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 ~  Abstract
 ~ Introduction
 ~  Fosfomycin: Back...
 ~  Unique Mechanism...
 ~  Advantageous Pha...
 ~  Pharmacodynamic ...
 ~  Resistance to Fo...
 ~  Susceptibility T...
 ~  Fosfomycin In...
 ~  Clinical Evidenc...
 ~ Conclusion
 ~  References

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  Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 34  |  Issue : 4  |  Page : 416-420
 

Exploring the hidden potential of fosfomycin for the fight against severe Gram-negative infections


Department of Medical Services, Glenmark Pharmaceuticals Ltd., Mumbai, Maharashtra, India

Date of Submission28-Sep-2016
Date of Acceptance03-Oct-2016
Date of Web Publication8-Dec-2016

Correspondence Address:
P V Saiprasad
Department of Medical Services, Glenmark Pharmaceuticals Ltd., Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.195379

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 ~ Abstract 

Gram-negative resistance is a serious global crisis putting the world on the cusp of 'pre-antibiotic era'. This serious crisis has been catalysed by the rapid increase in carbapenem-resistant Enterobacteriaceae (CRE). Spurge in colistin usage to combat CRE infections leads to the reports of (colistin and carbapenem resistant enterobacteriaceae) CCRE (resistance to colistin in isolates of CRE) infections further jeopardising our last defence. The antibacterial apocalypse imposed by global resistance crisis requires urgent alternative therapeutic options. Interest in the use of fosfomycin renewed recently for serious systemic infections caused by multidrug-resistant Enterobacteriaceae. This review aimed at analysing the recent evidence on intravenous fosfomycin to explore its hidden potential, especially when fosfomycin disodium is going to be available in India. Although a number of promising evidence are coming up for fosfomycin, there are still areas where more work is required to establish intravenous fosfomycin as the last resort antibacterial for severe Gram-negative infections.


Keywords: CCRE, carbapenem-resistant Enterobacteriaceae, fosfomycin disodium, global resistance crisis, serious systemic infections


How to cite this article:
Saiprasad P V, Krishnaprasad K. Exploring the hidden potential of fosfomycin for the fight against severe Gram-negative infections. Indian J Med Microbiol 2016;34:416-20

How to cite this URL:
Saiprasad P V, Krishnaprasad K. Exploring the hidden potential of fosfomycin for the fight against severe Gram-negative infections. Indian J Med Microbiol [serial online] 2016 [cited 2017 Feb 23];34:416-20. Available from: http://www.ijmm.org/text.asp?2016/34/4/416/195379



 ~ Introduction Top


Gram-negative resistance is a serious global crisis putting the world on the cusp of 'pre-antibiotic era'. This serious crisis has been catalysed by the rapid increase in carbapenem-resistant Enterobacteriaceae (CRE). Spurge in colistin usage to combat CRE infections leads to the reports of CCRE (resistance to colistin in isolates of CRE) infections further jeopardising our last defence. The antibacterial apocalypse imposed by global resistance crisis requires urgent alternative therapeutic options.[1],[2]


 ~ Fosfomycin: Background Top


Fosfomycin, a phosphonic acid derivative (cis-1, 2-epoxypropyl phosphoric acid; C3H7 PO4), is a reemerging antibiotic. Fosfomycin represents epoxide class of antibiotics, and no other antibiotic belongs to this class currently. In 1969, then called phosphonomycin, was isolated from strains of Streptomyces (Streptomyces fradiae, Streptomyces wedomorensis and Streptomyces viridochromogenes). Today, fosfomycin is produced synthetically. Fosfomycin has the smallest molecular mass (138 Da) of existing antibiotics. Formulation with different salts such as calcium, trometamol and disodium is available across the globe. The intravenous formulation is a more water-soluble salt of disodium (C3H5O4 PNa2; MW 182.03 Da).[3],[4],[5]

Interest in the use of fosfomycin renewed recently for serious systemic infections caused by multidrug-resistant Enterobacteriaceae. The intravenous formulation is licensed in few countries for use in serious systemic infections (e.g., complicated urinary tract infections, nosocomial lower respiratory tract infections, acute osteomyelitis, bacterial meningitis and bacteraemia).[6]


 ~ Unique Mechanism of Action Top


Andrews et al. had standardised in vitro testing of fosfomycin in 1983 after 14 years of its purification.[7] Fosfomycin has a broad spectrum of activity against various Gram-positive and Gram-negative bacteria including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and CRE. Among non-fermenters, although Acinetobacter is intrinsically resistant to fosfomycin, there is in vitro activity towards Pseudomonas.[8],[9]

Fosfomycin inhibits peptidoglycan synthesis at a step earlier than beta-lactam or glycopeptide antibiotics. It causes inactivation of the cytosolic N-acetylglucosamine enolpyruvyl transferase (Mur A), thereby preventing the formation of N-acetylmuramic acid from N-acetyl glucosamine and phosphoenolpyruvate which ultimately leads to bacterial cell lysis and death. It enters into the bacterial cytoplasm via glycerol-3-phosphate transporter (Glp T) or glucose-6-phosphate (G6P) transporter (Uhp T) located on the cell wall. The chemical structure of fosfomycin mimics both glycerol-3-phosphate and G6P, which are transported under normal conditions through Glp T and Uhp T. Cyclic adenosine monophosphate (cAMP) regulates the expression of these transporters where G6P acts as an inducer. Hence, G6P is required for full expression of bactericidal activity of fosfomycin.[3],[4],[5]


 ~ Advantageous Pharmacokinetics of Intravenous Fosfomycin Top


Fosfomycin disodium displays a dose-proportional pharmacokinetic profile. Fosfomycin is a highly hydrophilic molecule with serum protein binding around 3% allowing good tissue availability while lower molecular mass ensures its wide diffusibility. After intravenous administration, fosfomycin concentrations in the blood undergo fast disposition phase followed by slow distribution phase.[10] A cumulative effect is observed after multiple doses. Elimination half-life of fosfomycin disodium is 1.5–2 h.[11],[12],[13] The Cmax observed in studies with standard intravenous dosing ranges from 200 to 644 mg/L, which is 10–20 times higher than with oral formulation.[5],[14] The volume of distribution at steady state is reported between 18 and 27 L.[3] Intravenous fosfomycin able to achieve sufficient concentration at various body sites including lung, cerebrospinal fluid, bone, muscle, gallbladder, the common bile duct, the appendix, ascitic fluid heart valves with site to serum concentration ratio between 0.04 and 0.71.[3],[14] Fosfomycin does not undergo enterohepatic circulation; hence, dose modification is not warranted in hepatic insufficiency.[3] Around 93% is excreted unchanged in urine through glomerular filtration, of which 50%–60% excretion will occur in first 3–4 h of fosfomycin administration.[3] It does not undergo tubular secretion. Dose adjustment of 70%, 60%, 40% and 20% of the total daily dose is recommended for creatinine clearance of 40, 30, 20 and 10 ml/min, respectively, is recommended.[4] Dosing of intravenous fosfomycin for serious systemic infections is not defined as a consensus. In clinical practice, fosfomycin disodium is used between 12 and 24 g as 2–4 divided doses. For creatinine clearance below 40 ml/min, reduction of the daily dose is required. In patients undergoing intermittent haemodialysis, additional 2 g dose after each session is recommended. In continuous renal replacement therapy, no dose adjustment required.[4]


 ~ Pharmacodynamic Index: Functional Area under Curve (Fauc)/minimum Inhibitory Concentration and not T>Mic for Enterobacteriaceae Top


The pharmacodynamic index that best links drug exposure with antimicrobial efficacy is important for an optimising clinical use of intravenous fosfomycin. Historically, fosfomycin has been considered an agent that exhibits time-dependent antibacterial activity. Recently, Docobo-Pérez in hollow-fibre infection model with clinical extended-spectrum beta-lactamases-producing Escherichia coli strains showed same rate and depth of bacterial killing after exposure to a various dosing regimen of intravenous fosfomycin.[6] Both regimens 8 g/q8 h (24 g/day) and 24 g q24 h completely suppressed resistance amplification. This evidence corroborates that the fAUC/minimum inhibitory concentration (MIC) ratio as a pharmacodynamic index.[6] Fosfomycin has demonstrated the post-antibiotic effect of 3.4–4.7 h. against E. coli and Proteus.[15]


 ~ Resistance to Fosfomycin in Clinical Setting Is a Complex and Uncommon Process Top


The unique mechanism of action makes cross-resistance unlikely though many mechanisms of resistance have been described in vitro. Resistance observed among clinical isolates is primarily due to chromosomal than plasmid-mediated.[16] Acquired resistant mechanisms mainly include blockage in the uptake pathways.[17] This is peculiarly observed in E. coli as a chromosomal mutation in Glp T and Uhp T genes, which encode fosfomycin transporters.[18],[19] Lower cAMP levels leading to downregulation of fosfomycin transporters due to mutations in cya A and pts I genes is also observed.[20] Modification of Mur A (amino acid substitution at the binding site) reduces the affinity of fosfomycin. Overexpression of the target (Mur A) also leads to resistance towards fosfomycin.[21] Plasmid-mediated fosfomycin-modifying enzymes (Fos A, Fos B) known to catalyse inactive adduct with fosfomycin.[22] Kinases (Fom A, Fom B) cause fosfomycin degradation through phosphorylation.

In Japan, where fosfomycin has been used clinically for the treatment of systemic infections for around 20 years, there was not much change in susceptibility of E. coli and Pseudomonas aeruginosa isolates.[23] Similarly, many European studies have not shown much difference in fosfomycin susceptibility over the years in clinical practice.[23] This subtly highlights the underlying biological cost in the process of resistance development.


 ~ Susceptibility Testing for Fosfomycin in the Setting of Intravenous Use Top


There is much ambiguity pertaining to susceptibility breakpoints of fosfomycin. The Clinical and Laboratory Standards Institute (CLSI) 2016 has defined the fosfomycin breakpoints for E. coli urinary isolates for oral formulation (fosfomycin trometamol). Breakpoints are ≤64 and ≥256 for sensitive and resistant, respectively.[24] CLSI breakpoints are higher as compared to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, because in urine, fosfomycin has been observed to reach levels up to 4000 µg/ml after a single 3 g dose of oral granules (fosfomycin trometamol); whereas the EUCAST 2016 has defined breakpoints for both oral and intravenous formulation. The EUCAST breakpoints for intravenous formulation are based on the dose of 4–8 g TDS. Clinical breakpoints for Enterobacteriaceae are ≤32 and >32 for sensitive and resistant isolates, respectively. Even though clinical breakpoints are not defined for Pseudomonas, the ecological cut-off value of 128 mg/L is mentioned and can be used as a reference in interpreting the results.[25]

The practical problem is with automated systems used for culture and sensitivity interpretation. The panel in this system generally has interpretation criteria as per the CLSI for urinary isolates only hence one cannot use them for giving the report to clinicians. One can use gradient MIC strips incorporated with 25 µg of G6P and interpret as per the EUCAST breakpoints for infections other than lower urinary tract infection.[25]


 ~ Fosfomycin In Vitro Susceptibility and Synergy Studies Top


Monotherapy with fosfomycin has been associated with regrowth of heteroresistant mutant population; hence knowing the synergy with other antimicrobials becomes utmost important. Chitra et al.[26] have performed MIC interpretation of fosfomycin for 200 CRE isolates. As per the EUCAST, 35.7% of Klebsiella sp. and 95.1% of E. coli were susceptible to fosfomycin. In another study by Rajenderan et al. in 418 Enterobacteriaceae clinical isolates from both community and hospital settings from urine, blood and sputum, fosfomycin showed 90% inhibition of the isolates.[27] In Livermore et al.'s study, fosfomycin found to be active against 41/85 (60.5%) isolates. As per the carbapenem-resistance mechanisms, 76% NDM, 77% IMP, 57% Oxa-48, 54% KPC isolates were susceptible to fosfomycin.[28]

In Samonis et al.'s study,[29] when fosfomycin was tested with imipenem, meropenem, doripenem, colistin, netilmicin or tigecycline against fifty KPC isolates, synergy was noted for 30%–74%. A time-kill by Souli et al. for fosfomycin-based combinations against KPC isolates reported 65% synergy with meropenem, 12% synergy with colistin and indifferent activity with gentamicin. Antagonism was not observed in any of the combinations.[30]

Albur et al. evaluated the combination of colistin and fosfomycin against six well-characterised NDM-1-producing Enterobacteriaceae to assess the activity of single-agent versus combination and also to assess the risk of emergence of secondary resistance by deploying clinically relevant dosage regimens of colistin and fosfomycin. Single chamber in vitro Pk/Pd model simulating clinical dosing regimen applied over 96 h. Rapid bactericidal observed at all concentrations against susceptible strains, which lasted >48 h with no detectable regrowth at peak concentrations. An increased antibacterial efficacy was evident in the combination up to the trough concentration against fosfomycin susceptible and up to 12 h against fosfomycin-resistant isolates.[31] This study for the first time demonstrated superior bactericidal activity of colistin and fosfomycin combination against NDM-1 producing Enterobacteriaceae isolates with suppression of heteroresistant mutant populations. Above in vitro evidence highlights the potential role of fosfomycin against resistant Gram-negative organisms, especially CRE including NDM-1 as a combination.


 ~ Clinical Evidence in Resistant Gram-Negative Infections Top


Clinical evidence on fosfomycin in resistant Gram-negative infections is limited but promising. Michalopoulos et al. used fosfomycin in 11 patients with nosocomial carbapenemase-producing Klebsiella pneumoniae (CPKP) infections. The mean APACHE-II score was 23.4. Intravenous fosfomycin was given as 2–4 g/6 hourly in combination with colistin (n = 6), gentamicin (n = 3), piperacillin-tazobactam (n = 1) in 11 patients for 14 ± 5.6 days. Good clinical and microbiological outcome with all-cause mortality of 18% was observed.[32] Mortality is significantly less as compared to average mortality with invasive CRE infections (~50%).

A prospective study was conducted by Hellenic study group finding the outcome of fosfomycin in extensively drug-resistant and pandrug-resistant (PDR) Gram-negative infections. Fifteen Intensive Care Units enrolled in the study. Sixty-five per cent of the study population was in severe sepsis or septic shock. Resistance profile of clinical isolates was CPKP (85%), VIM-2 (35%) and PDR (36.6%). The median dose of intravenous fosfomycin was 24 g/day for 14 days and used in combination with colistin (66%), meropenem (25%), tigecycline (39%) and gentamycin (31%). 54% successful clinical outcome at 14 days with 565 bacterial eradication was observed. Furthermore, resistance development during therapy, which has been a matter of concern in previous studies, did not (3/66) occur frequently.[33]

There is an interesting case series from India by Mukherjee et al., where fosfomycin combination was used in CCRE infections. Four critically ill patients with fosfomycin only sensitive K. pneumoniae infection (colistin MIC ≥4) started on intravenous fosfomycin (2 g 8 hourly) with meropenem (2 g 8 hourly) for an average duration of 10 days. Three out of four patients survived.[34] These evidence suggest the definite place of intravenous fosfomycin in the management of severe Gram-negative infection.


 ~ Conclusion Top


Although a number of promising evidence are coming up for fosfomycin, there are still areas where more work is required to establish intravenous fosfomycin as the last resort antibacterial for severe Gram-negative infections.

  • Along with harmonisation current breakpoints, the EUCAST and CLSI appear to be high for the treatment of serious systemic infections. Furthermore, breakpoints for Pseudomonas sp. need to be defined urgently
  • Dose of fosfomycin requires to be defined for serious infections where probably higher daily dosages (24 g/day) may be required to prevent heteroresistant mutant selection
  • Well controlled, randomised study comparing fosfomycin versus colistin as mono and combination therapy in a critically ill population with resistant Gram-negative infection will identify optimal regimens of fosfomycin.


Until above need gaps are clear, we believe that fosfomycin should not be used as monotherapy to treat severe systemic infections.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

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Falagas ME, Kanellopoulou MD, Karageorgopoulos DE, Dimopoulos G, Rafailidis PI, Skarmoutsou ND, et al. Antimicrobial susceptibility of multidrug-resistant Gram negative bacteria to fosfomycin. Eur J Clin Microbiol Infect Dis 2008;27:439-43.  Back to cited text no. 16
    
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22.
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Samonis G, Maraki S, Karageorgopoulos DE, Vouloumanou EK, Falagas ME. Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates. Eur J Clin Microbiol Infect Dis 2012;31:695-701.  Back to cited text no. 29
    
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Souli M, Galani I, Boukovalas S, Gourgoulis MG, Chryssouli Z, Kanellakopoulou K, et al. In vitro interactions of antimicrobial combinations with fosfomycin against KPC-2-producing Klebsiella pneumoniae and protection of resistance development. Antimicrob Agents Chemother 2011;55:2395-7.  Back to cited text no. 30
    
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Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: A prospective evaluation. Clin Microbiol Infect 2010;16:184-6.  Back to cited text no. 32
    
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Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents 2014;43:52-9.  Back to cited text no. 33
    
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