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REVIEW ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 3  |  Page : 303-316
 

An update on antimicrobial resistance and the role of newer antimicrobial agents for Pseudomonas aeruginosa


1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, USA

Date of Web Publication14-Nov-2018

Correspondence Address:
Dr. Keith S Kaye
Division of Infectious Diseases, University of Michigan Medical School, 5510A MSRB I, SPC 5680, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5680, Michigan
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_18_334

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 ~ Abstract 

Infections due to Pseudomonas aeruginosa is a major health concern, especially hospital-acquired infections, in critically ill individuals. Antimicrobial resistance (AMR) increases the morbidity and mortality rates associated with pseudomonal infections. In this review, we aim to address two major aspects of P. aeruginosa. The first part of the review will focus on the burden of AMR and its prevailing mechanisms seen in India, while the second part will focus on the challenges and approaches in the management with special emphasis on the role of newer antimicrobial agents.


Keywords: Antimicrobial resistance, India, newer antimicrobials, Pseudomonas aeruginosa, treatment


How to cite this article:
Pragasam AK, Veeraraghavan B, Nalini E, Anandan S, Kaye KS. An update on antimicrobial resistance and the role of newer antimicrobial agents for Pseudomonas aeruginosa. Indian J Med Microbiol 2018;36:303-16

How to cite this URL:
Pragasam AK, Veeraraghavan B, Nalini E, Anandan S, Kaye KS. An update on antimicrobial resistance and the role of newer antimicrobial agents for Pseudomonas aeruginosa. Indian J Med Microbiol [serial online] 2018 [cited 2018 Dec 10];36:303-16. Available from: http://www.ijmm.org/text.asp?2018/36/3/303/245394



 ~ Introduction Top


Pseudomonas aeruginosa is a non-fermenting Gram-negative pathogen that causes severe infections. This includes bacteraemia, pneumonia, urinary tract infections and skin and soft-tissue infections. It occurs more frequently in critically ill patients particularly in immunocompromised and hospitalised patients. In critically ill patients, P. aeruginosa contributes 3%–15% of blood stream infections with high mortality rate of about 27%–48%. In spite of recent advances in therapy, P. aeruginosa bacteraemia remains fatal in more than 20% of cases. Over 50% of deaths happen within a few days of infection. Selection of appropriate empirical therapy reduces the mortality rates, while inappropriate empirical therapy leads to the development of resistance, results in clinical failure.[1]


 ~ Antimicrobial Resistance in Pseudomonas aeruginosa Top


P. aeruginosa is well known for its intrinsic ability to resist wide range of antipseudomonal agents. Antimicrobial resistance (AMR) in P. aeruginosa is mediated by chromosomal/intrinsic and plasmid/acquired-mediated mechanisms.[2] Chromosomal mechanisms include the following: (i) mutational derepression of the chromosomally encoded ampc beta-lactamase (penicillins and cephalosporins), (ii) mutational modification of antimicrobial targets such as gyrase and topoisomerase (fluoroquinolones – gyrA, gyrB, parC and parE), (iii) presence of mutated and/or loss of outer membrane proteins preventing the uptake of antimicrobials (carbapenems-OprD) and (iv) overexpression of efflux systems (beta-lactams, fluoroquinolones and aminoglycoside resistance – mexAB, mexCD, mexEF and mexXY).[3] Whereas the acquisition of plasmid-mediated resistance genes coding for various beta-lactamases and aminoglycoside-modifying enzymes have been identified and reported. This includes beta-lactamases (blaPSE,blaSHV, blaVEB, blaPER, blaIMP, blaVIM, blaNDM and blaSPM), aminoglycosides-modifying enzymes (aminoglycoside acetyltransferases [AAC], aminoglycoside nucleotidyltransferase [ANT] and aminoglycoside phosphotransferase [APH]) and 16S rRNA methylases (armA, rmtA-rmtH and npmA). The various mechanisms along with its specific substrates described here are summarised in [Table 1].[4],[5]
Table 1: Antimicrobial resistance mechanisms described in Pseudomonas aeruginosa

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Phenotypes of multidrug resistant (MDR), extensive drug resistant (XDR) and pan drug resistant (PDR) are frequently encountered in P. aeruginosa causing nosocomial infections. Strains are categorised as MDR, XDR and PDR when resistance is observed for antipseudomonal agents of ≥1 agent in ≥3 classes, all agents in ≥3 classes and resistant to all agents in all classes, respectively.[6] Notably, the emergence of phenotype from MDR to XDR to PDR in P. aeruginosa occurs in a timely fashion using the complex regulatory mechanisms accumulated by intrinsic and extrinsic determinants as detailed above.


 ~ Current Status of Antimicrobial Resistance in Pseudomonas aeruginosa in India Top


Phenotypic resistance

In 2017, Government of India has included P. aeruginosa as one of the important pathogens to National Programme for the Containment of Antimicrobial Resistance (within the 12th 5-year plan, 2012–2017) under National Centre for Disease control. World health organisation in 2017 published a list of bacterial pathogens in which carbapenem-resistant P. aeruginosa stands second as a critical pathogen for which identification of new antibiotic is essential to overcome its MDR properties. Pan India susceptibility profile of P. aeruginosa varies from one region to other. The interquartile range of antibiotic susceptibility for various therapeutic agents are Ceftazidime-24 (lower quartile –31 and Upper quartile –55), Cefepime-32.75 (26–58.75), Beta-lactam/beta lactamase inhibitor-piperacillin/tazobactam-38 (36.5–74.5), under carbapenems, interquartile range for imipenem - 29.5 (43–72.5) and meropenem - 36 (33–69), for azithromycin only limited data are available, for fluoroquinolone levofloxacin - 28.5 (39–67.5) and ciprofloxacin-28.5, in aminoglycoside for amikacin-36 (33.25–69.25), netilmicin - 43.5 (42.25–85.75), gentamicin- 22.5 (24–46.5) and in polymyxin for colistin - 3.75 (96.25–100). Antibiotic susceptibility percentage of P. aeruginosa from different regions varies with the presence of different antibiotic-resistant genes. Among different antipseudomonas drugs tested, almost all are highly susceptible to colistin whereas less susceptible to gentamicin, ceftazidime and cefepime. [Table 2] summarises the current scenario of antimicrobial susceptibility rates reported by Indian studies.[7],[8],[9],[10],[11],[12],[13],[14],[15],[16]
Table 2: Antibiotic susceptibility pattern of Pseudomonas aeruginosa in India

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Molecular resistance

P. aeruginosa has intrinsic resistance mediated through chromosomal gene expression which promotes specific structural and compositional features that protect bacteria from various antimicrobials. Lie et al., 2015, observed constitutive protection with MexAB-OprM efflux pump by expelling multiple antibiotics.[17] AmpC expression plays an important role in intrinsic resistance as it is induced by exposure to aminopenicillin and cephalosporins.[18] Acquired resistance through horizontal transfer of resistance genes also aids in survival of the pathogen under different antibiotic stress.[19] Mutations in regulatory regions contribute to increased expression of antibiotic-resistant genes. Mutations in ampD and ampR regulatory proteins led to increased expression of ampC.[18],[20] Hence, the prevalence of carbapenem resistance and ampC expression varies with influence of antibiotic exposure, environmental-influenced horizontal gene transfer and also on mutations on regulatory regions. In case of pan-India Scenario, studies by Bharti et al., 2016, showed increased percentage of blaNDM-1.[21] Paul et al., 2015, have reported co-occurrence of blaKPC-2 + NDM-1 which is an unusual phenotype.[22] [Table 3] summarises Indian reports on molecular mechanisms of AMR in P. aeruginosa.[8],[10],[21],[22],[23],[24],[25],[26],[27],[28]
Table 3: Molecular profile of beta lactamases reported in India

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Approaches to overcome resistance

The emergence of resistance in P. aeruginosa during treatment is of great concern which limits treatment options.[29] It is mainly due to the inappropriate definite therapy that results in poor clinical outcomes. One main approach to be addressed is the use of combination therapy.[30] The potential clinical outcome of treatment with monotherapy and combination therapy remains controversial particularly for infections that are caused by MDR P. aeruginosa.[31],[32] However, several studies addressed the importance and effectiveness of combination therapies than monotherapy. Importantly, increased rate of survival is achieved upon adequate combination therapy.

Combination therapy includes two agents either β-lactams with aminoglycosides and/or with fluoroquinolones to achieve better clinical outcome.[33] The rationale behind the theory of combination therapy is to reduce the emergence of resistance rate during therapy and to achieve synergy, where the minimum inhibitory concentrations (MIC) can be achieved with two antibiotics with different spectrum of activity. Eric chamot et al., recommend the direction of empirical therapy with two antipseudomonal agents.[34] Later, combination therapy could be deescalated to monotherapy based on susceptibility pattern of the isolate.

Challenges in laboratory

In vitro antimicrobial susceptibility testing determines and guides clinical decision-making on antimicrobial therapy for the management. Unlike Enterobacteriaceae, interpreting susceptibility to P. aeruginosa is challenging.[35] Due to complex chromosomally encoded resistance mechanisms, differential susceptibility phenotypes are being increasingly noted. This includes resistance to imipenem and susceptible to meropenem within the carbapenem agents.[36],[37] Similarly, ceftazidime being susceptible, while carbapenems showing resistance.[38],[39] Such discrepant susceptibility profile appears due to chromosome-mediated resistance mechanisms. Therefore, clinical decisions must be made based on in vitro susceptibility of each agent. Due to these reasons, extrapolation of one agent's susceptibility to another agent within the same group must be strictly avoided especially for P. aeruginosa.

Challenges in management of P. aeruginosa infections

The differences exist in the clinical breakpoints for Enterobacteriaceae and P. aeruginosa. This is especially for all antipseudomonal agents belonging to β-lactams (ceftazidime and cefepime), β-lactam/β-lactamase inhibitor (pip/tazo), fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (amikacin, gentamicin and tobramycin) and polymyxins (colistin). With respect to clinical breakpoint differences, dosage of the agent suggested for the treatment of P. aeruginosa also varies.[40] In case of ceftazidime, for Enterobacteriaceae, MIC of ≤4 μg/ml is considered susceptible with the dosage recommended being 1 g every 8 h. In contrast, for P. aeruginosa, MIC of ≤8 μg/ml is considered susceptible with a recommended dosage of 1 g every 6 h or 2 g every 8 h because, P. aeruginosa infections requires high drug dosage. One of the main challenges in the management of P. aeruginosa infections is the MIC of an antipseudomonal agent. Studies have shown that MIC of an antimicrobial for an Enterobacteriaceae isolates are usually less than the clinical susceptibility breakpoints.[41] Whereas, in P. aeruginosa, MIC is generally very near to susceptible breakpoints. This, in turn, requires high dosage for therapy and/or addition of the second agent for a combined effect to reduce MIC of the first agent.[42],[43]


 ~ New Agents with Antipseudomonal Activity Top


[Table 4] summarises list of newer antimicrobial agents and its clinical indications for use.
Table 4: Newer antimicrobial agents with anti-pseudomonal activity

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[Table 5] summarises data evidences for the activity of newer agents.
Table 5: Susceptibility of newer agents in Pseudomonas aeruginosa as reported by various studies

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Ceftolozane/tazobactam

Ceftolozane/tazobactam (C/T) combination of a fifth-generation cephalosporin, with a beta-lactamase inhibitor. Ceftolozane has an antipseudomonal activity which was stable against AmpC enzymes and remained unaffected by porins and efflux systems of P. aeruginosa.[62] This combination was approved by the Food and Drug Administration (FDA) in December 2014, includes ceftolozane, which is a novel cephalosporin active against bacterial ampC enzymes, efflux system and membrane impermeability. However, it can be hydrolysed by extended-spectrum beta-lactamases (ESBLs) and carbapenemase. Therefore, the addition of tazobactam broadens the spectrum of activity against ESBL producers. It is licensed for use in adults for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTI) including pyelonephritis.[63] It is approved for infections caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, P. aeruginosa, Proteus mirabilis, Bacteroides fragilis and Streptococcus spp.

The safety and efficacy of this drug have not been established for use in paediatric population.[64] C/T has been shown to demonstrate better in vitro activity against ceftazidime-resistant E. coli, K. pneumoniae and P. aeruginosa than other antimicrobials such as ceftriaxone, cefepime and piperacillin/tazobactam. The antimicrobial is available for intravenous (iv) use as injection and is administered at a dose of 1.5 g (1 g/0.5 g) every 8 h by IV infusion over 1 h for patients 18 years or older with creatinine clearance >50 mL/min.[63] Dosage in patients with impaired renal function varies according to the renal clearance rate.

Since ceftolozane overcomes efflux mechanism present in the bacteria, it is more effective against P. aeruginosa where efflux contributes to a majority of drug resistance.[65] However, in Enterobacteriaceae, the resistance mechanisms are mostly enzymatic inactivation of the beta-lactam antibiotics. This could be a possible reason for C/T being highly effective against P. aeruginosa compared to Enterobacteriaceae.[66]

At present, FDA approved C/T for the treatment of cIAI and cUTI. However, it was not approved for its use in bacteraemia. Recently, Patel et al., 2016, have used C/T for a 66-year-old bacteraemic patient with MDR P. aeruginosa infection.[67] In vitro, the isolate was susceptible to C/T with MIC of 2/4 μg/ml. 375 mg of C/T monotherapy was given for about 25 days, and the clinical outcome was successful. The concentration of the drug achieved in the serum was higher than the MIC of the organism and signifies the utility of C/T in bacteraemic cases. However, further studies need to be carried out to warrant the use of C/T in bacteraemia.

In due course of evaluating C/T as active antipseudomonal agents, Gangcuangco et al., 2016, have reported the case report of C/T resistance.[67] A 68-year-old male with persistent sepsis developed resistance during therapy. This report alerts clinicians, and microbiologist to perform repeated cultures and susceptibility testing for P. aeruginosa, as it develops resistance during therapy resulting in clinical failure. Although C/T is a new agent, routine susceptibility testing warrants its clinical success.

Studies have proven that tazobactam does not directly influence the activity of ceftolozane, yet it showed excellent activity against strains-producing ESBLs. Notably, Ceftolozane in vitro activity was proved to be 8-fold higher than ceftazidime.[68] Further, C/T was found to be superior than imipenem and piperacillin/tazobactam.[69] More importantly, against ceftazidime-resistant P. aeruginosa, C/T retained its activity; underlining the clinical utility of C/T against P. aeruginosa infections.

Further, studies have proven that, MICs of P. aeruginosa producing AmpC beta-lactamases are 2 and 4 μg/ml, suggesting the stability of C/T against AmpC enzymes. This was supported by Moya et al., wherein a common resistance mechanism in P. aeruginosa does not influence the MIC of C/T.[70] In contrary, Cabot et al., 2014, have reported that mechanisms of resistance to be due to the mutated and altered structure of ampC which could hydrolyse Ceftolozane.[71] More importantly, cross-resistance associated with C/T was not observed in any of the studies reported. Strains that are resistant to antipseudomonal agents retained its susceptibility against C/T. [Table 5] summarises MIC50 and MIC90 reported by various studies.

Ceftazidime/avibactam

Ceftazidime/avibactam combination was formerly known as “NXL104.” It is a coformulation of an antipseudomonal cephalosporin (ceftazidime) and a novel non-β-lactam-based β-lactamase inhibitor (avibactam). It is stable against clinical isolates producing β-lactamases such as Class A (TEM, SHV, CTX-M), Class C (AmpC), Class D (Oxa) and carbapenemase (KPC). In P. aeruginosa, ceftazidime resistance is contributed by the production of β-lactamases (AmpC and ESBLs). Addition of avibactam restores the activity of ceftazidime, whereas clavulanic acid and tazobactam, either lacks or partially restores ceftazidime activity. This combination of ceftazidime/avibactam was found to have an excellent antibacterial activity against a multidrug-resistant Gram-negative isolates.[72] However, it lacks activity against metallo β-lactamase-producing organisms.

This combination was approved by the FDA in February 2015 for the treatment of cIAIs in combination with metronidazole and cUTI including pyelonephritis. Dosage was formulated in the ratio of 4:1, with 2 g of ceftazidime and 0.5 g of avibactam. It is available for IV use, administered every 8 h over 2-h infusion period. However, the dosage varies for patients with impaired renal function such as 1.25 g IV q8 h (CLcr 30–50 mL/min), 0.94 g IV q12 h (CLcr 15–29 mL/min), 0.94 g IV q24 h (CLcr 6–15 mL/min) and 0.94 g IV q48 h (CLcr <5 mL/min). Safety of using this combination in paediatric population has not been established.

In a Phase 2 trial of ceftazidime/avibactam versus imipenem/cilastatin groups, cure rates observed were 70.4% and 71.4%, respectively. Similarly, for ceftazidime/avibactam+metronidazole versus meropenem, the cure rates were 91.2% and 93.4%, respectively. However, in patients with impaired renal function, clinical cure rates were 45% and 74%, respectively. Furthermore, mortality rates were 25.8% and 8.6% between the groups, respectively. Clinical trials of REPRISE study showed promising results wherein ceftazidime/avibactam is a better alternative to carbapenems for treating infections due to ceftazidime-resistant Gram-negative organisms. Against Class A carbapenemase (KPC)-producing organism in US, MIC50 and MIC90 of Avycaz were found to be 0.5 and 2 μg/ml, respectively. Interestingly, studies have reported reduction in the MIC90 of ceftazidime from 128 to 4 μg/ml upon addition of avibactam.[73]

FDA recommended breakpoint criteria were ≤8/4 and ≥16 μg/ml for interpreting susceptible and resistant for Enterobacteriaceae and P. aeruginosa, respectively. A number of studies evaluated the in vitro activity of ceftazidime/avibactam against clinical isolates across various sites. The results are summarised in [Table 5].[46],[53],[54],[55] Of all the reports, MIC50 and MIC90 were ranging from 2 to 8 μg/ml and 4 to 32 μg/ml, respectively. Notably, MIC50 and MIC90 were found to be 4 and 16 μg/ml for MDR and 8 and 32 μg/ml for XDR P. aeruginosa, respectively. This is comparatively lesser than the MIC of ceftazidime alone.[74]

Resistance to ceftazidime/avibactam is reported by Winkler et al., in the archived isolates of their collection.[75] It was reported that the mechanism of resistance is due to the chromosomal-mediated porin and efflux pumps.[75] This is a major concern, as resistances due to chromosomal-mediated mechanisms are difficult to treat, while this mechanism could not be transferred to another strain as they are chromosomal mediated. However, the addition of fosfomycin to this combination has been proven to improve the clinical outcome when more than one agent targeting the cell wall synthesis pathways is prescribed.

Imipenem/relebactam

Relebactam or MK-7655 is bicyclic diazabicyclooctane, non-beta lactam and a beta-lactamase inhibitor.[76] Physically, it resembles avibactam but contains an additional piperdine ring. It is stable in the pH range of 4–8 under aqueous environment.[77] Piperdine possesses positive charge under this pH, which resists efflux from bacteria.[78] Relebactam is effective against Class A β-lactamases (e.g., KPC) and Class C (eg: ampC) but is inactive against Class B metallo-β-lactamases (e.g., VIM, NDM and IMP) and Class D (e.g., OXA) β-lactamases.[56],[57],[79] Relebactam inhibits β-lactamases by acetylation and is highly reactive against β-lactamase PER-2 of P. aeruginosa.[80],[81] It is also effective against P. aeruginosa PDC-3, ESBL.[82] Addition of relebactam to imipenem inhibits the action of carbapenemase (β-lactamases) along with cell wall synthesis inhibition by imipenem providing potent protection against MDR pathogens. Zhanel et al. (2017) observed multiple-fold (8 fold) decrease in MIC against imipenem non-susceptible, β-lactamase-producing Enterobacteriaceae and in P. aeruginosa.[83]

Livermore et al., 2013, found that MIC value (1–2 mg/L) of imipenem susceptible P. aeruginosa with intrinsic AmpC imposed resistance was highly reduced to 0.25–0.5 mg/L with imipenem-relebactam combinations.[56] In case of imipenem-resistant isolates, concentration of relebactam is comparatively higher than that used in susceptible isolates. For different OprD absent isolates without any other resistant mechanisms, addition of relebactam has reduced MIC values from 16–64 to 2–8 mg/L, whereas in MDR isolates MIC was around 4–8 mg/L. Imipenem-relebactam combination is not significant in reducing MIC of isolates with metallo-carbapenemases as relebactam is inactive against it. Lapuebla et al., 2016, found that in 490 isolates of P. aeruginosa, imipenem-relebactam combination has reduced MIC from 2–16 to 0.5–2 μg/ml.[57] In imipenem non-susceptible isolates (n = 144), imipenem-relebactam combination reduced MIC as 1–2 μg/ml. In case of 30 carbapenemase-negative isolates, six of these isolates with OprD and AmpC as that of wild-type controls, MIC's reduced from 2 to 4 μg/ml to 1 μg/ml after addition of relebactam to imipenem. In 14 of the carbapenem-negative isolates, with AmpC as control but with reduced OprD, MIC's reduced from 1–>16 to 0.25–8 μg/ml. Remaining ten with elevated AmpC but with reduced OprD has its MIC reduced from 2–>16 to 1–8 μg/ml.[84]

In case of cIAIs, a non-inferiority, randomised, double-blinded, Phase II clinical trial (NCT01506271) used imipenem relebactam. Pathogens isolated were E. coli (n = 171), Klebsiella pneumoniae (n = 38) and P. aeruginosa (n = 37), in which 40 were imipenem non-susceptible. The primary outcome of the study revealed that discontinuous IV infusion with two different arms of relebactam 250 mg and 125 mg showed increased response variation of 1.1% and 3.7%, respectively, against imipenem alone. Overall response in curing disease with two different doses of relebactam along with the same dose of imipenem showed 86.5% (250 mg relebactam), 89.6% (125 mg relebactam) against 84.8% with imipenem alone for all tested pathogens.[85]

A global, double-blinded, randomised, non-inferiority Phase II trial, tested imipenem-cilastatin/relebactam (500–500/250 mg), imipenem-cilastatin/relebactam (500–500/125 mg) with imipenem-cilastatin alone (500–500 mg) in patients suffering with cUTI and acute pyelonephritis (AP). Pathogens isolated at baseline included E. coli (n = 143), K. pneumoniae (n = 34) and P. aeruginosa (n = 16). About 25 isolates were non-susceptible to imipenem while 15 were non-susceptible to imipenem-relebactam. Microbial response to the treatment in microbiologically evaluable population showed a primary outcome of 95.5% to 250 mg of relebactam while it was 98.7% with imipenem alone group. In case of 125 mg of relebactam primary outcome was 98.6% while it was 98.7% in imipenem alone. Hence, the trial showed both are non-inferior to imipenem alone. In microbiological response also, the outcome was same.

Two Phase III study, NCT02452047 (RESTORE-IMI 1) and NCT02493764 (RESTORE-IMI 2), which got over on September 2017 (results not yet published) and May 2019, use imipenem-relebactam in comparison with colistimethate sodium-imipenem and imipenem-relebactam in comparison with piperacillin tazobactam, respectively. The first trial tested in patients with hospital-associated bacterial pneumonia, ventilator-associated bacterial pneumonia, cIAIs and cUTI whereas the second trail deals with hospital-associated bacterial pneumonia and ventilator-associated bacterial pneumonia. Results from these studies would prove that imipenem-relebactam as the drug of choice to treat imipenem non-susceptible Enterobactericeae and also multiple drug-resistant P. aeruginosa.

Meropenem/vaborbactam

Vaborbactam is a non-β-lactam, with high propensity towards serine β-lactamases. Similar to relebactam, vaborbactam is active against Class A (e.g., KPCs) and Class C β-lactamases but are inactive against Class B and Class D β-lactamases.[86],[87] Boron atom of vaborbactam is electrophilic, forms covalent bond with serine of β-lactamases.[76],[86] As this is a reversible reaction, there is no hydrolysis of the antibiotic; hence, its action is more of inhibition.[88] Meropenems high activity against Gram-negative pathogens is because of its inclination to bind PBP2 followed with PBP1a, 1b and 3. Meropenem low affinity to PBP3 is its significant property as it results in enhanced bacterial cell lysis but not filamentation. This leads to decreased cell mass before lysis and also reduced endotoxin (lipopolysaccharide) release.[89]

Vaborbactam showed the increased activity when combined with meropenem in inhibiting KPC beta-lactamases in K. pneumoniae isogenic strains that showed multiple resistance such as ESBL, AmpC production along with less porin intake because of mutations in OmpK35 and OmpK36.[90] AcrAB-TolC efflux system involved in multiple drug resistance had less influence on vaborbactam activity. Vaborbactam restored meropenem activity at 8 μg/ml with the MIC of ≤2 μg/ml in isogenic strains with maximum mutations. There is no significant MIC reduction for P. aeruginosa and Acinetobacter baumanii with meropenem-relebactam combination.[58],[91]

In a Phase III clinical trial (TANGO I– NCT02166476), which was a randomised, multicentred, double-blinded, non-inferiority trial, meropenem-vaborbactam (2000/2000 mg), through IV infusion 3 h, every 8-h interval for 5–10 days, was tested along with piperacillin/tazobactam combination. Patients (n = 550) under the study were grouped as 1:1 based on geographical location and infection type such as AP, cUTI either with or without removable source. Patients were followed with oral levofloxacin for 5 days after discontinuation of IV (DCIV) of above-mentioned drug combinations. The primary outcome calculated based on microbiologic-modified intention to treat (m-MITT) or m-MITT after DCIV. Treatment success is defined by microbiological cure with baseline microbial load decreased to <104 CFU/ml as per FDA. m-MITT evaluation showed 98.4% for meropenem-vaborbactam and 94.0% for piperacillin/tazobactam. Hence, there is a significant difference of 4.5% with 95% confidence interval, thus proved non-inferiority of meropenem-vaborbactam.

In case of specific disease condition, m-MITT after DCIV was 100% for both complicated urinary tract infection with either removable or non-removable source, whereas it was 97% in case of AP. m-MITT for the above three complications were 92.1% and 95.3% for complicated urinary tract disease with removable and non-removable source, respectively, whereas it was 94.1% in acute pyelonephritis. Pathogens isolated in above three complications were Enterobactericeae (n = 333) and P. aeruginosa (n = 15). The secondary outcome was measured as test of cure (TOC) for 15–19 days. The baseline pathogen eradication should be <103 CFU/ml according to education maintenance allowance criteria. Hence, m-MITT at TOC was 66.7% for meropenem-vaborbactam and 57.7% for piperacillin/tazobactam, showing a significant variation of 9.0% at 95% confidence interval. Adverse events reported were 39% and 35.5% in meropenem-relebactam and piperacillin/tazobactam.[92]

Cefiderocol

Cefiderocol or CFDC (S-649266), is a new siderophore-drug conjugate with catechol siderophore conjugated with antibiotic cephalosporin, inhibits bacterial cell wall synthesis. It is phenotypically different from MB-1, BAL30072 and MC-1 with hydroxypyridone substituted monobactam siderophore. Cefiderocol showed high antibacterial activity against carbapenem-resistant P. aeruginosa, Enterobacteriaceae and A. baumannii with reduced MIC.[59] MIC90 of P. aeruginosa and beta-lactam-resistant (including metallo-beta-lactamase-VIM, GIM-1, SPM-1 and IMP) P. aeruginosa is 1 and 4 mg/L, respectively.[59]

Cefiderocol chelates extracellular ferric iron through catechol siderophore, gets transported intracellularly by iron transport pathways.[93] Catalytic efficiency (Kcat and Km) of cefiderocol was tested against many carbapenemases such as OXA-23, KPC-3, IMP-1, VIM-2 and NDM-1 and found that Kcat/Km of metallo-β-lactamases (L1, VIM-2 and IMP-1) is the lowest among other tested antibiotics. High Km value for cefiderocol with OXA-23 and KPC-3 than meropenem reflects its increased activity against pathogens that produced these enzymes. Kinetics of cefiderocol in comparison with ceftazidime was similar against tested β-lactamases but showed variations in antibacterial activities against OXA-23 positive A. baumannii. This variation could be the result of different antibiotic uptake mechanisms for cefiderocol and ceftazidime.

Dosage of 2 g in IV with 8-h interval for 10 days was good in healthy patients without any typical adverse side effects.[94],[95] Katsube et al., 2017, found that the dosage of cefiderocol in patients with different grades of augmented renal function as 2 g for every 6 h with 3-h infusion which showed a >90% (PTA) probability of target attainment with plasma drug concentration exceeding MIC of ≤4 μg/ml. The SIDERO-WT-2014 study tested in vitro broth microdilution method to determine MIC90 values for both carbapenem susceptible and carbapenem non-susceptible Enterobacteriaceae and P. aeruginosa. Cefiderocol MIC90 of P. aeruginosa was 0.5 μg/ml (n = 765, North America and Europe), with MIC of ≤4 μg/ml for 99.9% of isolates except a single isolate from North America had MIC of 8 μg/ml. In case of meropenem non-susceptible isolates (MIC ≥4 μg/ml, n = 353) with MIC90 values for cefiderocol in North America isolates (n = 151) was 0.5 and 1 μg/ml in case of Europe (n = 202) with overall MIC of ≤4 μg/ml. In case of meropenem susceptible isolates, MIC90 for cefiderocol was 0.5 μg/ml (n = 614) for North America and 0.5 μg/ml (n = 563) with 99.9% of these meropenem susceptible isolates had MIC's at ≤4 μg/ml. Variations in MIC values in these isolates could be due to either because of reduced expression of iron uptake components or might be due to mutations that disrupt siderophore-antibiotic conjugate attachment and entry as identified with previously studied siderophore-antibiotic conjugates.

Adaptation-based resistance with native siderophore competition as in MB-1 drug resistance was not identified with cefiderocol.[96] In another study with carbapenem non-susceptible isolates collected from 52 countries from the period of 2014–2016, in vitro antibacterial activity of cefiderocol showed MIC90 of P. aeruginosa (n = 262) was 1 μg/ml with 99.2% (260/262) with an MIC of ≤4 μg/ml.[97]

Saisho et al., 2018, studied the pharmacokinetics, tolerability and safety of cefiderocol in Phase 1 trial with healthy Japanese and Caucasian males and Japanese females, as a single-centred, double-blinded, randomised, placebo-controlled study that was done in two groups with single ascending dose and with multiple ascending doses. This study indicated that healthy subjects given with cefiderocol in different dosage pattern tolerated it well without any significant adverse events.

A Phase II study on efficacy/safety of IV cefiderocol versus imipenem/cilastatin in cUTI with or without pyelonephritis or acute uncomplicated pyelonephritis caused by Gram-negative pathogens (APEKS-cUTI/NCT02321800), was an interventional, multicentred, randomised, open-label clinical study. Patients were administered with 2 g of drug by IV, 3 h of infusion for every 8 h for 7–14 days. Clinical and microbiological outcome of the study proposed the effectiveness of the tested drug cefiderocol, which resulted in reduced number of colony-forming units (<104) after 7 days from the end of treatment. Kawaguchi et al., 2018, tested population pharmacokinetics for cefiderocol and found that the dosage of 2 g with 1-h IV infusion for every 8-h interval for 7 or 14 days was efficient to treat complicated urinary tract infection and acute uncomplicated pyelonephritis.[98] Drug exposure or concentration of drug in patients with infection is comparatively lower which could be balanced by shortened dosing interval.

A Phase III clinical trial (CREDIBLE-CR/NCT02714595), is a multicentred, randomised, open-label clinical study of cefiderocol to treat patients with carbapenem-resistant Gram-negative pathogen is in progress from September 2016 and will get over in October 2018. Serious infections such as hospital-acquired pneumonia, healthcare-associated pneumonia, ventilator-associated pneumonia, bloodstream infections, cUTI and sepsis are treated with 2 g of cefiderocol as IV with 3 h of infusion time, every 8 h for 7–14 days. Thus, cefiderocol is one of the drugs of choice to treat carbapenem-resistant Gram-negative pathogens causing complicated urinary tract infection, bloodstream infections and nosocomial pneumonia.

Plazomicin

Plazomicin or ACHN-490 is basically a modified sisomicin (SIS) with improved activity against aminoglycoside-degrading enzymes of Enterobacteriaceae, P. aeruginosa and A. baumannii and Staphylococcus aureus. This property is because of the presence of hydroxymethyl group in 6' position in ACHN-490.[61] Prevalent aminoglycoside-resistant enzymes are AAC (N-acetylation), APH (O-phosphorylation) and by ANT (O-adenylylation).[99] MIC values of strains with different aminoglycoside resistance mechanisms with either single or multiple AG-resistant enzymes showed increased fold reductions in MIC values with plazomicin. E. coli with ANT (2”)-I with an MIC of 32 μg/ml with SIS and AMK showed effective reduction with an MIC of 0.25 μg/ml whereas a strain with AAC (3) 1 showed MIC of 2 μg/ml when compared to >64 μg/ml with SIS and GEN.

In case of P. aeruginosa with AAC (3)-I and AAC (6')-II reduced from 32 μg/ml (SIS), 64 μg/ml (GEN) to 8 μg/ml to plazomicin and 32 μg/ml (SIS and GEN) to 2 μg/ml, respectively.[61] Pankuch et al., 2011, studied the activity of plazomicin along with cefepime, imipenem, doripenem and piperacillin/tazobactam on P. aeruginosa by synergy time-kill assay.[100] MIC of plazomicin for all 25 isolates at 24 h ranges from 0.5 to 256 μg/ml, which included four strains with aminoglycoside-modifying enzymes. Combination of plazomicin with cefepime, doripenem, imipenem and piperacillin/tazobactam revealed synergism against ≥70%, ≥80% at 6 and 12 h, respectively, whereas at 24-h synergism is high for all strains. Among different combinations, MIC levels of plazomicin and piperacillin/tazobactam combination showed high synergism with 92% of isolates. Walkty et al., 2014, studied in vitro activity of plazomicin against both Gram-positive and Gram-negative pathogens isolated from Canadian hospitals as a part of CANWARD study from 2011 to 2012.[101] MIC50 and MIC90 for plazomicin and amikacin were 4 and 16 μg/ml and 4 and 8 μg/ml, respectively, whereas in case of MDR P. aeruginosa it was 8 and 32 μg/ml. When compared to other tested aminoglycosides, such as gentamicin and tobramycin, MIC90 of plazomicin is 2 and 8 times low, but according to in vivo studies, plazomicin showed effective serum concentration than gentamicin and tobramycin.[102],[103]

Cass et al., (2011) conducted two randomised, double-blinded, placebo-controlled Phase 1 clinical trial to study pharmacokinetics, tolerability and safety of plazomicin injection in healthy individuals.[103] In the first study, parallel group design was followed with increasing single and double doses. Totally, 39 individuals (30 with drug and 9 as placebo) were administered with single dose of 1 mg/kg (10 min IV) body weight of plazomicin, proceeded with single and multiple doses of 4, 7, 11 and 15 mg/kg for about 10, 10, 5 and 3 days, respectively. In study, 2 and 8 individuals (8 drugs and 2 places) received 15 mg/kg for 5 days. In both the studies, drug was well tolerated without major adverse effects.

In a multicentre, multinational double-blinded randomised, comparator-controlled Phase II clinical study (NCT01096849), plazomicin was administered intravenously and compared with levofloxacin in case of cUTI and in AP patients. Isolated baseline pathogens included Enterobacteriaceae (n = 68) MIC of ≤0.12–8 μg/ml for plazomicin, MIC of ≤0.12 to >4 μg/ml for levofloxacin and two other Gram-negative pathogen, E. coli and P. aeruginosa were with MIC of >4 μg/ml for plazomicin. Patients randomised as 1:1:1 and were given with 10 mg/kg (n = 22) and also 15 mg/kg (n = 76) of plazomicin, daily by IV (30 min) and comparator group with 750 mg/kg (n = 47) of levofloxacin IV daily for 5 consecutive days, respectively. The primary outcome of the study evaluated as microbiological eradication rate with TOC determined at 5–12 days after last dose of treatment in MITT and microbiological evaluable (ME) population groups. Microbiological eradication at TOC based on primary diagnosis baseline pathogen of the ME population in AP was 100% (2 is the number of patients with eradication at TOC/2 number of patients with the following primary diagnosis), 88.9% (16/18) and 80.0%(12/15), and in cUTI, it was 80.0% (4/5), 88.2 (15/17) and 83.3 (5/6), respectively, in all three groups. Number of patients with eradication at TOC to the number of patients infected with different pathogens for all three conditions were like for P. aeruginosa was 50% in case of 15 mg/kg group.[104] Hence, this study propound the administration of plazomicin either as 10 mg/kg or 15 mg/kg once daily for 5 days in patients with AP and other AP.

A Phase III clinical trial (NCT02486627), EPIC was a randomised multicentre, multinational, double-blind study comparing the efficacy and safety of plazomicin in comparison to meropenem with oral therapy of levofloxacin. A total of 609 participants with cUTI and PA were administered with plazomicin 15 mg/kg once daily and meropenem 1 g for every 8 h, through IV for 4–7 days followed with oral therapy with levofloxacin against ESBL-positive Enterobactericeae, E. coli, K. pneumoniae, Enterobacter cloacea and P. mirabilis.[105] MMITT values of Enterobactericeae were 97.3%(220/226), ESBL 35.0%(79/226), aminoglycoside non-susceptible 34.5%(78/226) in cUTI cases, and it was 100% (162/162), 17.35% (28/162) and 14.2%(23/162) in AP. Microbiological eradication rates at TOC for plazomicin were 86.9%(n = 93), for meropenem 75.6% (n = 90) in cUTI and 73.1%(n = 57) for plazomicin and 73.1%(n = 69) for meropenem in AP. Hence, plazomicin was well tolerated in both tested disease conditions with higher microbiological eradication rates and thus could be the drug of choice to treat MDR Enterobacteriaceae.


 ~ Conclusion Top


Although new agents are being developed, it is well known that efflux pumps play a major role in the AMR in P. aeruginosa. It will pose a great challenge for the development of any antipseudomonal agent to bypass this mechanism. This could be achievable by the use of efflux inhibitors as therapeutic purposes. Henceforth, efflux inhibitors for clinical use are the need of hour to achieve clinical success in the treatment of P. aeruginosa infections. Further, randomised controlled trials evaluating the syndrome-specific combination of agents would support improved clinical success rates.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

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2004 - Indian Journal of Medical Microbiology
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