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Published in: Drugs 9/2017

01-06-2017 | Leading Article

The Potential Role of Fosfomycin in Neonatal Sepsis Caused by Multidrug-Resistant Bacteria

Authors: Grace Li, Joseph F. Standing, Julia Bielicki, William Hope, John van den Anker, Paul T. Heath, Mike Sharland

Published in: Drugs | Issue 9/2017

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Abstract

The broad-spectrum activity of fosfomycin, including against multidrug-resistant (MDR) strains, has led to renewed interest in its use in recent years. Neonatal sepsis remains a substantial cause of morbidity and mortality at a global level, with evidence that MDR bacteria play an increasing role. The evidence for use of fosfomycin in neonatal subjects is limited. We summarise current knowledge of the pharmacokinetics and clinical outcomes for the use of fosfomycin in neonatal sepsis and issues specific to neonatal physiology. While fosfomycin has a broad range of coverage, we evaluate the extent to which it may be effective against MDR bacteria in a neonatal setting, in light of recent evidence suggesting it to be most effective when administered in combination with other antibiotics. Given the urgency of clinical demand for treatment of MDR bacterial sepsis, we outline directions for further work, including the need for future clinical trials in this at-risk population.
Literature
1.
2.
Laxminarayan R, Matsoso P, Pant S, et al. Access to effective antimicrobials: a worldwide challenge. Lancet. 2016;387:168–75.CrossRefPubMed
3.
Seale AC, Head MG, Fitchett EJA, et al. Neonatal infection: a major burden with minimal funding. Lancet Glob Health. 2015;3(11):e669–80.CrossRefPubMed
4.
Synnes A, Luu TM, Moddemann D, On behalf of the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network, et al. Determinants of developmental outcomes in a very preterm Canadian cohort. Arch Dis Child Fetal Neonatal Ed. 2017;102:F234–5.
5.
Dong Y, Speer CP. Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed. 2015;100:F257–63.CrossRefPubMed
6.
Russell ARB, Kumar R. Early onset neonatal sepsis: diagnostic dilemmas and practical management. Arch Dis Child Fetal Neonatal Ed. 2015;100:F350–4.CrossRef
7.
Stoll ABJ, Hansen NI, Watterberg KL, et al. Early onset neonatal sepsis : the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817–26.CrossRefPubMedPubMedCentral
8.
Tsai M, Hsu J, Chu S, et al. Incidence, clinical characteristics and risk factors for adverse outcome in neonates with late-onset sepsis. Paediatr Infect Dis J. 2014;33(1):7–13.CrossRef
9.
Tsai L, Chen Y, Tsou K. The impact of small-for-gestational-age on neonatal outcome among very-low-birth-weight infants. Pediatr Neonatol. 2015;56(2):101–7.CrossRefPubMed
10.
Vergnano S, Menson E, Kennea N, et al. Neonatal infections in England: the NeonIN surveillance network. Arch Dis Child Fetal Neonatal Ed. 2011;96(1):F9–14.CrossRefPubMed
11.
12.
Lutsar I, Trafojer UMT, Heath PT, et al. Meropenem vs standard of care for treatment of late onset sepsis in children of less than 90 days of age: study protocol for a randomised controlled trial. Trials. 2011;12(1):215.CrossRefPubMedPubMedCentral
13.
Hornik CP, Herring AH, Benjamin DK, et al. Adverse events associated with meropenem versus imipenem/ cilastatin therapy in a large retrospective cohort of hospitalized infants. Pediatr Infect Dis J. 2013;32(7):748–53.CrossRefPubMedPubMedCentral
14.
Cailes B, Vergnano S, Kortsalioudaki C, et al. The current and future roles of neonatal infection surveillance programmes in combating antimicrobial resistance. Early Hum Dev. 2015;91(11):613–8.CrossRefPubMed
15.
Russell AB, Sharland M, Heath PT. Improving antibiotic prescribing in neonatal units: time to act. Arch Dis Child Fetal Neonatal Ed. 2012;97(2):F141–6.CrossRefPubMed
16.
Simon A, Tenenbaum T. Surveillance of multidrug-resistant Gram-negative pathogens in high-risk neonates—does it make a difference? Pediatr Infect Dis J. 2013;32(4):407–9.CrossRefPubMed
17.
Folgori L, Livadiotti S, Carletti M, et al. Epidemiology and clinical outcomes of multidrug-resistant, Gram-negative bloodstream infections in a European tertiary pediatric hospital during a 12-month period. Pediatr Infect Dis J. 2014;33(9):929–32.CrossRefPubMed
18.
Bielicki JA, Lundin R, Sharland M, et al. Antibiotic resistance prevalence in routine bloodstream isolates from children’s hospitals varies substantially from adult surveillance data in Europe. Pediatr Infect Dis J. 2015;34(7):734–41.CrossRefPubMed
19.
Abdula N, Macharia J, Motsoaledi A, et al. National action for global gains in antimicrobial resistance. Lancet. 2016;387(10014):e3–5.CrossRefPubMed
20.
Downie L, Armiento R, Subhi R, et al. Community-acquired neonatal and infant sepsis in developing countries: efficacy of WHO’s currently recommended antibiotics—systematic review and meta-analysis. Arch Dis Child. 2013;98(2):146–54.CrossRefPubMed
21.
Le Doare K, Bielicki J, Heath PT, et al. Systematic review of antibiotic resistance rates among Gram-negative bacteria in children with sepsis in resource-limited countries. J Pediatr Infect Dis Soc. 2015;4(1):11–20.CrossRef
22.
Investigators of the Delhi Neonatal Infection Study (DeNIS) collaboration. Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study. Lancet Glob Health. 2016;4(10):e752–60.CrossRef
23.
Hendlin D, Stapley EO, Jackson M, et al. Phosphonomycin, a new antibiotic produced by strains of streptomyces. Science. 1969;166:122–3.CrossRefPubMed
24.
Castañeda-García A, Blázquez J, Rodríguez-Rojas A. Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance. Antibiotics. 2013;16(2):217–36.CrossRef
25.
Kahan FM, Kahan JS, Cassidy PJ, et al. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci. 1974;235:364–86.CrossRefPubMed
26.
Takahata S, Ida T, Hiraishi T, et al. Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli. Int J Antimicrob Agents. 2010;35(4):333–7.CrossRefPubMed
27.
Cao XL, Shen H, Xu YY, et al. High prevalence of fosfomycinresistancegene fosA3 in bla CTX-M-harbouring Escherichia coli from urine in a Chinese tertiary hospital during 2010–2014. Epidemiol Infect. 2016;12:1–7.
28.
Engel H, Gutiérrez-Fernández J, Flückiger C, et al. Heteroresistance to fosfomycin is predominant in Streptococcus pneumoniae and depends on the murA1 gene. Antimicrob Agents Chemother. 2013;57(6):2801–8.CrossRefPubMedPubMedCentral
29.
Molina MA, Olay T, Quero J. Pharmacodynamic data on fosfomycin in underweight infants during the neonatal period. Chemotherapy. 1977;23:217–22.CrossRefPubMed
30.
Guggenbichler JP, Kienel G. Fosfomycin, a new antibiotic drug. Pediatr Padol. 1978;13(4):429–36.
31.
Guibert M, Magny JF, Poudenx F, et al. Comparative pharmacokinetics of fosfomycin in the neonate: 2 modes of administration. Pathol Biol. 1987;35(5):750–2.PubMed
32.
Suzuki S, Murayama Y, Sugiyama E, et al. Dose estimation for renal-excretion drugs in neonates and infants based on physiological development of renal function. Yakugaku Zasshi. 2009;129(7):829–42.CrossRefPubMed
33.
Iwai N, Nakamura H, Miyazu M, et al. A study of the absorption and excretion of fosfomycin sodium in children [in Japanese]. Jpn J Antibiot. 1991;44(3):345–56.
34.
Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67–76.CrossRefPubMed
35.
Andrews JM, Baquero F, Beltran JM, et al. International collaborative study on standardization of bacterial sensitivity to fosfomycin. J Antimicrob Chemother. 1983;12(4):357–61.CrossRefPubMed
36.
Pfausler B, Spiss H, Dittrich P, et al. Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis. J Antimicrob Chemother. 2004;53(5):848–52.CrossRefPubMed
37.
Sauermann R, Karch R, Langenberger H, et al. Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles. Antimicrob Agents Chemother. 2005;49(11):4448–54.CrossRefPubMedPubMedCentral
38.
Mazzei T, Cassetta MI, Fallani S, et al. Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections. Int J Antimicrob Agents. 2006;28(Suppl 1):S35–41.CrossRefPubMed
39.
Docobo-Pérez F, Drusano GL, Johnson A, et al. Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance. Antimicrob Agents Chemother. 2015;59(9):5602–10.CrossRefPubMedPubMedCentral
40.
Bergan T. Degree of absorption, pharmacokinetics of fosfomycin trometamol and duration of urinary antibacterial activity. Infection. 1990;18:S65–9.CrossRefPubMed
41.
Borgia M, Longo A, Lodola E. Relative bioavailability of fosfomycin and of trometamol after administration of single dose by oral route of fosfomycin trometamol in fasting conditions and after a meal. Int J Clin Pharmacol Ther Toxicol. 1989;27(8):411–7.PubMed
42.
Cree M, Stacey S, Graham N, et al. Fosfomycin-investigation of a possible new route of administration of an old drug. A case study. J Cyst Fibros. 2007;6(3):244–6.CrossRefPubMed
43.
Llorens J, Lobato A, Olay T. The passage of fosfomycin into the cerebrospinal fluid in children’s meningitis. Chemotherapy. 1977;23(S1):189–95.CrossRefPubMed
44.
Traunmüller F, Popovic M, Konz KH, et al. A reappraisal of current dosing strategies for intravenous fosfomycin in children and neonates. Clin Pharmacokinet. 2011;50(8):493–503.CrossRefPubMed
45.
De Cock RFW, Allegaert K, Schreuder MF, et al. Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. Clin Pharmacokinet. 2012;51(2):105–17.CrossRefPubMed
46.
Iarikov D, Wassel R, Farley J, et al. Adverse events associated with fosfomycin use: review of the literature and analyses of the FDA adverse event reporting system database. Infect Dis Ther. 2015;4(4):433–58.CrossRefPubMedPubMedCentral
47.
48.
49.
Taylor CG, Mascarós E, Román J, et al. Enteropathogenic E. coli gastroenterocolitis in neonates treated with fosfomycin. Chemotherapy. 1977;23(1):310–4.
50.
Rossignol S, Regnier C. Fosfomycin in severe infection in neonatology. Ann Pediatr. 1984;31(5):437–44.
51.
Algubaisi S, Buhrer C, Thomale UW, et al. Favorable outcome in cerebral abscesses caused by Citrobacter koseri in a newborn infant. IDCases. 2015;2(1):22–4.CrossRefPubMed
52.
Guillois B, Guillemin MG, Thoma M, et al. Neonatal pleuropulmonary staphylococcal infection with multiple abscesses of the liver. Ann Pediatr. 1989;36(10):681–4.
53.
Gouyon JB, François C, Semama D, et al. Nosocomial Staphylococcus epidermidis and Staphylococcus aureus septicemias in neonates. Ann Pediatr. 1990;37(1):21–5.
54.
Hepping N, Simon A. Fosfomycin in paediatric cancer patients: a feasible alternative to glycopeptides? Int J Antimicrob Agents. 2009;33(4):389.CrossRefPubMed
55.
Falagas ME, Giannopoulou KP, Kokolakis GN, et al. Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008;46(7):1069–77.CrossRefPubMed
56.
Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis. 2011;15:e732–9.CrossRefPubMed
57.
Vardakas KZ, Legakis NJ, Triarides N, et al. Susceptibility of contemporary isolates to fosfomycin: a systematic review of the literature. Int J Antimicrob Agents. 2016;47(4):269–85.CrossRefPubMed
58.
Yu X, Song X, Cai Y, et al. In vitro activity of two old antibiotics against clinical isolates of methicillin-resistant Staphylococcus aureus. J Antibiot. 2010;63(11):657–9.CrossRefPubMed
59.
Lu C, Liu C, Huang Y, et al. Antimicrobial susceptibilities of commonly encountered bacterial isolates to fosfomycin determined by agar dilution and disk diffusion methods. Antimicrob Agents Chemother. 2011;55(9):4295–301.CrossRefPubMedPubMedCentral
60.
61.
Chiquet C, Maurin M, Altayrac J, et al. Correlation between clinical data and antibiotic resistance in coagulase-negative Staphylococcus species isolated from 68 patients with acute post-cataract endophthalmitis. Clin Microbiol Infect. 2015;21(6):592.e1–8.
62.
Falagas ME, Maraki S, Karageorgopoulos DE, et al. Antimicrobial susceptibility of Gram-positive non-urinary isolates to fosfomycin. Int J Antimicrob Agents. 2010;35(5):497–9.CrossRefPubMed
63.
González JJ, Andreu A, Grupo de Estudio de Infección Perinatal, Sociedad Espanola de Enfermedades Infecciosas y MicrobiologiaClinica. Susceptibility of vertically transmitted Group B streptococci to antimicrobial agents [in Spanish]. Enferm Infecc Microbiol Clin. 2004;22(5):286–91.CrossRefPubMed
64.
Matthews PC, Barrett LK, Warren S, et al. Oral fosfomycin for treatment of urinary tract infection: a retrospective cohort study. BMC Infect Dis. 2016;16(1):556.CrossRefPubMedPubMedCentral
65.
Chen YT, Ahmad Murad K, Ng LS, et al. In vitro efficacy of six alternative antibiotics against multidrug resistant Escherichia coli and Klebsiella pneumoniae from urinary tract infections. Ann Acad Med Singapore. 2016;45(6):245–50.PubMed
66.
Ranjan A, Shaik S, Mondal A, et al. Molecular epidemiology and genome dynamics of New Delhi metallo-β-lactamase-producing extraintestinal pathogenic Escherichia coli strains from India. Antimicrob Agents Chemother. 2016;60(11):6795–805.CrossRefPubMedPubMedCentral
67.
Sahni RD, Balaji V, Varghese R, et al. Evaluation of fosfomycin activity against uropathogens in a fosfomycin-naive population in South India: a prospective study. Future Microbiol. 2013;8(5):67580.CrossRef
68.
Cheng A, Liu C, Tsai H, et al. Bacteremia caused by Pantoea agglomerans at a medical center in Taiwan, 2000–2010. J Microbiol Immunol Infect. 2013;46(3):187–94.CrossRefPubMed
69.
Pogue JM, Marchaim D, Abreu-Lanfranco O, et al. Fosfomycinactivity versus carbapenem-resistant Enterobacteriaceae and vancomycin-resistant Enterococcus, Detroit, 2008–10. J Antibiot. 2013;66(10):625–7.CrossRefPubMed
70.
Vanscoy B, Mccauley J, Bhavnani SM, et al. Relationship between fosfomycin exposure and amplification of Escherichia coli subpopulations with reduced susceptibility in a hollow-fiber infection model. Antimicrob Agents Chemother. 2016;60(9):5141–5.CrossRefPubMedPubMedCentral
71.
Nilsson AI, Berg OG, Aspevall O, et al. Biological costs and mechanisms of fosfomycin resistance in Escherichia coli. Antimicrob Agents Chemother. 2003;47(9):2850–8.CrossRefPubMedPubMedCentral
72.
Karageorgopoulos DE, Wang R, Yu XH, et al. Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in gram-negative pathogens. J Antimicrob Chemother. 2012;67(2):255–68.CrossRefPubMed
73.
Lara N, Cuevas O, Arroyo M, et al. Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli. J Antimicrob Chemother. 2010;65(11):2459–63.CrossRefPubMed
74.
Rodríguez-Avial I, Pena I, Picazo JJ, et al. In vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing Enterobacteriaceae strains. Int J Antimicrob Agents. 2015;46(6):616–21.CrossRefPubMed
75.
Walsh CC, Landersdorfer CB, McIntosh MP, et al. Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance. J Antimicrob Chemother. 2016;71(8):2218–29.CrossRefPubMed
76.
Sime FB, Johnson A, Whalley S, et al. Pharmacodynamics of aerosolized fosfomycin and amikacin against resistant clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a hollow-fiber infection model: experimental basis for combination therapy. Antimicrob Agents Chemother. 2016;61(1):pii: e01763–16.
77.
De Man P, Verhoeven BA, Verbrugh HA, et al. An antibiotic policy to prevent emergence of resistant bacilli. Lancet. 2000;355(9208):973–8.CrossRefPubMed
Metadata
Title
The Potential Role of Fosfomycin in Neonatal Sepsis Caused by Multidrug-Resistant Bacteria
Authors
Grace Li
Joseph F. Standing
Julia Bielicki
William Hope
John van den Anker
Paul T. Heath
Mike Sharland
Publication date
01-06-2017
Publisher
Springer International Publishing
Published in
Drugs / Issue 9/2017
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-017-0745-x

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