CARMELO IACOBELLO

UOC MALATTIE INFETTIVE

AOE CANNIZZARO

CATANIA

LA FOSFOMICINA

DISCLOSURES

MSD

CORREVIO

GILEAD

Fosfomicina - la più piccola molecola in clinica

La Fosfomicina è l’unico antibiotico della classe degli antibiotici epossidici, il cui gruppo chimico

epossidico gli conferisce l’attività battericida.

Meccanismo d’azione

La fosfomicina ha una modalità

d’azione che differisce da

quella di tutte le altre classi di

antibiotici senza evidenza di

resistenza crociata con altri

antibiotici.

Ha evidenziato attività

sinergica o additiva con molti

altri antibiotici.

La fosfomicina inibisce la fase

iniziale della biosintesi del

peptidogliacano della parete

cellulare batterica.

Interferisce nella formazione

della parete cellulare batterica

più precocemente rispetto a

antibiotici glicopeptidi e beta-

lattamici.

glycerol-3-phosphate transporter

(GlpT)

glucose-6-phosphate [G6P]

transporter (UhpT)

Tissue penetration – Bone and Soft Tissue

Tissue penetration: Bone and Soft Tissue

Microdialysis results: Concentration vs. time profiles of fosfomycin in plasma,

subcutaneous adopose tissue and metatarsal bone in severe DFI after a single dose of

100 mg/kg (n=9).

Fosfomycin achieves plasma levels in bone tissue 3h after start of infusion

Schintler et al. J Antimicrob Chemother 2009; 64: 574-8

Tissue penetration: Cerebrospinal fluid

Drain associated ventriculitis

6 patients in neurointensive care with drain associated ventriculitis.

3x8 g i.v. Cerebrospinal fluid levels measured with microdialysis

susceptible bacteria are covered despite working blood-brain-barrier

good tolerability despite very high dose (24 g)

Pfausler, B et al. J Antimicrob Chemother (2004)

Tissue penetration: Lung

Fosfomycin reaches nearly serum levels in lung tissue of critically ill patients.

A dose of 4 g is above MIC for highly susceptible pathogens (MIC≤16 µg/ml).

A dose of 3x8g may be neccessary for MIC=32µg/ml.

MIC90 ESBL E.coli

MIC90 S. aureus

Matzi et al. J Antimicrob Chemother 2010; 65: 995-98.

8 patients scheduled to undergo

elective thoracotomy due to severe

complications of bacterial

pneumonia

Extracellular concentrations of fosfomycin in lung tissue of septic patients

Fosfomycin: intracellular bactericidal activity against

Staphylococci

Intracellularly located Staphylococci within

granulocytes – persistence

Exposing to extracellular fosfomycin

corresponding to peak serum values in

humans – intracellular killing

Trautmann et al, Infection, 1992

Hirakawa et al, Frontiers in Microbiology, 2018

Fosfomycin activity increases under oxygen-limited conditions unlike other commonly used

antimicrobials such as β-lactams, fluoroquinolones and aminoglycosides

Cells grown anaerobically exhibit a higher expression of glpT encoding a glycerol-3-phosphate

transporter which is responsible for fosfomycin uptake, then lead to increased intracellular

accumulation of the drug

Increased antibacterial activity of fosfomycin to P. aeruginosa under anaerobic conditions is

attributed to elevated expression of GlpT, then leads to increased uptake of the drug.

glycerol-3-phosphate

transporter (GlpT)

Fosfomycin competes for the same renal binding sites as aminoglycosides

Urinary levels of the proximal tubular enzymes NAG and AAP after 14 days treatment with

tobramycin/colomycin/fosfomycin were significantly lower than those recorded after treatment with

tobramycin/colomycin alone. NAG and AAP reflect tubular structural integrity

Fosfomycin offers some protection against the immediate proximal tubular injury

caused by tobramycin

The renoprotective effect of concomitant fosfomycin in the treatment of pulmonary

exacerbations in cystic fibrosis through plasma dosage of NAG and AAP

Al-Aloul et al, Clinical Kidney Journal, 2019

Alanino-amino-

PEPTIDASIN-Acetil-

GLUCOSAMINIDASI

Dinh A. et al., Scandinavian Journal of Infectious Diseases, 2012

Prospective cohort study: 116 assessable patients

Main indications: ostheoarthritis, RTI, cUTI, BSI

FOS dosage: most often 4g, 3/4 times a day; variations according to weight/renal failure

Most frequently involved pathogens:

Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus (MRSA+MRCNS)

Clinical outcome favourable in 76,8% of cases (76/99)

Prospective cohort study: 116 assessable patients

Main indications: ostheoarthritis, RTI, cUTI, BSI

FOS dosage: most often 4g, 3/4 times a day; variations according to weight/renal failure

Most frequently involved pathogens:

Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus (MRSA+MRCNS)

Clinical outcome favourable in 76,8% of cases (76/99)

Fosfomycin: Efficacy against infections caused by MDR

Esito clinico globale

76.8% (76/99)

Esito microbiolgico globale

79.5% (66/83)

Patogeni ESBL

86.1 (31/36)

Panresistenti

89.4% (17/19)

MDR

78.1 (41/55)

Reference Country Strains MIC50 MIC90 % S

Endimiani

AAC 2010 USA68 KPC-Kp

(PDR/XDR)16 64

93

(87)

Livermore IJAA 2011

UK81 CRE

Various mechanisms of

resistance

32 >128 61

Kaase

JCM 2014 Germany107 CRE

Various mechanisms of

resistance

8 512 78

Rizek

JIC 2015 Brazil 50 KPC-Kp 16 32 95-100?

Rodriguez-Avial IJAA 2015

Spain164 CRE

Various mechanisms of

resistance

16 256 71(66-100)

Vasoo

AAC 2015 USA Singapore173 CRE

Various mechanisms of

resistance

NR NR 7871-100%

Attività di Fosfomicina Vs. CRE

75 patients with Gram-positive bacteremia treated with fosfomycin combination. 61/75 weresuccessfully treated (81%)

Daptomycin plus fosfomycin was the most effective combination (93% success rate)

Treatment with Fosfomycin was safe and side effects were minor

Time-kill studies showed increased activity of FOS combination, with FOS/DAP being the most active

Coronado-Alvarez et al, Enferm Infecc Microbiol Clin. 2017

Clinical efficacy of Fosfomycin combination against a

variety of gram-positive cocci

Source: Lee YC et al. BMC Pharmacology and Toxicology, 2019

A study on combination of daptomycin with selected antimicrobial agents: in vitro

synergistic effect of MIC value of 1 mg/L against MRSA strains

Synergism of Fosfomycin and Daptomycin

Synergistic effects of daptomycin in combination with other antibiotics against MRSA with an MIC (DAP)=1 mg/L

were measured using the microbroth checkerboard assay in vitro and evaluated using the fractional inhibitory

concentration index

A total of 100 MRSA isolates was tested. Isolates susceptibility: 100% to LIN, 85% to FOS, 8% to GEN, 69% to

RIF

The combination of daptomycin plus fosfomycin may be an effective therapeutic option for MRSA infection

Synergism of Fosfomycin and Daptomycin on DAP-resistant VRE

Lingscheid et al, Antimicrobial Agents and Chemotherapy, 2015;

Hall Snyder et al, Antimicrobial Agents and Chemotherapy, 2016

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro

Pharmacokinetic-Pharmacodynamic Model

The addition of fosfomycin resulted in a further reduction of cell surface charge, which is a

plausible explanation for the enhanced killing demonstrated when combined with daptomycin

The combination of DAP plus FOF may provide improved killing against VRE (including DAP-

resistant strains) through modulation of cell surface charge

I ceppi più suscettibili hanno carica di superficie negativa e questo rende l’azione

della Daptomicina più potente e sinergica, con meccanismo molto simile alla

Oxacillina+Daptomicina

Mortality Associated with Bacteremia Due to Colistin-Resistant

Klebsiella pneumoniae with High-Level Meropenem Resistance

Combination therapy is associated with reduced mortality in patients with bacteremia due to colistin-resistant KPC-producing Klebsiella pneumoniae

with high-level carbapenem resistance in patients with septic shock

Avoiding the use of carbapenems may also reduce the selecting pressure in centers with ongoing transmission of KPC-producing Klebsiella pneumoniae.

Fosfomycin in carbapenem-sparing regimens Machuca et al, AAC, 2017

Mortality Associated with Bacteremia Due to Colistin-Resistant

Klebsiella pneumoniae with High-Level Meropenem Resistance

Fosfomycin in carbapenem-sparing regimens

combination therapy has a protective effect for mortality among patients with septic shock.

Machuca et al, AAC, 2017

Synergy of Fosfomycin with carbapenems, colistin, netilmicin and tigecycline against MDR

Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa clinical isolates

Samonis, Eur J Clin Microbiol Infect Dis, 2011

Tumbarello et al, Clin Infect Dis., 2019

Fosfomycin vs Acinetobacter baumanni

94 patients infected with CR Acinetobacter baumannii randomized to receive colistin alone

or colistin plus fosfomycin for 7 to 14 days.

Most of the study patients were elderly, had chronic underlying diseases, received

mechanical ventilators, and developed ventilator-associated pneumonia (VAP)

Fosfomycin dosage was 4 g every 12 h

The patients who received combination therapy had a significantly more favorable

microbiological response and a trend toward more favorable clinical outcomes and lower

mortality than those who received colistin alone.

Sirijathupat, Antimicrobial Agents and Chemotherapy, 2014

Preliminary Study of Colistin versus Colistin plus Fosfomycin for Treatment of Carbapenem-

Resistant Acinetobacter baumannii Infections

Fosfomycin vs Acinetobacter baumanni

Sharma, J Antimicrob Chemother, 2017; Sirijathupat, Antimicrobial Agents and Chemotherapy, 2014

The colistin-susceptible isolates showed the highest synergistic effect with

fosfomycin-amikacin against pan resistant Acinetobacter baumanni

Against carbapenem resistant Acinetobacter baumanni clinical isolates:

surprisingly, the combination of imipenem and fosfomycin was the most

effective in this study against A. baumannii, which is intrinsically resistant

to fosfomycin.

Combined use of sulbactam and fosfomycin may provide an alternative

therapeutic option for CRAB infections.

Leite et al, 2016, Plos One

Singkham et al, 2018, Diagn Microbiol Infect Dis

Santimaleeworagun et al, 2011, Southeast Asian J Trop Med

Public Health

Synergism between Fosfomycin and other antimicrobial agents versus PDR and Carbapenem-

Resistant Acinetobacter baumanni

FOSFOMYCIN+AMIKACIN

FOSFOMYCIN+IMIPENEM

FOSFOMYCIN+SULBACTAM

Fosfomycin activity Vs. Biofilm in Orthopedic infection

Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-

Spectrum-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model.

fosfomycin + colistin

significant synergism, highest biofilm

activity, no bacterial regrowth

Corvec, Antimicrobial Agents and Chemotherapy ,March 2013 Volume 57 Number 3 p. 1421–1427

Management clinico-terapeutico

dell’endocardite in una paziente

complessa.

L. La Ferla, G. Liberti, G. Panto, M. Raspagliesi, R. Restivo, S. Sofia, G. Strano, G. Terranova, C. Iacobello U.O. Malattie Infettive Azienda Ospedaliera per l’Emergenza “Cannizzaro”

Anamnesi Patologica

Remota• D. P. donna di anni 83, ipertensione arteriosa, FAC in trattamento

con NAO

• Nel mese di Luglio 2018 sottoposta a TAVI per stenosi aortica

severa

• Da allora ripetuti ricoveri presso l’U.O. di Malattie Infettive di altro

Nosocomio per sepsi recidivanti da Pseudomonas aeruginosa

ultimo nel mese di Ottobre 2018 con indicazione al proseguimento

della terapia antibiotica domiciliare

• Allergie a diversi antibiotici: Amoxicillina/clavulanico, Meropenem,

Ciprofloxacina

Ricovero presso l’U.O. di

Malattie Infettive

• Ecocardiografia TT: protesi biologica in sede aortica

normofunzionante e normocontinente.• Very small (< 2 mm) vegetations, calcified mitral rings, thickened valves, absent or already

embolized vegetations might further lead to false negative results and false rejected PVE.Lee HS, J Cardiovasc Ultrasound. 2014;22:134–138.

Puls M. Eurointervention. 2013;8:1407–1418

Habib G,, et al. ESC guidelines for the management of infective endocarditis the task force for the management of infective endocarditis of the European Society of Cardiology (ESC) Eur Heart J.

2015;36:3075–3128

• PET: “…accumulo di tracciante di pertinenza dell’aorta ascendente

a livello del noto dispositivo protesico…”

• Valutazione CardioCH: in relazione all’età della paziente e delle

comorbilita’ non indicazioni al trattamento chirurgico

Ricovero presso l’U.O. di

Malattie Infettive

Gopichand P. et al. Infection and Drug Resistance 2019:12

30/09/2019

Continuous infusion of fosfomycin in

healthy volunteers

InfectoFos® Update - June 2019

Source: Matzneller et al, PosterECCMID, 2019

Fosfomycin administration: continuous infusion

II Ricovero presso l’U.O. di

Malattie Infettive• Eseguite emocolture seriate ed avviata terapia empirica ragionata

allergie a diversi antibiotici, isolamenti colturali precedenti, terapie già praticate, possibili drug-drug interactions

• Fosfomicina 4 g. ogni 6 ore associata a Ceftazidime 2 g. ogni 8 ore per 10 giorni.

• Remissione della febbre e normalizzazione degli indici di flogosi.

Terapia domiciliare

Fosfomicina 16 g. in infusione continua tramite pompa elastomerica (per 20 giorni).

+

Cefexime 400 mg 1 cp al dì

Dimissioni

• Rapido miglioramento delle condizioni cliniche generali della

paziente e degli esami di laboratorio (15 giorni di terapia e.v)

“Sepsi recidivante in paziente con nota infezione della protesi aortica

(TAVI) da P. aeruginosa con interessamento aortitico. Lesione

ipodensa al polo superiore della milza.”

• Proseguimento della terapia antibiotica domiciliare long-term

Minociclina 100 mg x 2 + Cefixime 400 mg die

EPIDEMIOLOGIA ED INCIDENZA

• L’incidenza dell’EI TAVI correlate varia tra lo 0,3% e il 3,4% a seconda delle casistiche (1-2-3)

• Più spesso l’etiologia è dovuta a gram-positivi. Meno frequente la presenza di Gram-negativi (4)

• La mortalità associata alla EI post-TAVI varia tra il 47% dei pazienti ospedalizzati e il 66% ad un anno

3)Amat-Santos IJ, Messika-Zeitoun D, Eltchaninoff H, et al. Infective endocarditis following transcatheter aortic valve implantation:results from a large multicenter registry. Circulation.

2015;131:1566–1574

2)Lee HS, Lee SP, Jung JH, et al. Infective endocarditis associated with transcatheter aortic valve replacement: potential importance of local trauma for a deadly nidus. J Cardiovasc Ultrasound.

2014;22:134–138.

1)Puls M, Eiffert H, Hünlich M, et al. Prosthetic valve endocarditis after transcatheter aortic valve implantation: the incidence in a single-centre cohort and reflections on clinical, echocardiographic and prognostic features.

Eurointervention. 2013;8:1407–1418

(4) Regueiro A, Linke A, Latib A, et al. Association between transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death. JAMA. 2016;316:1083–10892(4)

5 Van der Boon RM, Nuis RJ, Benitez LM, et al. Frequency, determinants and prognostic implications of infectious complications after transcatheter aortic valve implantation. Am J Cardiol. 2013;112:104–111