antibiotic resistance among gram positive bacteria

Antibiotic Resistance Among Gram Positive Bacteria – An Update : 

Antibiotic Resistance Among Gram Positive Bacteria – An Update Dr H.R.V.RAJKUMAR CONSULTANT MICROBIOLOGIST & DIRECTOR – LAB SERVICES KAMINENI HOSPITALS

Problems In Critical Care Units : 

Problems In Critical Care Units Infection rates in ICUs are 3 to 4 times more than in general wards. Most of them are HAI. (50-75%). Infection rates vary. Surgical ICUs > Medical ICUs. Vulnerable patient population. Advanced invasive techniques Antibiotic abuse ,Failure of aseptic procedures

Problems In Critical Care Units : 

Problems In Critical Care Units In order that a bacterium (resistant to an antimicrobial) can attack a particular patient, there are several other obvious requirements: The patient's defences should be "down", something that is common in ICU, where patients are often nutritionally compromised, with breaches in their integument; The microbe must gain access to the patient, usually carried on the hands of the attending doctors or nurses; The microbe must establish a "foothold" on the patient, competing with endogenous patient flora; The microbe must invade the patient, and cause disease. Equally clearly, if any one of these steps or predisposing states is removed, a bacterium or fungus will have a torrid time in trying to attack the patient

Major Categories of Infections : 

Major Categories of Infections Pneumonias. Blood Stream Infections. Urinary Tract Infections Surgical Site Infections.

Major Gram-Positive Pathogens : 

Major Gram-Positive Pathogens Staphylococcus aureus. Coagulase Negative Staphylococci Enterococci. Streptococcus pneumoniae Streptococcus spp Diptheroids. Actinomycetes spp. Corynebacterium spp.

Streptococcus pneumoniae : 

Streptococcus pneumoniae Unfortunately, S. pneumoniae resistant to beta-lactams are becoming more common There has been international dissemination of several penicillin-resistant clones of S. pneumoniae (from serotypes 6, 9, 14, 19 & 23) In the USA 'SENTRY' study, 1/3 of S. pneumoniae isolates were at least partially resistant to penicillin Multidrug resistance is on increase, with significant levels of resistance to cephalosporins, tetracyclines, & (commonly) co-trimoxazole

Enterococci : 

Enterococci COMMENSAL ORGANISM INFECTION OR COLONIZATION RESISTANCE INTRINSIC R (aminoglycosides & beta-lactams) ACQUIRED R (chloramphenicol, tetracyclines, macrolides, quinolones) SOURCE OF R GENES A few enterococci are intrinsically resistant to vancomycin, which has been related to the outrageously, extensive use of vancomycin in the USA in the 1980s

VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE) : 

VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE) SPECIATION NECESSARY Intrinsic resistance (E.gallinarum & E.casseliflavus) Acquired resistance (E.faecium & E.faecalis; also in E.raffinosus, E.avium, E.durans) Higher Vanco R in E.faecium vs. E.faecalis 8%(E.faecalis) & 80%(E.faecium) CUMC 2003 GENE VANCO (µg/ml) Van A > 128 (High) Van B 16 – 64 (Variable) Van C (Intrinsic) 2 – 16 (Low) Van D 64 - 128

MRSA : 

MRSA Methicillin Resistant Staphylococcus aureus. Resistant to all beta-lactam agents, including cephalosporins, beta-lactamase inhibitor combinations and carbapenems Hospital associated MRSA Often are multiply resistant to other commonly used antimicrobials including erythromycin, clindamycin and tetracyline Community associated MRSA Often resistant only to beta-lactam agents and erythromycin

MRSA PROFILE : 

MRSA PROFILE PENICILLIN INTRODUCED IN 1944 Plasmid-mediated resistance by beta-lactamase that hydrolyzes beta-lactam ring. Prevalent in hospitals in 1950s. METHICILLIN INTRODUCED IN 1959 MRSA appeared in 1961 & prevalent in 1970s. Resistance from 4 Penicillin Binding Proteins (PBP) encoded by 4 mec genes (30-50 kb). Chromosomal, not plasmid mediated. MRSA acquired the mec A gene which codes for the production of unique PBP 2a.

MRSA PROFILE : 

MRSA PROFILE Introduction of methicillin in 1959 was followed rapidly by reports of MRSA isolates. Recognised hospital pathogen since the 1960s. Major cause of nosocomial infections worldwide. contributes to 50% of infectious morbidity in ICUs in Europe surveillance studies suggest prevalence has increased worldwide, reaching 25–50% in 1997

Features of MRSA: epidemic strains : 

Features of MRSA: epidemic strains Problem escalated in the early 1980s with emergence of epidemic strains (EMRSA) first recognised in the UK 17 EMRSAs identified to date Impact on hospitals is variable presence of EMRSA can account for >50% of S. aureus isolates

Emergence of MRSA in the community : 

Emergence of MRSA in the community MRSA in hospitals leads to an associated rise in incidence in the community Community-acquired MRSA strains may be distinct from those in hospitals In a hospital-based study, >40% of MRSA infections were acquired prior to admission Risk factors for community acquisition included: recent hospitalisation previous antibiotic therapy residence in a long-term care facility intravenous drug use Colonisation and transmission are also seen in individuals (including children) lacking these risk factors

Antimicrobial features of MRSA : 

Antimicrobial features of MRSA Mechanism involves altered target site new penicillin-binding protein — PBP 2' (PBP 2a) encoded by chromosomally located mecA gene Confers resistance to all -lactams Gene carried on a mobile genetic element — staphylococcal cassette chromosome mec (SCCmec) Laboratory detection requires care Not all mecA-positive clones are resistant to methicillin (2% sensitive)

Antimicrobial features of MRSA : 

Antimicrobial features of MRSA Cross-resistance common with many other antibiotics Ciprofloxacin resistance is a worldwide problem in MRSA: involves ≥2 resistance mutations usually involves parC and gyrA genes renders organism highly resistant to ciprofloxacin, with cross-resistance to other quinolones Intermediate resistance to glycopeptides first reported in 1997

Current therapy & Challenges for serious gram positive infections : 

Current therapy & Challenges for serious gram positive infections Who’s winning the war…

Serious Gram positive infections : 

Serious Gram positive infections Infections caused by Gram positive pathogens have always been a challenge and a major public health problem Gram positive bacteria are major cause of serious infections such as1 Complicated Skin & Soft tissue infections (cSSTIs) Bacteraemia Infective Endocarditis (IE) 1 = Drugs 2007 ; 67 (10); 1483-1512 ; 2 = Clin Microbiol Infect 2008; 14 (Suppl. 2): 3–9 Over the past 2 decades there has been a shift in the epidemiology of serious bacterial infections2 (Increased severity & Number of Gram positive infections) Increasing proportion being attributed to Gram positive bacteria, which have become the predominant cause of many infections. Similarly there has been a substantial increase to antimicrobials for Gram positive infections2

Skin & Soft tissue infections : 

Skin and soft tissue infections (SSTIs) are infections of the epidermis, dermis and subcutaneous tissue that induce a host response1 1. Eron LJ, et al. J Antimicrob Chemother 2003;52 (Suppl 1):i3–i17 2. DiNubile MJ & Lipsky BA. J Antimicrob Chemother 2004;53 (Suppl 2):ii37–ii50 Skin & Soft tissue infections

Skin & Soft tissue infections : 

Skin & Soft tissue infections DiNubile MJ & Lipsky BA. J Antimicrob Chemother 2004;53(Suppl 2):ii37–ii50 FDA draft: Guidance for Industry – Uncomplicated and Complicated Skin and Skin Structure Infections (http://www.fda.gov/CDER/guidance/2566dft.pdf)

Bacterial Pathogens Causing SSTI* : 

Bacterial Pathogens Causing SSTI* * Europe, 2004 **Coagulase-negative staphylococci ** 1. Moet GJ, et al. Diagn Microbiol Infect Dis 2007;57:7–13 Am J Infect Control 1999;27:97–132. Staphylococcus aureus is the leading cause of SSTIs worldwide

Bacteraemia and Bloodstream infections : 

Bacteraemia and Bloodstream infections Bacteraemia Presence of viable bacteria in the bloodstream Bloodstream infection Bacteraemia plus clinical manifestations of infection (e.g. fever, chills and/or hypotension) Sepsis Systemic response to infection Systemic inflammatory response syndrome (SIRS) Systemic inflammatory response to a variety of severe clinical insults (infectious or non-infectious) Bacteraemia Sepsis Severe sepsis Septic shock Bloodstream infection Progression of severity: Munford RS. Sepsis, severe sepsis and septic shock. In Principles and practice of infectious diseases 6th edition (Mandell GL, Bennett JE, Dolin R, editors). 2005, pp. 906–927

Types of Bacteremias : 

Types of Bacteremias Transient Lasts for minutes to hours Occurs after manipulation of infected tissues (abscess) ; surgical procedures ; dental procedures ; at onset of acute bacterial infections (pneumonia or meningitis) Intermittent Recurring infection Associated with undrained, closed space infections (intra-abdominal abscess) Continuous Characteristic of Infective Endocarditis Endovascular infections (suppurative thrombophlebitis , infective aneurysms)

Leading pathogens isolated from nosocomial bloodstream infections (BSI) : 

Leading pathogens isolated from nosocomial bloodstream infections (BSI) Methicillin resistance 75% of CoNS isolates 41% of S. aureus isolates Vancomycin resistance 60% of Enterococcus faecium isolates 2% of Enterococcus faecalis isolates SCOPE surveillance study 1995–2002 Wisplinghoff H et al. Clin Infect Dis 2004;39:309–317 (CoNS = Cougulase negative Staph. Aureus)

Bacteraemia and Bloodstream infections : 

Bacteraemia and Bloodstream infections Risk factors for Bacteremias : Breaks in skin (i.e. wounds, surgery, i.v. lines, catheters, i.v. drug use) S. aureus, CoNS Invasion of bloodstream from other sites of infection (e.g. pneumonia, UTI) Pneumococci, E. coli, enteroccoci Dental ‘trauma’ (tooth extraction, brushing, chewing) Oral streptococci Translocation of bacteria across wall of gut Enterococci

Bacteraemia and Bloodstream infections : 

Bacteraemia and Bloodstream infections Staph . aureus is a significant cause of bacteraemia in both nosocomial and community settings and is associated with complications that include : Deep tissue abscesses Osteomyelitis and Infective endocarditis Complications are particularly more in bacteraemic episodes of > 48 hours Similarly, a rise in antibiotic resistance to S.aureus impacts both prognosis and treatment of Staph. Aureus Bacteremia (SAB) Mortality rate & Duration of hospital stay is significantly greater in MRSA as compared to MSSA Eisenstein BI, Clin Microbiol Infect 2008; 14 (Suppl. 2): 10–16

Infective Endocarditis (IE) : 

Infective Endocarditis (IE) 1. Millar BC & Moore JE. Emerg Infect Dis 2004;10:1110–1116 2. Wilson W, et al. Circulation 2007;138:739–760 (Non Bacterial Thrombotic Endocarditis) IE can affect both Native and Prosthetic heart valves

Causative organisms of IE : 

International Collaboration on Endocarditis ~1700 prospective IE cases from 16 countries S. aureus CoNS S. bovis Viridans streptococci Enterococcus spp. Other pathogens/culture negative Causative organisms of IE Fowler VG et al. JAMA 2005; 293: 3012–3021

Current therapy for Gram positive infections : 

Current therapy for Gram positive infections Current Antibiotic choices for cSSTIs vary between specialties & institutions, reflecting : Different patient populations, Anatomical sites, MRSA risks and Local policies. Published guidance is deliberately non-prescriptive with respect to antibiotic choice, in part Reflecting these complexities but also because SSTI clinical trials typically exclude the most severely unwell patients and are powered to only show non-inferiority between agents.

Current therapy for Gram positive infections : 

Current therapy for Gram positive infections

Current therapy for Gram positive infections : 

Current therapy for Gram positive infections

Current therapy for Gram positive infections : 

Current therapy for Gram positive infections

Practical considerations in the treatment of MRSA : 

Practical considerations in the treatment of MRSA Bactericidal drugs – Kill the bacteria Bacteriostatic – Do not kill the bacteria, They stop the growth of bacteria Weakly bactericidal – Potency to kill bacteria is weak, Kill mostly the rapidly growing bacteria without targeting the stationery bacteria

Challenges in current therapy for gram positive infections : 

Challenges in current therapy for gram positive infections Agent factors Environmental factors Drug related factors Host/Patient factors Increasing co-morbitities (risk factors) among patients : Diabetes Hypertension Dyslipidemia Severe illnesses Immunosupression Antibiotics can no longer be seen as magic bullets : Bacteriostatic activity Reduced susceptibility Increasing MICs Toxicity Frequent dosing Drug interactions Clin Microbiol Infect 2008;14 (suppl.2): 3-9 ; Clin Microbiol Infect 2008;CMI 7 (suppl.4) iii ; J Antimicr Chem 2008, 62, Supl 3. iii3-iii6

Challenge 1 : Shifting epidemiology of serious infections : 

Challenge 1 : Shifting epidemiology of serious infections SSTIs are frequently observed in clinical practice & account for 10 % of all hospital admission in US1 Factors attributing : ↑ Age , Obesity , Diabetes, Immunodeficiency , IV access. In many institutions Gram positive infections account for >50 % of all blood stream infections (BSI)2 BSI can lead to complications : Deep abscess ; Osteomyelitis ; Infective Endocarditis , Catheter related infections Considerable increase in S. aureus as well as Coagulase negative Staph. aureus (CoNS) infections Increasing burden of Enterococci (especially E. faecium) is clearly revealing that the these infections have expanded much beyond just prosthetic material and invasive techniques.2 Global scenario : 1 = Eisenstein BI , Clin Microbiol Infect 2008;14 (suppl.2): 17-25 ; 2 = Clin Microbiol Infect 2008;CMI 7 (suppl.4) iii ; 3 = Moet GJ, et al. Diagn Microbiol Infect Dis 2007;57:7–13 ; 4 = Wisplinghoff H et al. Clin Infect Dis 2004;39:309–317

Nosocomial bloodstream infections & mortality due to S. aureus : 

Nosocomial bloodstream infections & mortality due to S. aureus Wisplinghoff H et al. Clin Infect Dis 2004;39:309–317 Data from US SCOPE surveillance study 1995–2002 Challenge 1 : Shifting epidemiology of serious infections Global scenario :

Slide 36: 

Prevalence of Methicillin resistant S. Aureus (MRSA) is increasing significantly in many parts of the world to as high as 50 % in the US and European countries. SENTRY program reveals doubling of MRSA rates - 27% in 1997 to 54% in 2006 Methicillin resistant CoNS has also been increasing 70% in 1995 to 80% in 2002 The use of Vancomycin, the current drug of choice for MRSA, is also currently compromised by recent emergence of vancomycin-intermediate or resistant S. aureus (VISA or VRSA) Challenge 2 : The MRSA threat Clin Microbiol Infect 2008; 14 (Suppl. 2): 3–9

Challenge 2 : The MRSA threat : 

Previous hospital stay Prolonged length of stay prior to infection Surgical procedure(s) Enteral feeding Previous antibiotic use Central venous catheter insertion History of colonization/infection with CA-MRSA Close contact with person colonized/infected with CA-MRSA Participation in contact sports Injection drug use Living in correctional facilities, residential homes or shelters Military personnel Men who have sex with men Adults ≥65 years; children <2 years Concurrent SSTI; recent influenza-like illness and/or severe pneumonia Graffunder E, Venezia R. J Antimicrob Chemother 2002;49:999–1005 Oztoprak N et al. Am J Infect Control 2006;34:1–5 Boucher HW, Corey GR. Clin Infect Dis 2008;46:S344–S349 Traditional risk factors for nosocomial MRSA infection1,2 Risk factors for Community associated-MRSA3 Challenge 2 : The MRSA threat

Challenge 2 : The MRSA threat : 

Challenge 2 : The MRSA threat Risk factors for MRSA Srinivasan etal, Indian Journal of Medical Microbiology vol. 24, No. 3, 2006 Indian scenario

Challenge 2 : The MRSA threat : 

Challenge 2 : The MRSA threat MRSA prevalence – Site of prevalence Indian scenario K Rajaduraipandi etal, Prevalence Of Methicillin Resistant Staphylococcus Aureus: A Multicentre Study ,Indian Journal of Medical Microbiology, (2006) 24 (1):34-8 Multicenter study from South India

Challenge 2 : The MRSA threat : 

Challenge 2 : The MRSA threat MRSA prevalence – Clinical & Carriers Indian scenario K Rajaduraipandi etal, Prevalence Of Methicillin Resistant Staphylococcus Aureus: A Multicentre Study ,Indian Journal of Medical Microbiology, (2006) 24 (1):34-8 Multicenter study from South India 31 % of clinical specimens examined were MRSA 39 % of carrier samples were MRSA

Challenge 2 : The MRSA threat : 

Challenge 2 : The MRSA threat MRSA prevalence – Nosocomial or Community Indian scenario Study from North India (New Delhi) 60 % of all MRSA were hospital acquired 40 % of all MRSA were community acquired Vidhani et al - Study of MRSA Isolates from hight risk patients (Burns & Ortho units), Indian Journal of Medical Microbiology, (2001) 19(2)

Challenge 2 : The MRSA threat : 

Challenge 2 : The MRSA threat Significantly higher hospital costs Higher Length of hospital stay MRSA vs MSSA : Engemann JJ, Carmeli Y, Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis. 2003;36:592-598

Challenge 3 : The Vancomycin resistance threat : 

Challenge 3 : The Vancomycin resistance threat Types of vancomycin resistance : VRSA (Vancomycin Resistant S. Aureus) VISA (Vancomycin Intermediate S. Aureus) hVISA (heterogenous VISA) Vancomycin MIC breakpoints (Revised by CLSI 2006) Susceptible < 2 mg/L hVISA 2 – 4 mg/L VISA 4 – 8 mg/L Resistance > 16 mg.L Vancomycin tolerance : Minimum bactericidal concentration (MBC):MIC ratio > 32 or an MBC:MIC ratio > 16 associated with a resistant-level vancomycin MBC of > 32 mg⁄ L, represents a lack of bactericidal activity CLSI = Clinical & Laboratory Standards Institute Jones RN, Clin Microbiol Infect 2008; 14 (Suppl. 2): 3–9

Challenge 3 : The Vancomycin resistance threat : 

Challenge 3 : The Vancomycin resistance threat Vancomycin resistance is increasing globally including India hVISA is the most common type of vancomycin resistance Soong etal, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2004, p. 4926–4928 Prevalence of MRSA = 20 % Prevalence of hVISA = 6.3 % Indian scenario

Challenge 3 : The Vancomycin resistance threat : 

Challenge 3 : The Vancomycin resistance threat Vancomycin resistance is increasing globally including India hVISA is the most common type of vancomycin resistance Soong etal, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2004, p. 4926–4928 More concentration of vancomycin Required for bactericidal action (due to rising Minimum Inhibitory Concentration) Indian scenario

Strategies to cope up with the dynamic environment : 

Strategies to cope up with the dynamic environment Challenging the challenge…

1. Need for developing an hospital Antibiogram : 

1. Need for developing an hospital Antibiogram Need for hospital Antibiogram An antibiogram provides guidance on antibiotic susceptibility data, resistance patterns between institution and across geographic areas Detect antimicrobial Resistance (Emergence as well as dissemination) ↓ Develop control policies. Pathogens may vary from hospital to hospital, and even unit to unit Published Guidelines are not prescriptive as most clinical trials are powered to detect non – inferiority ↓ Dilemma for the first line choice. Multiple drugs as first line Guide need for empiric therapy eg. for MRSA ↓ Current UK guidelines recommend empiric anti-staphylococcal therapy when MRSA exceeds 10% in hospitals V. Lakshmi, Indian Journal of Medical Microbiology 2008, 26(2), 105-7 Seaton etal, Journal of Antimicrobial Chemotherapy (2008) 62, Suppl. 3, iii15–iii23

2. Susceptibility testing : 

2. Susceptibility testing Standard methods for Susceptibility testings Broth Microdilution (BMD) Disk Diffusion Method E test

3. Control of infections : 

3. Control of infections Improved hand hygiene Cleaning of shared equipment between uses Separation of infected patients Avoidance of overcrowding Selective decolonization Adequate hospital staffing Treatment of MRSA carriers (optional) Prevention of Transmission Grayson, N Engl J Med 355;7 August 17, 2006 Screening for MRSA in high risk pts ↓ Identification of independent risk factors (eg. Inpatient transfer) ↓ Treatment based on Antibiotic sensitivity pattern ↓ Specified period predetermined prior to initiation of therapy ↓ Stop/Switch to other antimicrobial if no clinical improvement

4. Need for new antimicrobial agents : 

4. Need for new antimicrobial agents The emergence of serious staphylococcal infections with reduced susceptibility to vancomycin highlights the need for more antimicrobial options with : Increased potency or Enhanced bactericidal activity against MRSA, hVISA, VISA & VRSA Jones etal, Clinical Microbiology and Infectious Diseases 2008, 14 (Suppl. 2), 3–9

NEWER AGENTS : 

NEWER AGENTS Quinupristin/dalfopristin Derived from the streptogramins pristinamycin IA and IIB Belong to the family of macrolides-lincosamides-streptogramins The drugs are present in a fixed 30:70 ratio and are synergistic Local irritation during administration. Has to be given very slowly.

NEWER AGENTS : 

NEWER AGENTS Daptomycin LY333328 (glycopeptide) Semi synthetic tetracyclines (glycylcylines)

NEWER AGENTS : 

NEWER AGENTS Daptomycin Cyclic Lipopeptide group of antibiotic Derived from soil saprotrop Streptomyces roseosporus It has proven in vitro activity against Enterococci (including Glycopeptide-resistant Enterococci (GRE)), Staphylococci (including MRSA), Streptococci and Corynebacteria Highly effective against VISA and VRSA Shows synergy with beta lactam antibiotics in-vitro

Daptomycin – Current indications : 

Daptomycin – Current indications Therapeutic indications Daptomycin is indicated for the treatment of the following infections in adults Complicated skin and soft-tissue infections (cSSTI). Right-sided infective endocarditis (RIE) due to Staphylococcus aureus. Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.

Daptomycin – Targeting the unmet need : 

Unique mechanism of action Daptomycin – Targeting the unmet need Daptomycin is the only antimicrobial which targets the cell membrane Targets bacterial cell membrane Disrupts multiple aspects of bacterial cell membrane

Slide 56: 

“Relax – MRSA will get you before the Swine flu” Thank you !!