Post on 11-Mar-2020
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