów maleje wraz ze spadkiem pH.

Mechanizm działania delafloksacyny podobnie jak wszystkich fluorochinolonów polega na hamowaniu aktywności gyrazy i topoizomerazy IV [81]. Wykazano jednak, że działa ona z porównywalną siłą na obie te topoizomerazy zarówno u E. coli jak i u S. aureus. Podczas gdy pozostałe fluorochinolony wykazują u bakterii Gram-dodatnich większą aktywność wobec topoizomerazy IV, a u bakterii Gram-ujemnych większą aktywność wobec gyrazy. Hamowanie aktywności gyrazy jest bardziej efektywnym sposobem hamowania replikacji DNA, ze względu na zaangażowanie tego enzymu we wcześniejszym jej etapie (usuwanie dodatnich superskrętów przed widełkami replikacyjnymi) niż ma to miejsce w przypadku topoizomerazy IV, która działa po przejściu widełek replikacyjnych (dekatenacja DNA i rozdzielanie chromosomów). Tym samym, silniejsze od pozostałych fluorochinolonów oddziaływanie delafloksacyny na gyrazę u bakterii Gram-dodatnich przyczynia się do zwiększonej aktywności nowego fluorochinolonu wobec tych bakterii.

Dodatkowo, oddziaływanie z równą siłą na obie topoizomerazy sugerowało, że delafloksacyna w porównaniu do pozostałych fluorochinolonów powinna w mniejszym stopniu predysponować szczepy do wytworzenia oporności, w związku z koniecznością powstania mutacji jednocześnie w obydwu genach kodujących te topoizomerazy. W badaniach in vitro opisano niższy niż u innych fluorochinolonów potencjał selekcji spontanicznych mutantów szczepów S. aureus MRSA [92]. Wartości stężeń hamujących selekcję spontanicznych mutantów (mutant prevention concentration – MPC) delafloksacyny były od 8 do 32 razy niższe niż wartości MPC moksyfloksacyny, lewofloksacyny i cyprofloksacyny, a dodatkowo u uzyskanych mutantów obserwowano spadek żywotności w porównaniu do szczepu macierzystego. Analiza wrażliwości szczepów izolowanych od pacjentów leczonych delafloksacyną w trakcie badań klinicznych potwierdziła, że delafloksacyna zachowywała wysoką aktywność także wobec szczepów z mutacjami w regionach determinujących oporność na chinolony (quinolone resistance-determining region – QRDR) [72]. Wartości MIC delafloksacyny nie ulegały znaczącemu zwiększeniu (tj. MIC > 0,5 mg/l) dopóki nie występowały jednocześnie podwójne mutacje zarówno w obrębie genów gyrA jak i parC.

Zgodnie z przewidywaniami, w badaniach in vitro delafloksacyna wykazywała większą aktywność niż trowafloksacyna, lewofloksacyna i cyprofloksacyna wobec wrażliwych oraz opornych na chinolony szczepów bakterii Gram-dodatnich (Staphylococcus spp., Enterococcus spp., Streptococcus spp., Listeria monocytogenes), wybrednych bakterii Gram-ujemnych (H. influenzae, Moraxella catarrhalis, N. gonorrhoeae, Legionella pneumophila) oraz H. pylori. Jej aktywność wobec szczepów Enterobacterales i P. aeruginosa była porównywalna z pozostałymi fluorochinolonami, a aktywność wobec Chlamydia spp. porównywalna z trowafloksacyną i wyższa niż lewofloksacyny [3, 29, 81]. W warunkach in vitro delafloksacyna jest również aktywna wobec szczepów Mycoplasma pneumoniae, Mycoplasma fermentans, Mycoplasma hominis i Ureaplasma spp. [113]. Wykazuje również aktywność wobec biofilmu tworzonego przez S. aureus MSSA oraz MRSA, ze zdolnością penetracji do wnętrza biofilmu sięgającą 52% (w zależności od proporcji polisacharydów w macierzy) i zwiększoną skutecznością wobec biofilmów charakteryzujących się niższym pH [100]. Wykazano, że wobec szczepów Streptococcus pneumoniae, H. influenzae i M. catarrhalis delafloksacyna działa zazwyczaj bakteriobójczo [34].

Wysoka aktywność delafloksacyny wobec gronkowców (także MRSA) i paciorkowców, szczepów najczęściej wywołujących ostre bakteryjne zakażenia skóry i tkanki podskórnej (acute bacterial skin and skin structure infections – ABSSSI), połączona z jej wysoką aktywnością w środowisku kwaśnym (typowym dla skóry) ukierunkowała dalsze badania na zastosowanie delafloksacyny w tej jednostce chorobowej. Opublikowane ostatnio wyniki badań przeglądowych wrażliwości 11 866 szczepów wyizolowanych w latach 2014–2019 w Stanach Zjednoczonych i Europie od pacjentów z ABSSSI potwierdziły wysoką aktywność delafloksacyny [99]. Najczęściej izolowanymi szczepami były S. aureus MSSA (~ 30,6%), E. coli (11%), Streptococcus spp. (10%) oraz S. aureus MRSA (7,2%). Wrażliwość na ten antybiotyk stwierdzono u 98,7% szczepów MSSA, 98,4% szczepów Streptococcus spp., 58% szczepów E. coli oraz 65,6% szczepów MRSA.

W badaniach klinicznych delafloksacyna okazała się być lekiem o liniowej farmakokinetyce, minimalnej akumulacji oraz dobrze tolerowanym – zaburzenia żołądkowo-jelitowe obserwowane były jedynie przy doustnych dawkach jednorazowych > 1200 mg lub wielokrotnych dawkach > 800 mg [44]. Doustna dawka 450 mg oraz dożylna 300 mg okazały się być porównywalne, zapewniając możliwość zmiany drogi podania w czasie terapii [43].

W randomizowanych badaniach klinicznych z udziałem pacjentów z powikłanymi zakażeniami skóry i tkanki podskórnej (ropnie oraz infekcje ran po operacjach, urazach, oparzeniach i ugryzieniach) podawana dożylnie delafloksacyna (300 mg 2 razy dziennie) okazała się być równie skuteczna jak tygecyklina (50 mg 2 razy dziennie) [83], wankomycyna z aztreonamem (15 mg/kg+2 g 2 razy dziennie) [91] i linezolid (600 mg 2 razy dziennie)[56] oraz skuteczniejsza niż wankomycyna (15 mg/kg masy ciała 2 razy dziennie) [56]. Skuteczność nie gorszą niż wankomycyny z aztronamem wykazano także dla delafloksacyny dawkowanej w schemacie 300 mg dożylnie (2 razy dziennie) przez 2 dni a następnie 450 mg doustnie [82]. Ten sam schemat dawkowania delafloksacyny okazał się również nie mniej skuteczny niż moksyfloksacyna (400 mg dożylnie, a następnie 400 mg doustnie raz dziennie) w leczeniu pozaszpitalnych zapaleń płuc (community-acquired bacterial pneumonia – CABP), także zapaleń płuc wywoływanych przez atypowe patogeny (M. pneumoniae, Chlamydia pneumoniae, L. pneumophila) [45]. Delafloksacyna wykazywała co najmniej 16-krotnie wyższą aktywność niż moksyfloksacyna wobec bakterii Gram-dodatnich oraz wybrednych pałeczek Gram-ujemnych, jak również zachowywała aktywność wobec szczepów opornych, np. S. pneumoniae MDR, Haemophilus spp. wytwarzających β-laktamazy oraz szczepów opornych na makrolidy, a także S. aureus MRSA oraz opornych na fluorochinolony [71, 73].

Delafloksacyna w pojedynczej dawce 900 mg okazała się być jednak nieskuteczną formą leczenia niepowikłanej rzeżączki – niepowodzeniem zakończyło się wiele terapii zakażeń szczepami N. gonorrhoeae, dla których wartości MIC były poniżej 0,008 mg/l, co wskazuje na konieczność modyfikacji schematu dawkowania [41].

W Unii Europejskiej delafloksacyna została dopuszczona 16.12.2019 roku, do stosowania w leczeniu ostrych bakteryjnych zakażeń skóry i tkanki podskórnej (ABSSSI) oraz pozaszpitalnego zapalenia płuc (CABP) u osób dorosłych, gdy stosowanie innych leków przeciwbakteryjnych powszechnie zalecanych w początkowym leczeniu tych zakażeń jest uważane za niewłaściwe. Zarejestrowana została zarówno postać doustna (tabletki 450 mg) jak i dożylna (300 mg) po nazwą handlową Quofenix [20].

6. Nowe tetracykliny

Tetracykliny to naturalne lub półsyntetyczne związki o właściwościach amfoterycznych, zawierające w swojej cząsteczce cztery skondensowane pierścienie karbocykliczne (w tym jeden aromatyczny) [31]. Ich mechanizm działania polega na hamowaniu syntezy białka poprzez wiązanie do podjednostki 30S rybosomu. Dla wszystkich związków z tej grupy charakterystyczne jest szerokie spektrum aktywności, zarówno wobec bakterii Gram-dodatnich, Gram-ujemnych, mykoplazm, chlamydii, riketsji oraz niektórych pierwotniaków. Różnice między poszczególnymi przedstawicielami dotyczą właściwości farmakokinetycznych oraz siły działania. Pierwsze antybiotyki tetracyklinowe (wytwarzane przez różne gatunki promieniowców – Streptomyces) wprowadzono do lecznictwa na przełomie lat 40. i 50. XX wieku. Niestety, ich intensywne stosowanie w lecznictwie doprowadziło do szybkiego pojawiania się i rozpowszechnienia oporności, związanej z obecnością genów tet, kodujących białka pomp błonowych biorących udział w zjawisku tzw. efflux (m.in. geny tet(A), tet(B), tet(K), tet(L)), białka ochronne rybosomu (m.in. geny tet(M), tet(O), tet(P), tet(S)) lub enzymy rozkładające tetracykliny tj. gen tet(X).

Narastająca lekooporność drobnoustrojów na antybiotyki z innych grup przyczyniła się jednak do ponownego wzrostu zainteresowania tetracyklinami. Ustalenie struktury kokryształu tetracyklina-podjednostka 30S rybosomu wykazało, że w wiązanie do rybosomu nie jest zaangażowany jedynie rejon wokół atomów węgla C5-C9 [13]. W związku z tym, podjęte zostały próby wprowadzenia modyfikacji strukturalnych przy atomach C7 i C9, które zaowocowały wprowadzeniem do obrotu półsyntetycznych tetracyklin (minocykliny, tygecykliny, omadacykliny). Nowe tetracykliny charakteryzują się wyższą aktywnością przeciwbakteryjną oraz mniejszą podatnością na bakteryjne mechanizmy oporności [31]. Liczba chemicznych modyfikacji naturalnych tetracyklin i tym samym możliwości uzyskiwania nowych półsyntetycznych pochodnych jest jednak ograniczona. Dopiero synteza de novo kolejnych związków zawierających szkielet tetracyklinowy znacząco zwiększyła liczbę nowych związków z tej grupy [107].

Erawacyklina (wcześniej TP-434) to pierwsza w pełni syntetyczna tetracyklina wprowadzona do lecznictwa [20]. Jej cząsteczka charakteryzuje się obecnością fluoru przy atomie węgla C7 oraz grupy pirolidynoacetoamidowej przy węglu C9 szkieletu tetracyklinowego i wykazuje aktywność także wobec opornych na tetracyklinę szczepów posiadających geny tet(M) i tet(Q) (odpowiedzialne za zablokowanie miejsca wiązania tetracyklin do rybosomu) oraz geny tet(A), tet(B) i tet(K) (odpowiadające za syntezę białek błonowych pomp MDR) [33, 123]. Spektrum aktywności erawacykliny obejmuje szczepy S. aureus (także MRSA oraz MRSA oporne na linezolid), Streptococcus spp., Enterococcus spp. (także VRE), E. coli, K. pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, S. marcescens, Salmonella spp., Shigella spp., A. baumannii, Acinetobacter lwoffii, S. maltophilia, Legionella pneumophila, H. influenzae, M. catarrhalis, N. gonorrhoeae, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides ovatus, Prevotella spp., Clostridioides difficile, Clostridium perfringens. Erawacyklina zachowuje swoją aktywność również wobec szczepów opornych na fluorochinolony, aminoglikozydy, cefalosporyny III generacji, karbapenemy, polimyksyny oraz szczepów MDR, a jej aktywność jest zwykle 2–4-krotnie wyższa lub równa z tygecykliną, zarówno wobec bakterii Gram-dodatnich jak i Gram-ujemnych [1, 23, 50, 62, 103, 110, 125, 127]. Wykazano ponadto, że w warunkach in vitro erawacyklina działa synergistycznie z kolistyną wobec szczepów A. baumannii, także opornych na karbapenemy oraz kolistynę [84]. Niewrażliwe na nią są natomiast szczepy z gatunków P. aeruginosa oraz Burkholderia cenocepacia [110].

Ponadto wykazano aktywność erawacyny wobec biofilmu uropatogennego szczepu E. coli w stopniu porównywalnym z gentamycyną i lewofloksacyną oraz wyższym niż w przypadku kolistyny i meropenemu [32]. Nie wykazano jednak aktywności erawacykliny wobec biofilmu tworzonego przez szczepy S. aureus izolowane z okołoprotezowych zakażeń stawów [130].

Ostatnio opublikowane wyniki dużych badań przeglądowych potwierdziły wysoką aktywność erawacykliny wobec szerokiego spektrum szczepów klinicznych [76, 77]. Odsetki szczepów wrażliwych wynosiły odpowiednio: 97,6% dla S. aureus (95,5% dla MRSA i 99,8% dla MSSA), 84,6% dla S. epidermidis, 89,9% dla S. haemolyticus, 99,4% dla E. faecalis (98,3% dla szczepów VR, 99,5% dla VS), 97,7% dla E. faecium (96,1% dla szczepów VR i 98,9% dla VS) oraz 92,6% dla Enterobacterales (82% dla szczepów MDR). Z kolei w przypadku szczepów A. baumannii, dla których nie zdefiniowano wartości granicznych MIC, wartości MIC50/MIC90 wynosiły odpowiednio 0,5 mg/l i 1 mg/l (dla szczepów MDR MIC90 wynosił 2 mg/l).

Zagrożeniem dla skuteczności klinicznej erawacykliny w przyszłości może stać się jednak narastająca oporność związana z mechanizmem usuwania antybiotyku (efflux), enzymatycznym rozkładem tego antybiotyku oraz modyfikacją miejsca jego wiązania w rybosomie. Jak dotąd wykazano, że u szczepów S. aureus (zarówno MRSA jak i MSSA), E. faecalis oraz S. agalactiae wartości MIC erawacykliny (podobnie jak tygecykliny) wykazywały znaczące spadki w obecności inhibitorów pomp MDR takich jak cyjanek karbonylowy 3-chlorofenylohydrazonu (carbonyl cyanide 3-chlorophenylhydrazone – CCCP) i L-fenyloalanino-L-arginino-β-naftyloamid (L-phenylalanine-L-arginine-β-naphthylamide – PAβN) [61, 118, 127]. Opisano również oporne na erawacyklinę kliniczne szczepy A. baumannii z nadekspresją systemu pompy AdeABC [98], K. pneumoniae z nadekspresją pomp OqxAB i MacAB--TolC [128] oraz izolowane od zwierząt hodowlanych w Chinach szczepy K. pneumoniae typu PDR (pan-drug resistant) z ekspresją nowej pompy typu RND, z rodziny MexCD-OprJ, o nazwie TMexCD1-TOprJ1, odpowiadającą za oporność m. in. na wszystkie tetracykliny [68]. Ponieważ kodujące ją geny są zlokalizowane w plazmidzie, ich rozpowszechnienie wśród odzwierzęcych szczepów K. pneumoniae może w przyszłości stanowić poważne zagrożenie kliniczne. Drugim równie istotnym zagrożeniem dla skuteczności stosowania w lecznictwie erawacykliny jest rozprzestrzenianie się zlokalizowanych w plazmidach i transpozonach genów tet(X). Kilka wariantów tych genów opisano ostatnio w Chinach u szczepów A. baumannii (środowiskowych i klinicznych) [16, 116] oraz u szczepów Enterobacterales izolowanych z próbek kału od zdrowych osób dorosłych w Singapurze [18]. Są one również szeroko rozpowszechnione wśród izolowanych od zwierząt (świnie, kurczaki, ptaki wędrowne) oraz z gleby szczepów E. coli [17, 109], a ostatnio obecność tych genów potwierdzono również u Proteus sp. wyizolowanego z handlowej wieprzowiny [38]. Oporność na erawacyklinę może być również wynikiem mutacji w genach kodujących białka podjednostki 30S rybosomu, co opisano już u szczepów S. aureus oraz S. agalactiae [61, 117].

W badaniach klinicznych wykazano, że erawacyklina (podawana 1 mg/kg co 12 h) jest dobrze tolerowana i bezpieczna, a także nie gorsza niż meropenem (podawany 1 g co 8 h) i nie mniej skuteczna niż ertapenem (1 g co 24 h) w leczeniu powikłanych zakażeń wewnątrzbrzusznych [104, 105]. Na podstawie uzyskanych wyników erawacyklina została 20.09.2018 roku dopuszczona przez EMA do stosowania w tej jednostce chorobowej i zarejestrowana pod nazwą handlową Xerava 50 mg – proszek do sporządzania koncentratu roztworu do infuzji [20].

7. Pleuromutyliny

Lefamulina to nowy antybiotyk z grupy pleuromutylin – pochodnych naturalnie występującej pleuromutyliny, wyizolowanej w latach 50. XX wieku z grzyba gatunku Pleurotus mutilus (obecnie Clitophilus scyphoides) [86]. Pierwsze półsyntetyczne pochodne pleuromutyliny (tiamulina i walnemulina) dopuszczono do stosowania w weterynarii odpowiednio w 1979 i 1999 roku. Leki te były jednak stosowane wyłącznie w leczeniu zakażeń płucnych i jelitowych zwierząt, nie były natomiast stosowane w procesie produkcji żywności pochodzenia zwierzęcego jako stymulatory wzrostu lub dodatki zwiększające wydajność pasz (w przeciwieństwie m.in. do tetracyklin, streptogramin czy sulfonamidów). Może to wyjaśniać nisko rozpowszechnioną oporność wśród bakterii na pleuromutyliny. Pierwszym antybiotykiem z tej klasy dopuszczonym do stosowania u ludzi była retapamulina – dostępna jednak jedynie w postaci maści do stosowania miejscowego w krótkotrwałym leczeniu powierzchniowych zakażeń skóry (liszajec, niewielkie rany szarpane, otarcia lub rany szyte). Lefamulina (wcześniej BC-3781) to druga pleuromutylina dopuszczona do stosowania u ludzi, jednak pierwsza dopuszczona do stosowania ogólnego, zarówno w postaci dożylnej jak i doustnej [86].

Pod względem chemicznym, pleuromutyliny to diterpenoidy zawierające w swojej cząsteczce 14-węglowy, tricykliczny szkielet (kluczowy dla aktywności przeciwbakteryjnej) oraz ugrupowanie estru glikolowego tworzące łańcuch boczny w pozycji C14, którego różne modyfikacje odpowiadają m.in. za odmienne właściwości farmakodynamiczne pochodnych [126]. Mechanizm działania tej grupy antybiotyków polega na hamowaniu syntezy białka poprzez wiązanie do podjednostki 50S rybosomu w centrum peptydylotransferazy (PTC), w środkowej części domeny V cząsteczki 23S rRNA. Za przyłączenie pleuromutylin do rybosomu odpowiada tricykliczny rdzeń, tworzący wiązania wodorowe z nukleotydami w kieszonce w pobliżu miejsca A rybosomu, podczas gdy łańcuch boczny w pozycji C14 rozciąga się w stronę miejsca P, uniemożliwiając ruch końca 3’ tRNA w kierunku miejsca P. Cząsteczka lefamuliny charakteryzuje się silniejszym od innych pleuromutylin wiązaniem z rybosomem dzięki obecności 2-(4-amino-2-hydroksycykloheksylo)sulfanylooctanowego łańcucha bocznego w pozycji C14, którego grupa aminowa zapewnia możliwość utworzenia jeszcze jednego wiązania wodorowego. Dodatkowo, obecność w tym łańcuchu grupy hydroksylowej i I-rzędowej aminowej zwiększa rozpuszczalność lefamuliny w wodzie [21].

W warunkach in vitro lefamulina wykazuje aktywność wobec większości Gram-dodatnich ziarenkowców (S. aureus MSSA oraz MRSA, S. epidermidis, E. faecium opornych na wankomycynę, S. pneumoniae (także opornych na penicylinę, makrolidy oraz szczepów MDR), S. pyogenes, S. agalactiae, Streptococcus spp. z grupy C i G), oraz niektórych bakterii Gram-ujemnych (H. influenzae, Haemophilus parainfluenzae, L. pneumophila, M. catarrhalis, N. gonorrhoeae) i patogenów atypowych (M. pneumoniae, Ch. pneumoniae). Nie jest natomiast aktywna wobec Gram-ujemnych pałeczek niefermentujących oraz Enterobacterales [49, 74, 85, 93, 94, 114].

W badaniach przeglądowych potwierdzono, że lefamulina jest wysoce aktywna wobec patogenów wywołujących pozaszpitalne zapalenie płuc, izolowanych od pacjentów na całym świecie (SENTRY Antimicrobial Surveillance Program) [85, 87]. Ogólny odsetek szczepów z wartościami MIC lefamuliny poniżej 1 mg/l (breakpoint dla S. pneumoniae) wynosił 99,2%, w tym 100% dla szczepów S. pneumoniae oraz M. catarrhalis, 99,8% dla S. aureus, 93,8% dla H. influenzae i 88,1% dla E. faecium. Jednocześnie nie stwierdzono oporności krzyżowej między lefamuliną a β-laktamami, fluorochinolonami i makrolidami.

Oporność na lefamulinę u szczepów zazwyczaj wrażliwych na nią gatunków bakterii może powstać w wyniku mutacji w domenie V 23S rRNA, np. w wyniku metylacji nukleotydu w pozycji 2503 pod wpływem metylotransferazy Cfr [75]. Enzym Cfr zapewnia oporność krzyżową na oksazolidynony, linkozamidy, fenikole i streptograminy. Ponadto nabycie oporności może być wynikiem mutacji w genach kodujących rybosomalne białka L3 (rplC) i L4 (rplD), co powoduje zmianę w strukturze PTC i zaburza przyłączanie do niej lefamuliny. Wykazano, że oporność może być również związana z ochroną miejsca docelowego wiązania lefamuliny przez białka pomp błonowych z podrodziny ABC-F kodowane przez geny vga(A), vga(B), vga(E) oraz Isa(E). Białka ABC-F mogą powodować oporność krzyżową na linkozamidy i streptograminy A [75]. Wykazano również, że inaktywacja pompy MtrCDE (ale nie MacAB i NorM) u N. gonorrhoeae znacząco (min. 4-krotnie) obniża wartości MIC lefamuliny [49].

W badaniach klinicznych wykazano, że lefamulina (podawana 150 mg dożylnie co 12 h przez 3 dni a następnie 600 mg doustnie co 12 h) jest na równi skuteczna co moksyfloksacyna (podawana 400 mg dożylnie co 24 h przez 3 dni a następnie 400 mg doustnie co 24 h) w leczeniu pozaszpitalnego zapalenia płuc [22]. Podobne rezultaty uzyskano stosując lefamulinę i moksyfloksacynę wyłącznie doustnie [2]. Z kolei w leczeniu ostrych bakteryjnych zakażeń skóry i tkanek podskórnych wywoływanych przez patogeny Gram-dodatnie, w grupie pacjentów leczonych lefamuliną (podawaną 100 lub 150 mg dożylnie co 12 h) odsetek sukcesów klinicznych był porównywalny z grupą pacjentów leczonych wankomycyną (1 g dożylnie co 12 h) [90]. Aktualnie, postacie dożylna (iniekcje 150 mg co 12 h) oraz doustna (tabletki 600 mg) lefamuliny, pod nazwą handlową Xenleta, zostały dopuszczone 27.07.2020 r. do stosowania jedynie w leczeniu pozaszpitalnych zakażeń płuc u osób dorosłych [20].

8. Podsumowanie

Od 2018 na rynku europejskim zarejestrowano 6 nowych, szeroko spektralnych leków przeciwbakteryjnych, aktywnych wobec szczepów zaliczanych wg WHO do patogenów o krytycznym oraz wysokim priorytecie konieczności poszukiwania dla nich nowych leków. Dwa z nich to nowe połączenia β-laktamów z nie-β-laktamowymi inhibitorami β-laktamaz (meropenem z waborbaktamem oraz imipenem/cylastatyna z relebaktamem), jeden jest przedstawicielem nowej grupy antybiotyków sideroforowych (cefiderokol), kolejne dwa są nowymi pochodnymi znanych grup antybiotyków: fluorochinolonów (delafloksacyna) oraz tetracyklin (erawacyklina). Ponadto jako ostatni z nowych leków w lipcu 2020 r. EMA dopuściła do obrotu lefamulinę, tj. pierwszego przedstawiciela nowej grupy leków – pleuromutylin, przeznaczoną do stosowania ogólnego u ludzi. Lefamulina w odróżnieniu od ww. nowych leków nie jest aktywna wobec Gram-ujemnych pałeczek niefermentujących i Enterobacterales, które są na nią naturalnie oporne. Według kryteriów przyjętych przez WHO, dwa z 6 nowych leków przeciwbakteryjnych (delafloksacyna i lefamulina) zostały zarejestrowane jako skuteczne wobec patogenów o wysokim priorytecie (enterokoki oporne na wankomycynę, gronkowce MRSA), a pozostałe cztery (meropenem/waborbaktam, imipenem/cylastatyna/relebaktam, erawacyklinna oraz cefiderokol) jako aktywne wobec patogenów krytycznych (Enterobacterales oporne na karbapenemy), przy czym tylko jeden (cefiderokol) wykazuje wysoką skuteczność również wobec opornych na karbapenemy szczepów P. aeruginosa oraz A. baumannii. Kryterium innowacyjności WHO w pełni spełnia jedynie meropenem/waborbaktam (w kategorii nowa klasa chemiczna) oraz częściowo lefamulina z zastrzeżeniem, że przedstawicieli tej grupy (pleuromutylin) stosowano już w weterynarii oraz do leczenia miejscowego u ludzi. Natomiast kryterium innowacyjności w kategorii braku oporności krzyżowej spełnia potencjalnie meropenem/waborbaktam oraz cefiderokol.

Spośród zarejestrowanych leków dwa są dostępne zarówno w formie dożylnej jak i doustnej (delafloksacyna i lefamulina). Dzięki nowym rejestracjom wzrosła liczba opcji terapeutycznych w leczeniu powikłanych zakażeń dróg moczowych (meropenem/waborbaktam, cefiderokol), powikłanych zakażeń wewnątrzbrzusznych (meropenem/waborbaktam, erawacyklina), szpitalnych zapaleń płuc, w tym związanych z wentylacją mechaniczną (meropenem/waborbaktam, imipenem/cylastatyna/relebaktam), ostrych bakteryjnych zakażeń skóry i tkanek podskórnych (delafloksacyna) oraz pozaszpitalnych zapaleń płuc (lefamulina). Według ostatniego raportu WHO dotyczącego nowych antybiotyków liczba nowych opcji terapeutycznych dostępnych w leczeniu zakażeń wywołanych patogenami o wysokim i krytycznym priorytecie, jak również patogenami typu PDR (pan-drug resistant) oraz XDR (extensively drug resistant) jest wciąż niewystarczająca [120]. Ostatnio opisano jednak przypadek sukcesu terapeutycznego w leczeniu zakażenia wywołanego przez Achromobacter sp. typu PDR u 10-letniej pacjentki z mukowiscydozą, po zastosowaniu skojarzonego leczenia cefiderokolem, meropenemem z waborbaktamem i terapii fagowej (Ax2CJ45ϕ2). Kuracja była dobrze tolerowana i doprowadziła do eradykacji Achromobacter sp. [25]. Możliwe zatem, że dzięki terapii skojarzonej nowe antybiotyki okażą się skuteczne również wobec patogenów typu PDR oraz XDR, co poszerzy możliwości ich zastosowania w lecznictwie.

Acknowledgments

The article was created with the support of the Berlin-Chemie company.

10.21307_PM-2021.60.4.20-f002.jpg

Podziękowania

Artykuł powstał przy wsparciu firmy Berlin-Chemie.

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FIGURES & TABLES

Figure 1.

Structures of new antimicrobial compounds

Compounds are active against priority pathogens according to WHO, approved in the European Union since 2018: A) vaborbactam – a boron inhibitor of β-lactamases (combined with meropenem); B) relebactam – a diazabicyclooctane β-lactamase inhibitor (in combination with imipenem / cilastatin); C) cefiderocol – siderophore cephalosporin; D) delafloxacin – the fourth generation fluoroquinolones; E) eravacycline – the first fully synthetic tetracycline; F) lefamulin – the first pleuromutilin for systemic use in humans.

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Wzory strukturalne nowych związków przeciwbakteryjnych

Struktury nowych zwiąków aktywnych wobec priorytetowych patogenów wg WHO, dopuszczonych do obrotu na terenie Unii Europejskiej od 2018 roku: A) waborbaktam – boronowy inhibitor β-laktamaz (skojarzony z meropenemem); B) relebaktam – diazabicyklooktanowy inhibitor β-laktamaz (skojarzony z imipenemem/cilastatyną); C) cefiderokol – cefalosporyna sideroforowa; D) delafloksacyna – fluorochinolon IV generacji; E) erawacyklina – pierwsza w pełni syntetyczna tetracyklina; F) lefamulina – pierwsza pleuromutylina do stosowania ogólnego u ludzi.

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Rycina 1.

Wzory strukturalne nowych związków przeciwbakteryjnych

Struktury nowych zwiąków aktywnych wobec priorytetowych patogenów wg WHO, dopuszczonych do obrotu na terenie Unii Europejskiej od 2018 roku: A) waborbaktam – boronowy inhibitor β-laktamaz (skojarzony z meropenemem); B) relebaktam – diazabicyklooktanowy inhibitor β-laktamaz (skojarzony z imipenemem/cilastatyną); C) cefiderokol – cefalosporyna sideroforowa; D) delafloksacyna – fluorochinolon IV generacji; E) erawacyklina – pierwsza w pełni syntetyczna tetracyklina; F) lefamulina – pierwsza pleuromutylina do stosowania ogólnego u ludzi.

Full Size   |   Slide (.pptx)

Wzory strukturalne nowych związków przeciwbakteryjnych

Struktury nowych zwiąków aktywnych wobec priorytetowych patogenów wg WHO, dopuszczonych do obrotu na terenie Unii Europejskiej od 2018 roku: A) waborbaktam – boronowy inhibitor β-laktamaz (skojarzony z meropenemem); B) relebaktam – diazabicyklooktanowy inhibitor β-laktamaz (skojarzony z imipenemem/cilastatyną); C) cefiderokol – cefalosporyna sideroforowa; D) delafloksacyna – fluorochinolon IV generacji; E) erawacyklina – pierwsza w pełni syntetyczna tetracyklina; F) lefamulina – pierwsza pleuromutylina do stosowania ogólnego u ludzi.

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