ANTIBIOTIC RESISTANCE & CA-MRSA Present by Manita Attasuriyanan, MD.

 Antibiotic resistance  Community-associated MRSA

 Many bacterial have developed antibiotic resistance  80% of Staphylococcus resistant to penicillin  “Superbugs” resistant to all antibiotics  Multi-drug resistant tuberculosis  Misuse of antibiotics accelerates rates of resistance

Penicillin Cephalosporin Fluoroquinolone Carbapenem Discovery void

Resistance mechanisms GeneticIntrinsicAcquiredBiochemicalEnzymatic inactivationAlterated targetEfflux pumpDecrease permeability

Natural resistance  Chromosomic genetic support  Affect almost all species strains  Existed before antibiotic use e.g. Enterobacter sp. - amoxicillin Acquired resistance (mutation)  Chromosomic, plasmid or transposon genetic support  Affects a fraction of strains  Increased with antibiotic use e.g. extended spectrum beta-lactamase producing E. coli

Intrinsic Mutation Horizontal gene tranfer Conjugation Transduction Transformation

 Transmission of resistance genes via plasmid exchange.  Resistance spreads much faster than simple mutation and vertical evolution would permit.

 Transduction: virus transfers gene.  Transformation: DNA released from a bacterium is picked up by a new cell.

New Resistant Bacteria Mutations XX Susceptible Bacteria Resistant Bacteria Resistance Gene Transfer

Resistant Strains Rare x x Resistant Strains Dominant Antimicrobial Exposure x x x x x x x x x x

1. Inactivation of drug:  -lactamases 2. Alteration of the ATB target - Penicillin binding proteins - Ribosomes 3. Efflux pump 4. Decreased permeability

 Enzymes can destroy or disable antibiotics.  For example,  -lactamase hydrolyzes  -lactam ring of penicillins.  Without a  -lactam ring, penicillins ineffective.

 Bacteria can modify the ATB target to escape its activity.  Bacteria must change structure of the target but the modified target must still be able to function. 2.1 Mutation of the gene coding for the target protein 2.2 Importing a gene that codes for a modified target e.g. MRSA (methicillin- resistant - S. aureus ), similar to PBP (penicillin- binding- protein)

 PBPs are targets for penicillin.  Bacteria have PBPs in their plasma membranes.  MRSA has acquired a gene (mec A) that codes for a different PBP. - Different 3-dimensional structure - MRSA less sensitive to penicillins

 MRSA is resistant to all β-lactam antibiotics, cephalosporins, and carbapenems. - It is a very dangerous pathogen particularly in burn patients  Streptococcus pneumoniae also modifies PBP. - It can make as many as five different types of PBP. - It does this by rearranging, or shuffling, the genes.

 Bacterial ribosomes are a primary target for antibiotics - Different antibiotics affect them in different ways  Resistance can be the result of modification of ribosomal RNA so it is no longer sensitive  Some organisms use target modification in conjunction with efflux pumps - Resistance is even more effective

 Efflux pumping is an active transport mechanism. › It requires ATP  Efflux pumps are found in: › The bacterial plasma membrane › The outer layer of gram-negative organisms  Pumping keeps the concentration of antibiotic below levels that would destroy the cell

 Genes that code for efflux pumps are located on plasmids and transposons.  Transposons are sequences of DNA that can move or transpose move themselves to new positions within the genome of a single cell.  Transposones: › Readily acquired by non-resistant bacteria › Transforms them into resistant bacteria

 As a way of keeping ATB out  Bacteria turn off production of porin and other membrane channel proteins.

Enzymatic inactivation  lactam Aminoglycoside Macrolide Alternated target  lactam Quinolone Aminoglycoside Vancomycin Macrolide TMP/SMP Efflux pump Tetracycline Quinolone Macrolide Decrease permiability  lactam Aminoglycoside

Increasing resistance  Inpatient (MRSA, VRE, Pseudomonas, Acinetobacter)  Outpatient (E. coli, CA-MRSA, S. pneumoniae) Clinical ConditionMortality Risk MRSA vs. MSSA bacteremia MRSA vs. MSSA SSI VRE vs. VSE bacteremia Emergence of resistant Pseudomonas Enterobacter resistant to 3 rd gen ceph MDR-Acinetobacter vs. non-MDR Acin bacteremia Clin Infect Dis 2003;36: Arch Intern Med 1999;159: Clin Infect Dis 2003;36: Arch Intern Med 2002;162: Clin Infect Dis 2005;41: Infect Control Hosp Epidemiol 2007;28:713-9

 Staphylococcus aureus: common cause of infection in the community  Methicillin-resistant Staphylococcus aureus (MRSA):  Increasingly important cause of healthcare- associated infections since 1970s  In 1990s, emerged as cause of infection in the community

 CDC definition: early than 48 hrs after admission  CA-MRSA do not transferred from the hospitals  Patients usually have no previous contact with healthcare centers  Cause mostly skin and soft tissue infections  rarely cause URI or UTI, which are common with healthcare strains

Clin infect Dis Aug 41 (supplement 4)

 Difference in clinical manifestations may be due to the presence in community strains of toxins e.g. PVL or Panton Vanlentine Leukocidine, that causes severe inflammation  Molecular markers for CA-MRSA: - SCC (staphylococcus cassette chromosome) mec type IV, V - PVL

MRSA in Healthcare MRSA in the Community Prevalent genotypes (U.S.)USA100, USA200 USA300, USA400 Antimicrobial resistanceMultiple agents Few agents SCCmec (genetic element carrying mecA resistance gene) Types I-IIITypes IV, V PVL toxin geneRareCommon

 MRSA culture in outpatient setting or 1 st 48 hours of hospitalization AND patient lacks risk factors for healthcare-associated MRSA:  Hospitalization  Surgery  Long-term care  Dialysis  Indwelling devices  History of MRSA

 Often first detected as clusters of abscesses or “spider bites”  Various settings  Sports participants  Inmates in correctional facilities  Military recruits  Daycare attendees  Native Americans / Alaskan Natives  Men who have sex with men  Tattoo recipients

 Crowding  Frequent contact  Compromised skin  Contaminated surfaces and shared items  Poor hygiene  Antimicrobial use

Disease Syndrome (%) Skin/soft tissue1,266 (77%) Wound (Traumatic) 157 (10%) Urinary Tract Infection 64 (4%) Sinusitis 61 (4%) Bacteremia 43 (3%) Pneumonia 31 (2%) Fridkin et al NEJM 2005;352:

 MRSA belongs in the differential diagnosis of skin and soft tissue infections (SSTI) compatible with S. aureus infection: Abscesses, pustular lesions, “boils” “Spider bites” Cellulitis?

MRSA should also be considered in differential diagnosis of severe disease compatible with S. aureus infection e.g. osteomyelitis, empyema thoracic, necrotizing pneumonia, septic arthritis, endocarditis, sepsis syndrome, necrotizing fasciitis, purpura fulminans

 I&D should be routine for purulent skin lesions  Obtain material for culture  No data to suggest molecular typing or toxin- testing should guide management  Empiric antimicrobial therapy may be needed  Alternative agents have +’s and –’s: More data needed to identify optimal strategies

Antimicrobial Selection (SSTIs)  Alternative agents Clindamycin – Potential for inducible resistance, Relatively higher risk of C. difficile associated disease? TMP/SMX – Group A strep isolates commonly resistant Tetracyclines – Not recommended for <8 yo Rifampin – Not as a single agent Linezolid – Expensive, Potential for resistance with inappropriate use

Antimicrobial Selection (SSTIs)  Not optimal for MRSA (High prevalence of resistance or potential for rapid development of resistance) - Macrolides - Fluoroquinolones

Beta-Lactam Modified from David Spach, MD Cell Wall Cell Membrane Alternative Penicillin Binding Protein PBP2a DNA

IntravenousOral - Vancomycin* - Linezolid* - Daptomycin* - Tigecycline* - Quinupristin/dalfopristin * - TMP-SMX - Minocycline/Doxy - Clindamycin** - Fluoroquinolone - Linezolid* *FDA approved for MRSA **test for inducible resistance if erythromycin–R and clindamycin-S Rifampin should not be routinely used in combination for SSTI and NEVER alone due to rapid emergence of resistance.

So what are non-vanco options? Linezolid  Pros  100% oral bioavailability  Benefit in MRSA PNA?  Protein synthesis inhibitor  Cons  Static drug  Limited data in bacteremia and endocarditis  Adverse events ▪Marrow suppression ▪Serotonin syndrome ▪Lactic acidosis ▪Optic neuritis, peripheral neuropathy, Bell’s palsy  Cost Daptomycin  Pros  Cidal drug  Approved for bacteremia and right sided endocarditis  Cons  Not active in the lung  Parenteral only  Decreased susceptibility to vancomycin associated with decreased susceptibility to daptomycin  Emergence of resistance on therapy  Cost

 The most important contributing factor for resistance is overuse.  A good example is prescribing antibiotics that don’t kill viruses for the common cold.  These antibiotics do destroy the normal flora.  Opportunistic pathogens that are resistant survive and can take hold.

 For the acquisition of resistance › compromised people › extremely pathogenic organism › large amounts of different ATB use  Increased use of antibiotics  resistance  So hospital is a place where resistance can develop rapidly.

 The potential for global antibiotic resistance is real due to: > overuse of ATB > improper adherence to hospital infection control protocols > difficulty finding new ATB > ease of worldwide travel