DOCSLIB.ORG

Inhibition of Class a and C Β-Lactamases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inhibition of Class a and C Β-Lactamases INHIBITION OF CLASS A AND C β-LACTAMASES: CHALLENGES AND PROMISE by SARAH MICHEL DRAWZ Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Adviser: Robert A. Bonomo, M.D. Department of Pathology CASE WESTERN RESERVE UNIVERSITY May 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS TABLE OF CONTENTS 1 LIST OF TABLES 3 LIST OF FIGURES 5 ACKNOWLEDGEMENTS 8 LIST OF ABBREVIATIONS 9 ABSTRACT 10 CHAPTER 1 - Introduction Overview 12 Mechanism of Action of β-Lactam Antibiotics 13 Resistance to β-Lactam Antibiotics 14 -Lactamases 16 Circumventing β-Lactamases 28 β-Lactamase Inhibitors in Clinical Practice 30 Inhibitor-Resistant Class A β-Lactamases 39 The Promise of Novel β-Lactamase Inhibitors 50 Inhibition of Metallo-β-Lactamases 76 Tables 78 Figures 82 CHAPTER 2 - The Role of SHV Asn276 in Clavulanate Resistance Introduction 94 Materials and Methods 97 Results 103 Discussion 107 Conclusion 114 Tables 116 Figures 121 CHAPTER 3 - Inhibition of ADC by Boronates and Carbapenems Introduction 126 Materials and Methods 128 Results 135 Discussion 141 Conclusion 148 Tables 150 Figures 153 CHAPTER 4 - Catalytic and Inhibitory Properties of the Pseudomonas aeruginosa AmpC: Implications for an Inhibitor-Resistant Phenotype Introduction 167 1 Materials and Methods 169 Results 181 Discussion 190 Conclusion 205 Tables 206 Figures 216 CHAPTER 5 - Summary, Future Directions, and Lessons Learned Chapter 2 Summary 222 Chapter 2 Future Directions 223 Chapter 3 Summary 225 Chapter 3 Future Directions 226 Chapter 4 Summary 227 Chapter 4 Future Directions 228 Lessons Learned 230 A Perspective 234 Table 236 APPENDIX A – Molecular Modeling Terms 237 APPENDIX B – Penicillin Sulfone Inhibitors of Class D β-Lactamases 238 REFERENCES 271 2 LIST OF TABLES 1-1. Comparison of Ambler and Bush-Jacoby-Medeiros -lactamase 77 classification schemes 1-2. Kinetic properties of representative -lactamases 78 1-3. Kinetic properties of representative class A inhibitor-resistant enzymes 79 1-4. Kinetic properties of select inhibitors against different -lactamase 80 Ambler classes 2-1. MIC values (μg/ml) of E. coli DH10B expressing SHV-1 and Asn276 115 variants 2-2. Kinetic properties of SHV-1 and Asn276Asp for ampicillin, piperacillin, 116 nitrocefin, and cephalothin 2-3. Kinetic properties of SHV-1 and Asn276Asp for clavulanate, cephalothin 117 boronic acid derivatives, methylidene penem, and meropenem 2-4. Ratio of kcat/Km for IR to wild-type TEM and SHV enzymes 118 2-5. Ratio of kinact/Ki for IR to wild-type TEM and SHV enzymes 119 3-1. Ki and Ki appss of inhibitors in direct competition assays with ADC 149 3-2. ESI-MS analysis (amu) of ADC alone and incubated with inhibitors 150 3-3. MIC values (μg/ml) of ceftazidime and ceftazidime in combination with 4 151 μg/ml of boronic acid cephalothin analogs 4-1. Bacterial strains used in Chapter 4 studies 206 4-2. Primers used for cloning and mutagenesis in Chapter 4 207 4-3. MIC values (μg/ml) of P. aeruginosa strains PAO1 and 18SH, expressing 208 PDC-1 and PDC-3 β-lactamases, respectively 4-4. PDC-3 -lactamase substrate kinetics 209 4-5. Ki and Ki appss of inhibitors in direct competition assays with PDC-3 - 210 lactamase and NCF 4-6. kinact rates of inhibitors screened in Chapter 4 212 4-7. ESI-MS analysis (amu) of PDC-3 alone and incubated with inhibitors for 213 15 min at an I:E of 25:1 for boronate and 20:1 for PSR-3-283a and BAL29880. 3 4-8. Cefotaxime MICs (g/ml) of P. aeruginosa 18SH and PAO1 expressing 214 PDC-1 and PDC-3 β-lactamases, respectively, and E. coli DH10B expressing blaPDC-3 or blaPAO1 in pBC SK (-), inhibitors at 4 g/ml 4-9. MIC values (μg/ml) of P. aeruginosa 18SH and E. coli DH10B expressing 215 blaPDC-3 or blaPDC-3 variants at possible carboxylate binding sites. Inhibitors combined with 50 μg/ml ampicillin 5-1. Experiments planned or in progress for Pseudomonal AmpC 236 4 LIST OF FIGURES 1-1. Chemical structures of: (1) a penicillin; (2) a third-generation 81 cephalosporin; (3) a monobactam; (4-7) carbapenems; and (8-10) β- lactamase inhibitors in clinical practice. The numbering scheme for penicillins, cephalosporins, and monobactams is shown. Chemical structures of β-lactamase inhibitors in development: (11-14) monobactam derivatives; (15) a penicillin derivative; (16-20) penems; (21-23) penicillin sulfones; (24) a cephalosporin sulfone; (25) a boronic acid cephalothin analog; (26-29) non-β-lactams. 1-2. “Family portrait” of β-lactamase enzymes: (A) Class A, SHV-1; (B) 83 Class B, IMP-1; (C) Class C, E. coli AmpC; and (D) Class D, OXA-1 1-3. Proposed reaction mechanism for a penicillin β-lactam substrate by a 84 class A serine β-lactamase enzyme in which Glu166 participates in activating a water molecule for both acylation and deacylation. 1-4. Schmeatic representation of the Zn2+-binding site of a dinuclear subclass 85 B1 metallo--lactamase, such as B. cereus BcII 1-5. Proposed mechanism of inhibition for class A β-lactamases by 86 clavulanate showing the different acyl-enzyme fragmentation products (expressed in amu) that have been experimentally observed 1-6. Tautomers of imipenem hypothesized to form after acylation of 87 carbapenems by serine β-lactamases 1-7. Molecular representation of SHV-1-meropenem acyl-enzyme 88 1-8. Molecular representation of TEM-1 active site showing residues that are 89 most frequently implicated in the development of inhibitor-resistant TEM enzymes 1-9. Representation of proposed Henri-Michaelis preacylation complex of 90 TEM-1 and clavulanate 1-10. Proposed reaction mechanisms for the inactivation of a serine β- 91 lactamase by: (A) BRL 42715 showing formation of the seven-membered thiazepine ring; and (B) LN-1-255 showing intermolecular capture by the pyridyl nitrogen leading to a bicyclic aromatic intermediate 1-11. Molecular representation of cross-linked active site residues Ser64 and 92 Lys315 formed after aminolysis of O-aryloxycarbonyl hydroxamate inhibitor in E. cloacae P99 -lactamase 2-1. Chemical structures of compounds tested in Chapter 2 120 5 2-2. Immunoblot of E. coli DH10B expressing SHV-1, SHV Arg244Ser 121 variant, and Asn276 variants probed with SHV-1 polyclonal antibody 2-3. Deconvoluted ESI-MS spectra of: (A) SHV-1; and (B) SHV Asn276Asp 122 before and after 15 min inactivation with clavulanate at inhibitor:enzyme ratio of 1000:1 2-4. Molecular representation of SHV Asn276Asp based on SHV-1 showing 123 the increased interaction between Arg244 and 276Asp 2-5. Proposed reaction mechanism for inactivation of SHV-1 by clavulanate 124 3-1. Schemes illustrating the interactions of a serine β-lactamase with: (A) the 152 β- lactam cephalosporin ceftazidime; (B) the boronic acid ceftazidime analog, compound 2; and (C) the carbapenem imipenem 3-2. Chemical structures of: (A) commercially available inhibitors and 153 cephalosporin substrate cephalothin; (B) boronic acid derivatives; and (C) carbapenems used in Chapter 3 3-3. Overlay of the molecular coordinates for the E. coli AmpC covalently 154 bound to cephalothin substrate and boronic acid chiral cephalothin analog 3-4. Deconvoluted mass spectra of: (A) ADC β–lactamase alone; (B) ADC 155 after 15 min incubation with compounds 2 and 5; and (C) ADC β- lactamase after 15 min incubation with imipenem, ertapenem, doripenem, and meropenem 3-5. Proposed mechanism of the retroaldolic reaction leading to elimination of 157 C6 hydroxethyl substituent from the -lactamase: carbapenem acyl- enzyme 3-6. Discovery Studio multiple sequence protein alignment of crystal structure 158 coordinates for E. cloacae P99, E. coli AmpC, and E. coli CMY-2, and molecular models of PDC and ADC 3-7. Overlay of molecular coordinates for the E. coli AmpC-5 complex and 160 generated ADC-5 model colored by atom 3-8. Comparison of the binding site interactions between E. coli AmpC-5 (left 161 panel) and ADC-5 (right panel) 3-9. Molecular representation of: (A) ADC-imipenem acyl-enzyme model; 163 and (B) ADC-meropenem acyl-enzyme model 4-1. Chemical structures of: (A) β-lactam substrates; and (B) investigational 216 inhibitors tested in Chapter 4 4-2. Specific activity (M NCF hydrolyzed/sec/g protein) of crude protein 217 extract from P. aeruginosa PAO1 and 18SH without and following 3 hr 6 incubation with 50 µg/ml cefoxitin 4-3. Immunoblots of: (A) purified PDC-3 protein; and (B) purified β- 218 lactamase proteins from all Ambler classes and crude lysates of clinical strains 4-4. Proposed reaction intermediates detected on ESI-MS after 15 min 219 incubation of: (A) PSR-3-283a; and (B) BAL29880 with PDC-3 at an I:E -2 of 20:1. (C) Possible mechanism for elimination of the SO3 group from BAL29880 4-5. Structure of C6 α-hydroxymethyl penicillanate studied by Mobashery and 220 colleagues 4-6. Solvent-accessible surfaces of E. coli AmpC bound to the chiral 221 cephalothin analog boronate, compound 4c, and P. aeruginosa PDC-3 with the same inhibitor 7 ACKNOWLEDGEMENTS Many people have helped me complete this project. In particular, I thank my thesis committee for their time and attention to my academic development, and the members of the Bonomo lab for support and scientific guidance. My husband, Paul, has been my strongest source of support through these experiences. The encouragement from my parents has also been instrumental.
Load more

Recommended publications
  • WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) A61K 38/08 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 15/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/031213 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 15 May 2015 (15.05.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/000,43 1 19 May 2014 (19.05.2014) US kind of regional protection available): ARIPO (BW, GH, 62/129,746 6 March 2015 (06.03.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors; and TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicants : GELLER, Bruce, L.
    [Show full text]
  • General Items
    Essential Medicines List (EML) 2019 Application for the inclusion of imipenem/cilastatin, meropenem and amoxicillin/clavulanic acid in the WHO Model List of Essential Medicines, as reserve second-line drugs for the treatment of multidrug-resistant tuberculosis (complementary lists of anti-tuberculosis drugs for use in adults and children) General items 1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of the forthcoming WHO Model List of Essential Medicines (EML) and WHO Model List of Essential Medicines for Children (EMLc) to include the following medicines: 1) Imipenem/cilastatin (Imp-Cln) to the main list but NOT the children’s list (it is already mentioned on both lists as an option in section 6.2.1 Beta Lactam medicines) 2) Meropenem (Mpm) to both the main and the children’s lists (it is already on the list as treatment for meningitis in section 6.2.1 Beta Lactam medicines) 3) Clavulanic acid to both the main and the children’s lists (it is already listed as amoxicillin/clavulanic acid (Amx-Clv), the only commercially available preparation of clavulanic acid, in section 6.2.1 Beta Lactam medicines) This application makes reference to amendments recommended in particular to section 6.2.4 Antituberculosis medicines in the latest editions of both the main EML (20th list) and the EMLc (6th list) released in 2017 (1),(2). On the basis of the most recent Guideline Development Group advising WHO on the revision of its guidelines for the treatment of multidrug- or rifampicin-resistant (MDR/RR-TB)(3), the applicant considers that the three agents concerned be viewed as essential medicines for these forms of TB in countries.
    [Show full text]
  • Structure of a Penicillin Binding Protein Complexed with a Cephalosporin-Peptidoglycan Mimic M.A
    Structure of a Penicillin Binding Protein Complexed with a Cephalosporin-Peptidoglycan Mimic M.A. McDonough1, W. Lee2, N.R. Silvaggi1, L.P. Kotra 2, Z-H. Li2, Y. Takeda2, S .O. Mobashery2, and J.A. Kelly1 1Department of Molecular and Cell Biology and Institute for Materials Science, Univ. of Connecticut, Storrs, CT 2Institute for Drug Design and the Department of Chemistry, Wayne State Univ., Detroit, MI Many bacteria that are responsible for causing dis- lactams. Also, one questions why ß-lactamases hydro- eases in humans are rapidly developing mutant strains lyze ß-lactams and release them rapidly but they do resistant to existing antibiotics. Proliferation of these not react with peptide substrates. mutant strains is likely to be a serious health-care prob- To help answer these questions, structural studies lem of increasing proportions. Almost sixty percent of of the Streptomyces sp. R61 D-Ala-D-Ala-peptidase all clinically used antibiotics are beta-lactams, which have been undertaken to investigate how the enzyme stop the growth of bacteria by interfering with their cell- wall biosynthesis. The cell walls are made of glycan chains that polymerize to form a structure that gives strength and shape to the bacteria. An understanding of the process how the cell wall is synthesized may help in designing more potent antibiotics. D-Ala-D-Ala-carboxypeptidase/transpeptidases (DD-peptidases) are penicillin-binding proteins (PBPs), the targets of ß-lactam antibiotics such as penicillins and cephalosporins (Figure 1A). These enzymes cata- lyze the final cross-linking step of bacterial cell wall bio- synthesis. In vivo inhibition of PBPs by ß-lactams re- sults in the cessation of bacterial growth.
    [Show full text]
  • Correlation of Phenotypic Tests with the Presence of the Blaz
    b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 8 (2 0 1 7) 159–166 ht tp://www.bjmicrobiol.com.br/ Medical Microbiology Correlation of phenotypic tests with the presence of the blaZ gene for detection of beta-lactamase a,b a a Adriano Martison Ferreira , Katheryne Benini Martins , Vanessa Rocha da Silva , c a,b,∗ Alessandro Lia Mondelli , Maria de Lourdes Ribeiro de Souza da Cunha a Universidade Estadual Paulista (UNESP), Botucatu Biosciences Institute, Department of Microbiology and Immunology, Botucatu, SP, Brazil b Universidade Estadual Paulista (UNESP), Botucatu School of Medicine University Hospital, Department of Tropical Diseases, Botucatu, SP, Brazil c Universidade Estadual Paulista (UNESP), Botucatu School of Medicine University Hospital, Department of Internal Medicine, Botucatu, SP, Brazil a r a t i c l e i n f o b s t r a c t Article history: Staphylococcus aureus and Staphylococcus saprophyticus are the most common and most impor- Received 3 July 2015 tant staphylococcal species associated with urinary tract infections. The objective of the Accepted 20 June 2016 present study was to compare and to evaluate the accuracy of four phenotypic methods Available online 11 November 2016 for the detection of beta-lactamase production in Staphylococcus spp. Seventy-three strains Associate Editor: John Anthony produced a halo with a diameter ≤28 mm (penicillin resistant) and all of them were positive McCulloch for the blaZ gene. Among the 28 susceptible strain (halo ≥29 mm), 23 carried the blaZ gene and five did not.
    [Show full text]
  • Penicillin Skin Testing
    Penicillin Skin Testing Penicillin Skin Testing: Frequently Asked Questions Benzylpenicilloyl Polylysine (Pre-Pen®) and Diluted Penicillin G June 2012 VA Pharmacy Benefits Management Services, Medical Advisory Panel and VISN Pharmacist Executives Benzylpenicilloyl polylysine (Pre-Pen®) was FDA approved in 2009 for the assessment of sensitization to penicillin in those patients suspected, based upon previous experience, of having a clinical hypersensitivity to penicillin. Penicillin skin testing is the most reliable way to evaluate patients for IgE-mediated penicillin allergy. Skin testing is conducted using benzylpenicilloyl polylysine (major determinant), penicillin G diluted with normal saline to 10,000 units/ml (minor determinant), a positive and negative control. Testing with both the major and minor determinant of penicillin can identify up to 97% of patients with an immediate hypersensitivity to penicillin. The intent of this document is to help guide appropriate use of penicillin skin testing. 1. WHEN IS PENICILLIN SKIN TESTING INDICATED? Penicillin skin testing can be considered in those patients with a prior history of hypersensitivity to penicillin or allergy to penicillin in situations where the provider considers penicillin the drug of choice or prefers treatment with penicillin. If skin testing is indicated, the patient should be referred to a VA Allergy Specialist or other appropriately trained physician who is experienced in the application and interpretation of PCN skin testing, as locally designated. Although approximately 10% of patients will remain allergic to penicillin their entire lives, a large majority will stop expressing penicillin-specific IgE-mediated antibodies and can be safely treated with penicillin. Skin testing with benzylpenicilloyl polylysine is contraindicated in patients who are known to be extremely hypersensitive to penicillin and in those patients who have experienced a systemic or marked local reaction to prior administration of benzylpenicilloyl polylysine.
    [Show full text]
  • Antimicrobial Stewardship Guidance
    Antimicrobial Stewardship Guidance Federal Bureau of Prisons Clinical Practice Guidelines March 2013 Clinical guidelines are made available to the public for informational purposes only. The Federal Bureau of Prisons (BOP) does not warrant these guidelines for any other purpose, and assumes no responsibility for any injury or damage resulting from the reliance thereof. Proper medical practice necessitates that all cases are evaluated on an individual basis and that treatment decisions are patient-specific. Consult the BOP Clinical Practice Guidelines Web page to determine the date of the most recent update to this document: http://www.bop.gov/news/medresources.jsp Federal Bureau of Prisons Antimicrobial Stewardship Guidance Clinical Practice Guidelines March 2013 Table of Contents 1. Purpose ............................................................................................................................................. 3 2. Introduction ...................................................................................................................................... 3 3. Antimicrobial Stewardship in the BOP............................................................................................ 4 4. General Guidance for Diagnosis and Identifying Infection ............................................................. 5 Diagnosis of Specific Infections ........................................................................................................ 6 Upper Respiratory Infections (not otherwise specified) ..............................................................................
    [Show full text]
  • B-Lactams: Chemical Structure, Mode of Action and Mechanisms of Resistance
    b-Lactams: chemical structure, mode of action and mechanisms of resistance Ru´ben Fernandes, Paula Amador and Cristina Prudeˆncio This synopsis summarizes the key chemical and bacteriological characteristics of b-lactams, penicillins, cephalosporins, carbanpenems, monobactams and others. Particular notice is given to first-generation to fifth-generation cephalosporins. This review also summarizes the main resistance mechanism to antibiotics, focusing particular attention to those conferring resistance to broad-spectrum cephalosporins by means of production of emerging cephalosporinases (extended-spectrum b-lactamases and AmpC b-lactamases), target alteration (penicillin-binding proteins from methicillin-resistant Staphylococcus aureus) and membrane transporters that pump b-lactams out of the bacterial cell. Keywords: b-lactams, chemical structure, mechanisms of resistance, mode of action Historical perspective Alexander Fleming first noticed the antibacterial nature of penicillin in 1928. When working with Antimicrobials must be understood as any kind of agent another bacteriological problem, Fleming observed with inhibitory or killing properties to a microorganism. a contaminated culture of Staphylococcus aureus with Antibiotic is a more restrictive term, which implies the the mold Penicillium notatum. Fleming remarkably saw natural source of the antimicrobial agent. Similarly, under- the potential of this unfortunate event. He dis- lying the term chemotherapeutic is the artificial origin of continued the work that he was dealing with and was an antimicrobial agent by chemical synthesis [1]. Initially, able to describe the compound around the mold antibiotics were considered as small molecular weight and isolates it. He named it penicillin and published organic molecules or metabolites used in response of his findings along with some applications of penicillin some microorganisms against others that inhabit the same [4].
    [Show full text]
  • Who Expert Committee on Specifications for Pharmaceutical Preparations
    WHO Technical Report Series 902 WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS A Thirty-sixth Report aA World Health Organization Geneva i WEC Cover1 1 1/31/02, 6:35 PM The World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO’s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfils in part through its extensive programme of publications. The Organization seeks through its publications to support national health strat- egies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommen- dations for decision-makers. These books are closely tied to the Organization’s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO’s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publica- tions and encourages their translation and adaptation.
    [Show full text]
  • Zinforo, INN Ceftaroline Fosamil
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Zinforo 600 mg powder for concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains ceftaroline fosamil acetic acid solvate monohydrate equivalent to 600 mg ceftaroline fosamil. After reconstitution, 1 ml of the solution contains 30 mg of ceftaroline fosamil. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate for solution for infusion. A pale yellowish-white to light yellow powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Zinforo is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1): • Complicated skin and soft tissue infections (cSSTI) • Community-acquired pneumonia (CAP) Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Posology For the treatment of cSSTI and CAP, the recommended dose is 600 mg administered every 12 hours by intravenous infusion over 60 minutes in patients aged 18 years or older. The recommended treatment duration for cSSTI is 5 to 14 days and the recommended duration of treatment for CAP is 5 to 7 days. Special populations Elderly patients (≥ 65 years) No dosage adjustment is required for the elderly with creatinine clearance values > 50 ml/min (see section 5.2). Renal impairment The dose should be adjusted when creatinine clearance (CrCL) is ≤ 50 ml/min, as shown below (see sections 4.4 and 5.2). Creatinine clearance Dosage regimen Frequency (ml/min) > 30 to ≤ 50 400 mg intravenously (over 60 minutes) every 12 hours 2 There is insufficient data to make specific dosage adjustment recommendations for patients with severe renal impairment (CrCL ≤ 30 ml/min) and end-stage renal disease (ESRD), including patients undergoing haemodialysis (see section 4.4).
    [Show full text]
  • Summary of Product Characteristics
    SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Augmentin 125 mg/31.25 mg/5 ml powder for oral suspension Augmentin 250 mg/62.5 mg/5 ml powder for oral suspension 2. QUALITATIVE AND QUANTITATIVE COMPOSITION When reconstituted, every ml of oral suspension contains amoxicillin trihydrate equivalent to 25 mg amoxicillin and potassium clavulanate equivalent to 6.25 mg of clavulanic acid. Excipients with known effect Every ml of oral suspension contains 2.5 mg aspartame (E951). The flavouring in Augmentin contains maltodextrin (glucose) (see section 4.4). This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium- free’. When reconstituted, every ml of oral suspension contains amoxicillin trihydrate equivalent to 50 mg amoxicillin and potassium clavulanate equivalent to 12.5 mg of clavulanic acid. Excipients with known effect Every ml of oral suspension contains 2.5 mg aspartame (E951). The flavouring in Augmentin contains maltodextrin (glucose) (see section 4.4). This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium- free’. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for oral suspension. Off-white powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): • Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis 2 • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis • Bone and joint infections, in particular osteomyelitis.
    [Show full text]
  • New Β-Lactamase Inhibitor Combinations: Options for Treatment; Challenges for Testing
    MEDICAL/SCIENTIFIC AffAIRS BULLETIN New β-lactamase Inhibitor Combinations: Options for Treatment; Challenges for Testing Background The β-lactam class of antimicrobial agents has played a crucial role in the treatment of infectious diseases since the discovery of penicillin, but β–lactamases (enzymes produced by the bacteria that can hydrolyze the β-lactam core of the antibiotic) have provided an ever expanding threat to their successful use. Over a thousand β-lactamases have been described. They can be divided into classes based on their molecular structure (Classes A, B, C and D) or their function (e.g., penicillinase, oxacillinase, extended-spectrum activity, or carbapenemase activity).1 While the first approach to addressing the problem ofβ -lactamases was to develop β-lactamase stable β-lactam antibiotics, such as extended-spectrum cephalosporins, another strategy that has emerged is to combine existing β-lactam antibiotics with β-lactamase inhibitors. Key β-lactam/β-lactamase inhibitor combinations that have been used widely for over a decade include amoxicillin/clavulanic acid, ampicillin/sulbactam, and pipercillin/tazobactam. The continued use of β-lactams has been threatened by the emergence and spread of extended-spectrum β-lactamases (ESBLs) and more recently by carbapenemases. The global spread of carbapenemase-producing organisms (CPOs) including Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii, limits the use of all β-lactam agents, including extended-spectrum cephalosporins (e.g., cefotaxime, ceftriaxone, and ceftazidime) and the carbapenems (doripenem, ertapenem, imipenem, and meropenem). This has led to international concern and calls to action, including encouraging the development of new antimicrobial agents, enhancing infection prevention, and strengthening surveillance systems.
    [Show full text]
  • Australian Public Assessment Refport for Ceftaroline Fosamil (Zinforo)
    Australian Public Assessment Report for ceftaroline fosamil Proprietary Product Name: Zinforo Sponsor: AstraZeneca Pty Ltd May 2013 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <http://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. • An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
    [Show full text]