by author ESCMID Online Lecture Library

Transcription

1

2 The Karyatides at the Erechtheion Temple Devoted to the Women in the Audience

3

4 At the top of the Museum the Karyatides, watching you through the years to come

5 FOSFOMYCIN IN THE TREATMENT OF INFECTIONS BY CARBAPENEMASE- PRODUCING BACTERIA Helen Giamarellou 2/12/2011

6 Fosfomycin: An Old-New Antibiotic The increasing antimicrobial drug resistance of bacterial pathogens, together with the relative shortage of new antimicrobial agents, call for a new look at the therapeutic options. One of the alternative treatments for multidrugresistant pathogens is Fosfomycin.

7 Fosfomycin: The Revival of an Old Antibiotic! No Clinical Experience in MDR pathogens! Why?

8 Fosfomycin: An Old-New Antibiotic Fosfomycin was first discovered in Spain in 1969 from cultures of the Streptomyces species and was originally named fosfomycin. It has no structural relationship with other known classes of agents. It belongs to the class of phosphonic antibiotics. It has a broad antibacterial spectrum, targeting bacteria with mucopeptide synthesis by inhibiting phosphoenolpyruvate transferase, the first enzyme involved in the synthesis of peptidoglycan inhibing cell-wall synthesis. Raz R. CMI 2011

9 Fosfomycin: An Old-New Antibiotic Fosfomycin has the smallest molecular mass (138 Da) of existing antibiotics, which ensures extensive diffusibility. It is reasonably soluble in water and the drug substance is stable under normal storage conditions (2-3 years). Fosfomycin is also strongly polar and hence is a very soluble molecule. Therefore an advantageous molecule!

10 An Important Observation: Fosfomycin Modifies PBPs Production Will this properly of fosfomycin revert resistance of Streptococcus pneumoniae to Penicillin G and of MRSA strains to antistaphylococcal penicillins, whenever combined with β-lactams at the clinical level?

11 Fosfomycin: The Available Formulations Fosfomycin calcium Fosfomyin trometamol Fosfomycin disodium iv (vials of 1 or 2g) Infectofos (Infectopharm, Germany) Fosfocina (Laboratorios ERN, Spain) Dosage schedule 6-8g iv every 6-8 hours Per os 3g once daily

12 Fosfomycin has Become Available for many years in Spain, France, Germany, Austria, as well as in Japan, N. Africa, Turkey and Greece In the USA, the Food and Drug Administration has approved fosfomycin-trometamol only for the treatment of patients with uncomplicated cystitis (Monurol).

13 Fosfomycin: The Antimicrobial Spectrum Fosfomycin has a rapid bactericidal effect and a wide antibacterial spectrum including: Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant enterococci and Several Gram-negative pathogens. There is no cross-resistance with other antibiotics, and fosfomycin can be administered in combination with a number of other antimicrobial agents.

14 Susceptibility Break-points for Fosfomycin* CLSI EUCAST Sensitive 64μg/ml 32μg/ml Resistance >128μg/ml > 32μg/ml * S.O.S.: With the addition of glycose-6-phosphate Oteo J, et al. JAC 2009;64:712

15 The Significance of the Addition in Vitro of Glycose-6-phospate The determination of susceptibilities of fosfomycin requires the addition in vitro of glycose-6-phospate at concentrations of 25μg/ml, because: G-6-P is normally found in tissue at high levels permitting the complete expression of the antimicrobial activity of fosfomycin In red blood cells G-6-P levels range between μmol/l Increase in the activity of fosfomycin: 256 fold for E. coli and Enterobacter 128 fold for Klebsiella 62 fold for Citrobacter 16 fold for Staph aureus JAC 1983;11:467 AAC 2005;49:4448

16 The Antimicrobial Spectrum of Fosfomycin (MIC 90 μg/ml): Derived from Recent in Vitro Data (Gram-positives) Type of pathogen Old Studies Recent Studies S. aureus S. epidermidis na Enterococcus faecalis Streptococcus group A Streptococcus group B Streptococcus pneumoniae 8-16 na Popovic M, et al. EJCMID 2010;29:127

17 The Antimicrobial Spectrum of Fosfomycin (MIC 90 μg/ml): Derived from Recent in Vitro Data: Gram-negatives Type of pathogen Old Studies Recent Studies Enterobacter P. mirabilis Proteus spp. (indole pos.) Pseudomonas aeruginosa Serratia marcescens 8-16 na Hemophilus influenzae 2-4 na Bacteroides fragilis Inactive na Escherichia coli (ESBL+) 0, Klebsiella spp Popovic M, et al. EJCMID 2010;29:127

18 ACINETOBACTER SPP: INHERENTLY RESISTANT

19 In vitro Fosfomycin Activity Against ESBL(+) strains of E. coli Type of Antibiotic Percent Susceptible 71 strains: CTX-M 14 (+) Gentamicin 95,6% Nitrofurantoin 93,4% Fosfomycin 93,4% Hernãndez MS, et al. Rev Esp Quimioter 2009;22:25

20 Since 2004 until 2008 resistance to Fosfomycin against E. coli ESBL(+) increased from 2.2% to 21.7%. Simultaneously Fosfomycin consumption increased by 50%

21 Activity of Fosfomycin Against Greek ICU MDR Gram-Negative Microorganisms Sensitivities (μg/ml) Klebsiella pneumoniae (No 225) 73% 14% 6% Pseudomonas aeruginosa (No 289) 20% 35% 44% Acinetobacter baumannii (No 200) None None None Panagea Th, Giamarellou H. 2009

22 The Greek View of the Appropriate Definitions Based on the Chaos of Resistance Mechanisms 1. Pandrug Resistant (PDR): To all classes of antibiotics, since in the Greek language the prefix pan- means all or whole 2. Extensive Drug Resistant: To all classes of antibiotics except 1 or 2 3. Multidrug Resistant: Resistance to 3 classes of antibiotics Falagas ME, Karageorgopoulos DE. CID 2008;46:1121

23 An Outbreak of Infection Due to KPC-2-producing K. pneumoniae in a Greek University Hospital: Molecular Characterization, Epidemiology, and Outcomes. Souli M, Galani I, Antoniadou A, Papadomichelakis E, Poulakou G, Panagea T, Vourli S, Zerva L, Armaganidis A, Kanellakopoulou K, Giamarellou H. Colistin, Gentamicin and Fosfomycin were the only active in vitro antibiotic against 50 XDR Klebsiella pneumoniae strains Clin Infect Dis 2010;50:364

24 152 MDR: 93% susceptible to fosfomycin 75 XDR K. pneumoniae KPC(+): 92% susceptible to fosfomycin

25 In vitro activity of fosfomycin against blakpc-containing Klebsiella pneumoniae isolates, including strains nonsusceptible to tigecycline and/or colistin. 68 strains of KPC(+) Klebsiella pneumoniae: 93% susceptible to fosfomycin (agar dilution) MIC 50 = 16μg/ml MIC 90 = 64μg/ml 23 strains resistant to tigecycline or colistin: 87% susceptible to fosfomycin MIC 50 /MIC 90 = 32/128μg/ml 5 out of 6 PDR strains were susceptible to fosfomycin Endimiani A, et al. AAC 2010;54:526-9

26 In Vitro Interactions of Fosfomycin with other Antimicrobial Agents Against MDR Enterobacteriaceae and Pseudomonas aeruginosa: Conclusion out of 4 Studies Never Antagonism Against K. pneumoniae Synergy with Carbapenems in 30% to 78% of KPC(+) Unpredictable results with aminoglycosides, cephalosporins and ciprofloxacin ~35% synergistic results with colistin and tigecycline Against P. aeruginosa 47% to 73% synergistic results with carbapenems against Pseudomonas aeruginosa However, when given alone in the controls: 100% resistance development in Klebsiella strains Souli M, et al. AAC 2011;55:2995 Kastoris AC, et al. Eur J Clin Pharmacol 2010;66:359 Samonis B, et al. EJCMID 25 June 2011 Monden K, et al. J Infect Chemother 2002;8:2180

27 Electron microscopy data have shown that fosfomycin combined with ciprofloxacin induces bactriolysis in ciprofloxacinresistant P. aeruginosa isolates Yamada S, et al. Chemotherapy 2007;53:2002

28

29 Synergistic Interaction of Fosfomycin with Various Aminoglycoside

30 Parenteral Fosfomycin Dosage Schedule 4-6g iv 6 hourly or 8hourly However: It is arbitrary. Therefore based on Fosfomycin Safety the higher dosage should be preferred.

31 T1/2: 3.7 ± 2.2 h Parenteral Fosfomycin PK/PDs 4g iv: μg/ml 8g iv: μg/ml after a single iv dose of 8g C max Very low molecular weight It is not metabolized It is not protein binded advantage for non-inflamed tissues Bacteridal PAE: h for Enterobacteriaceae AUC: 929±280mg h/l Sauermann R, et al. AAC 2005;49:4448

32 Parenteral Fosfomycin PK/PDs It is excreted by glomerular filtration It is totally removed by hemofiltration fosfomycin should be given at the end of the session! Its structure is similar to hydroxyapatite (Important for bone infections!)

33 Fosfomycin Use in Specific Patient Groups In critically ill patients undergoing continuous venovenous haemofiltration, no adjustment in fosfomycin dosage is necessary. The presence of hepatic insufficiency does not necessitate any adjustments in fosfomycin dosage. The use of fosfomycin in pregnancy is not contraindicated (pregnancy category B), although it is known to cross the placenta. Data on human use of fosfomycin during lactation are lacking. Roussos N, et al. IJAA 2009;34:506

34 Lung Bronchical secrations Pleural fluid CSF Pharmacokinetics of Parenteral Fosfomycin in Different tissues Muscle and subcutaneous tissue Cardiac values Bone* Bile Gall-bladder Ascific fluid 12-16μg/ml (after 2g iv) 13.1μg/ml (after 4g iv) 42.6μg/ml (after 2g iv) >30μg/ml (after 5g iv) -in meningeal inflamation >90μg/ml- 50% to 70% of the corresponding serum levels μg/ml Clinically relevant concentration *In cortiral bone, concellous bone and post-osteomyelitis sequestrate there is a structural similarity between fosfomycin and the hydroxyapatife molecule! AAC 2005;49:4448 Roussos N, et al. IJAA 2009;34:506

35 The average concentration in pus was calculated to be 182 ±64 mg/liter at steady state, exceeding the MIC 50/90 s of several bacterial species which are commonly involved in abscess formation, such as streptococci, staphylococci, and Escherichia coli. Hereby. The exceptionally long mean half-life of fosfomycin of h in abscess fluid may favor its antimicrobial effect because fosfomycin exerts time-dependent killing. After an initial loading dose of 10 to 12 g, fosfomycin should be administered at doses of 8 g three times per day to reach sufficient concentrations in abscess fluid and plasma.

36 Fosfomycin Kinetics in CSF After 8g/8hourly in patients with external CSF drainage because of meningitis and under steady-state conditions: Cmax 38-62μg/ml Plausler B, et al. JAC 2004;53:846

37 Fosfomycin Kinetics Aquous humor levels without inflamation After 4g iv After 8g iv 28.3μg/ml 52-60μg/ml Forestier F, et al. Eur J Ophthalmol 1996;6:137

38 Fosfomycin: PK/PDs The main parameter: %T >MIC = 40% MIC Target attainment 8 μg/ml 98% 16 μg/ml 92% 32 μg/ml 61% Therefore if MICs 32μg/ml the highest doses should be given Roussos N, et al. IJAA 2009;34:506

39 FOSFOMYCIN: CLINICAL EXPERIENCE

40 Use of Parenteral Fosfomycin There have been reports of successful treatment of severe pneumonia in Denmark, staphylococcal and enterococcal meningitis in France, and methicillin-resistant Staphylococcus aureus infective endocarditis in Japan, using fosfomycin in combination with other antibiotics. However, these have been only case reports and it is not known how many times fosfomycin has been used for similar cases and failed.

41 Fosfomycin Use Beyond UTIs and GI Tract Infections: Literature Review 1604 patients from Spain, France, Germany and Austria 2-24g daily form 5-21 days mostly in combination with other antibiotics Cure rate:81.1% Improvement :2.9% Tolerance: GI symptoms 5.4% Skin rash 4% resistance development 3% P. aeruginosa10%

42 Intravenous Fosfomycin for the Treatment of Nosocomial Infections Caused By carbapenem- Resistant Klebsiella pneumoniae in Critically Ill Patients: a Prospective Evaluation. Fosfomycin at a dose of 2-4g/6hourly was given in combination with other active in vitro antibiotics in 11 patients for days Mortality 18,2% No side effects Michalopoulos A, et al. CMI 2009 Aug 20.

43 Fosfomycin Hellenic Study Group Preliminary Data: November patients hospitalized in the ICU APACHE II score: 20.5 (day of administration fosfomycin) Median age: 62 Severe sepsis + septic shoch: 65% Bacteremia: 55% / VAP: 20% XDR K. pneumuniae:70% Clinical improvement 7 th day: 50% Clinical improvement 14 th day: 20% Mortality 28 th day: 46% Superinfections: 7/16 (between day 7-14) Pontikis K, Karaiskos I, et al. 2011

44 Fosfomycin in the Therapy of Bacterial Meningitis Only for strains with MIC 4μg/ml: High dose of 8g iv/8 hours (fear of CSF antagonistic effect) Why? Never monotherapy to escape resistance JAC 2009;64:821 JAC 2008;57:931

45 Intravenous fosfomycin: Side Effects The most significant adverse effect related to the administration of fosfomycin disodium is a high sodium intake, which could be a limitation in patients with heart or renal failure: 1 g of intravenous fosfomycin brings 0.33 g (14.4 meq) of sodium, i.e. 24g= 345mEq Recently adverse effects associated with intravenous fosfomycin administered in 72 patients, i.e. mostly hypokalemia (25%), was reported. Michalopoulos AS, et al. IJAA 2011;37:82

46 Resistance Development to Fosfomycin Bacterial resistance to fosfomycin is usually chromosomally mediated. In rare instances, it may be plasmid mediated. Chromosomally mediated resistance occurs essentially because of mutations that interfere with the uptake transport systems of fosfomycin (rate 10-8 to 10-7 ), resulting in reduced intracellular concentrations of the drug in the target bacteria, i.e. the L-αglycerophosphate and hexose phosphate (Ann NY Acad Sci 1974;235:364).

47 THE STRANGE PROPERTIES OF FOSFOMYCIN

48 Use of Fosfomycin in Combination Drug Regimens to Escape Toxicity! Fosfomycin has been found in vivo to mitigate the toxicity of various co-administered antibiotics, for example nephrotoxicity related to aminoglycosides, glycopeptides or amphotericin B as well as ototoxicity related to aminoglycosides or polymyxin B. Roussos N, et al. IJAA 2009;34:506

49 The Strange Properties of Fosfomycin The reduction of nephro- and ototoxicity of aminoglycosides is attributed to the inhibition of their uptake by the epithelial cells of the renal tubes whereas fosfomycin protects the integrity of lysosomal membranes J Cyst Fibrs 2003;2:19

50 Fosfomycin and P. aeruginosa Biofilms It has the ability to penetrate into deep layers of newly formed or even mature biofilms along with enhancement of its antimicrobial activity under anaerobic conditions. The antimicrobial activity of fosfomycin in biofilms may be of particular clinical importance for the treatment of episodes of pulmonary exacerbation of cystic fibrosis, as has been shown in various relevant studies. Roussos N, et al. IJAA 2009;34:506

51 Immunomodulatory Effects of Fosfomycin Regarding the adaptive immune system: Fosfomycin has been shown to inhibit in vitro the activation of human B- and T-lymphocytes To decrease the production of pro-inflammatory cytokines [such as interleukin (IL)-1, IL-1, tumour necrosis factor-alpha (TNF) and IL-8)] To increase the production of other cytokines (IL-6 and IL-10) The clinical relevance of these findings has not been clarified Protection Against Sepsis Invade? Roussos N, et al. IJAA 2009;34:506

52 Immunomodulatory Effects of Fosfomycin Regarding the innate immune system: Fosfomycin has demonstrated to increase the susceptibility of certain bacteria to phagocytosis and particularly enhance the bactericidal function of neutrophils exhibiting intraphagocytic antibacterial activity. Roussos N, et al. IJAA 2009;34:506

53 Fosfomycin: Conclusions Un Unknown Antibiotic for the Treatment of MDR Gram-negative Infections Active in vitro against ESBL and Carbapenemase producing Enterobacteriaceae (Klebsiella pneumoniae!) and Pseudomonas aeruginosa as well as against MRSA and VRE Inactive inherently against Acinetobacter spp. Advantageous pharmacokinetics Dosage schedule: 6-8g iv/8 hourly Few clinical date in MDR infections: A prospective clinical trial is urgently required Does resistance develop in vivo under monotherapy? If yes, which is the best protective combination?