Microbiology and Antibiotics Flashcards

Question

Notes on tetracyclines

Answer 1

* Tetracycline, doxycycline, minocylcine * Irreversibly binds to 30S subunit * Broad spectrum GP, GN, intracellular organisms, protazoan parasites * Resistance common * Proteus mirabilis only GN to have intrinisic resistance

Answer 2

* Semi-synthetic derivative of minocycline * Inhibits bacterial protein synthesis by binding to 30S subunit - 5x greater affinity caompared with tetracyclines → can overcome the ribosomal protection mechanism of tetracycline resistome * Broad GP (including VRE, MRSA, listeria), GN, anaerobic and atypical cover * Eliminated via biliary tract → not useful for UTIs (and doesn't require dse adjustment in CKD) * Active against GPs (VREM MRSA), GNs (ESBLs and AmpC producers), anaerobes, rapid growing mycobacteria and Nocardia, Actinetobacter, Strenotrophomonas * High VD → low serum concentrations, not suitable for initial treatment of bacteraemia * Only 25% excreted in urine - limited use in UTIs * Potential salvage therapy for C dif * Black box warning → increased mortality

Answer 3

* 50S subunit * Very active against gram positive and gram negative → clhamydia, mycoplasma, rikettsia * ADRs → bone marrow aplasia and other haemtological abnormalities * Grey baby syndrome in neonates and premies * Widely used in developing countries

Answer 4

* 50S subunit (and 30S) * GP - effective for E. faecium including VRE, MRSA, and MDR S pneumonia * Gets into brain and bone * 100% oral bioavailability * Bacterostatic against enterococci and staphylococci, bactericidal for most streptococci * Gram negatives natrually resistance * ADRs: bone marrow suppression , serotonin syndrome, **irreversible** peripheral neuropathy, optic neuropathy (rare) **Tedizolid** * Better version of linezolid * OD dosing (linezolid BD) * More potent, smaller doses possibly with less myelotoxicity

Answer 5

1. Polymyxins 2. Cyclic lipopeptides

Answer 6

* Target = membrane phospholipids (LPS, and lipoproteins) * Bind to cell membrane, alters structure and makes it more permeable, disrupting osmotic balance * Cell wall of GPs too thick to permit access * Polymyxin B * Narrow spectrum for GN used for UTI, blood, CSF and eye infections * Colistin * Narrow spectrum for GNs, especially P aueruginosa infections in CF patients. * Recent use for MDR Acinetobacter infections

Answer 7

* Binds to components (Ca ions) of cells membranes of susceptible organisms and causes rapid depolarisation, inhibiting intracellular synthesis of DNA, RNA, protein * Active against GP including those resistant to methicillin, vancomycin and linezolid * Gram negatives resistant * Inactivated by surfactant → cannot used for resp * **Adverse effects →** myopathy (serial CKs), peripheral neuropathy, eosinophilic pnuemonia

Answer 8

**Sulfamethoxazole** * Nucleotide and DNA formation requires tatrehydrofolate (TH4) * Bacteria make their own TH4 using PABA * If sulfa drug present - bacteria use this instead of PABA → inhibits production of TH4 **Trimethoprim** * TH4 gives up carbon atoms to form purines and other metabolic building blocks → TH2 and must be reduced back by dihydrofolate reductase * TMP looks like dihydrofolate reductase → competitively inhibits reduction → inhibits bacterial DNA formation TMP/SMX act synergistically **Spectrum:** * Wide GP and GN cover, no anaerobes, certain parasites (PCP, toxoplasma gondii, isosopora belli) * ADRs (rare in non-HIV) → rash, BM suppression, increased creatinine/K * Do not co-administer with methotrexate * TMP inhibits renal tubular secretion of creatinine affecting GFR

Answer 9

1. Fluoroquinolones (norfloxacin, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin) 2. Ansamycins (rifampicin)

Answer 10

* Target → topoisomerases e.g. DNA gyrus, regulates DNA supercoiling * Most potent activity against aerobic GNB (Enterobacter, P auroginosa, haemophilius) * Active against resp pathogens (levo and moxi more so than cipro) - strep. pneumoniae, haemophlius, moraxella, legionella, chlamydia, mycoplasma * Norfloxacin concentrates in urine → minimal activity outside urinary tract * Rapid bactericidal activity * ARDs: tendinopathy, unmasking MG, QTc prolongation * Chelation is an issue when taken with multivalent cations (Ca, Mg, Al, Fe, Zn)

Answer 11

* Forms a stable complex with RNA polymerase → prevents DNA from being trascribed into RNA → inhibits protein synthesis * Bacteriostatic or bactericidal (depending on on organism and concentration) * Primarily GP and some GNs * Low barrier to resistance → must be co-administered with another antimicrobial * Used in combinations with other drugs → S. aureus, M. tuberculosis, and contacts of N. meningitidis

Answer 12

* MRSA and other penicillin resistant bacteria - alteration of target- or binding site e.g. PBP the binding/target site of penicillins * ESBL - beta lactamases * Fluoroquinolones - reduced antibiotic permeability via cell wall

Answer 13

**General** * Previous antimicrobial therapy * Prolonged hospital stays * Requirement for ICU/dialysis/invasive procedures, indwelling catheters/venous catheters **MRSA** * Maori and Pacific ethnicity **ESBL and VRE** * Rest home facilities **CRO (NDM-1)** * Patients who have received medical care in India or Pakistan

Answer 14

* Resistance conferred by mecA gene carried on a mobile genetic element - the Staphylococcal cassette chromosome - encodes and additional penicillin binding protein (PBP2a) → transpeptidase (cross-links bacterial cell wall peptidoglycan) with poor affinty for ALL beta lactam antibiotics (penicillins, cephalosporins (exception caftaroline) (I-IV), carbapenams) * Not enzymatic → can't be overcome by beta-lactamse inhibitor * **Panton-Valentine Leucocidin** * PVL → pore forming necrotising endotoxin. * Initially considered important in pathogenesis of necrotising pneumonia and soft tissue infections, but not endocarditis or bacteraemia * Now thought to be likely an epidemiological marker of a particular strain causing more severe disease rather than the key pathogenic factor * More commonly seen in community MRSA than hospital

Answer 15

**Non-severe** * Options include: co-trimoxazole, clindamycin, erythromycin, doxycycline, rifampicin, gentamicin * Rifampicin or fusidic acid = rapid resistance if used as monotherapy **Severe** * Vancomycin (glycopeptide) * Alternatives 1. **Daptomycin -** non inferior to vanc but poor CNS penetration, inactivated by surfactant 2. **Teicoplanin -** comparable efficacy to vanc, often underdosed and needs drug monitoring 3. **Ceftaroline (5th gen cephalosporin) -** high affinity for PBP2a 4. **Quinupristin-dalfopristin -** side effects - myalgias, infusion reactions, nausea 5. **Linezolid -** good oral bioavailability and tissue penetration, bone marrow suppression and peripheral neuropathy 6. **Clindamycin** - high oral bioavailability, not recommended for endovascular infections 7. **Co-trimoxazole -** inferior to vanc for endovascular infections, best for skin/soft tissue

Answer 16

* VRSA → acquisition of a plasmid containing the mobile transposon with the vanA gene from VRE → alters the unlinked peptidoglycan terminus * Rx daptomycin + another agent (Co-trim, gent, rifampicin) * VISA → vancomycin intermediate S. aureus (mechanism thought to be due to cell wall thickening) * hVISA → heterogenous VISA - isolates appear to have a susceptible MIC for vancomycin, but have a subpopulation that are VISA - population analysis profile required to detect these

Answer 17

* Enterococci (E. faecium, E. faecalis) * Typical sites of infection → UTI/catheter associated, central line, bacteraemia/endocarditis, pelvic/abdominal, wound * Typically treated with penicillin, amoxicillin/ampicillin or vancomycin * Intrinisic resistance to multiple antibiotics - _cephalosporins_, macrolides, glycopeptides, tetracyclines, fluroroquinolones * E.faecium typically resistant to amoxicillin, E. faecalis often sensitive * Changes enterococcal cell wall to prevent vancomycin binding. D-ALA-D-ALA → D-ALA-D-LAC * 5 groups of vancomycin resistance (Van A → E). VanA and VanB typically seen in E.faecium and E.faecalis * VanA gene cluster confers resistance to vancomycin and teicoplanin, vanB confers resistance to vancomycin only * Transferable resistance mechanism (plasmid) to eneterococci and other bacteria (e.g. VRSA) * Limited treatment options → penicillin (maybe only vanc resistant), teicoplanin (VanB, Van C), linezolid, daptomycin, tigecycline, quinupristin-dalfopristin, ceftroline (but not E. faecium) * Simple UTIs may be treated with nitrofurantoin or fosfomycin

Answer 18

1. Altered porins 2. Beta-lactamases - AmpC, ESCL, CRE 3. Prevention of binding - altered PBPs 4. Efflux pumps

Answer 19

* Most common mechanism of resistance in gram-negative bacteria against beta lactam drugs * May be called penicillinases or caphalosporinases * Many different enzymes now → nearly 900 identified * Include ESBLs KPC, NDM-1, AmpC, OXA

Answer 20

**ESCHAPPM organisms** * Found on chromosomes in the following bacteria * Enterobacter * Serratia * Citrobacter ffreundii (not koseri) - freundii not your friend * Hafnia alvei * Acinetobacter and Aeromonas * Proteus vulgaris (not mirabilis) * Providencia * Morganella **May appear sensitive to 2nd and 3rd generation cephalosporins on initial lab testing** **Resistance develops during treatment because of:** * An inducible cephalosporinase or * Antibiotic therapy selects out a derepressed mutant Cefepime is still effective against AmpC organisms * AmpC beta-lactamases either chromosomally mediated or plasmid mediated - plasmid mediated = infection control nightmare **Antibiotics for ESCHAPPM organisms** * Carbapenams - empiric antibiotic of choice * Cefepime * Tazocin maybe * Once sensitivies known - quinolones, co-trimoxazole, aminoglycosides may be an option

Answer 21

* Resistant to all penicillins, cephalosporins (including cefepime) and aztreonam * May also carry genes that confer resistance to several non-beta lactam antibiotics * Prior hospitalisation and antibiotic therapy (particularly cephalosporins) risk factors, also travel to Asia/India * ESBL genes carried on plasmids and easily transferrable between bacteria * Most commonly found on E.coli and Klebsiella **Treatment** * Carbapenams * ESBLs are inhibiteted by beta-lactamase inhibitors - clavulanate, tazobactam but some bacteria produce such large amounts of ESBL they can overwhelm the beta-lactamase inhibitor * **OP UTI treatment options for ESBL** * Nitrofurantoin - many ESBLs susceptible * Depending on susceptibilities - cipro, cotrim, boosted Augmentin, fosfomycin

Answer 22

* Mechanisms of resistance - efflux pumps, porin mutations, carbapenemase * 3 main groups: * Klebsiella pneumoniae carbapenemase (KPC) * Metallo-beta lactamases - e.g. New Delhi beta lactamases (NDM) * Oxacillinases (OXA 48) * Metallo-beta lactamases have a zinc moiety at active site, others have serine * Treatment with single agent = high mortality (40%). Combination therapy recommeneded * Colistin - effective against most, limited by nephro- and neurotoxicity * Tigecycline - bacteriostatic, poor tissue penetration * Amikacin - aminoglycoside, resistance mechanisms to the aminoglycosdes often carried on the same plasmid * Fosfomycin -efficacious in cystitis, data otherwise lacking * Ceftazidime-avibactam, ceftaroline-avibactam - efficacy against OXA and KPC groups but not NDM * Sometimes → high dose carbapenams

Answer 23

* Recent case report in NZ - mycobacterium chimaera following cardiac surgery * Limked with use of a heater/coller device commonly used in cardiac surgery * Should be suspected in patients who have had cardiac surgery presenting with fatigue/fever/pain (including muscle/joint), redness, heat or puss at surgical site/night sweats/weight loss/abdominal pain, nausea/vomiting * Cultures will be negative and patient will not respond to conventional antibiotics

Answer 24

* Aminoglycosides * Erythromycin * Tetracyclines * First generation cephalosporins

Answer 25

* Empiric → ceftriaxone and metronidazole **Specific antibiotics** * Pencillin G → covers most mouth flora inc. aerobic and anaerobic streptococci * Metronidazole - readily penetrates brain abscesses. Excellent activity against anaerobes, not active against aerobic oganisms * Ceftriaxone → covers most aerobic, microaerophilic streptococci, and enterobacteriaceae * Ceftazidime → use in the setting of abscess following neurosurgical procedure, or when culture grows Pseudomonas * Vancomycin → should be used following penetrating head injury or craniotomy, or S. aureus bacteraemia

Answer 26

* Non severe - oral vancomycin or fidaxomicin (metronidazole acceptable for low-risk patients) * Severe or fulminant → oral vancomycin or fidaxomicin. * FMT for refactory cases

Answer 27

* Recommend metronidazole in: * Putrid sputum * Severe peridontal disease * History of chronic hazardous alcohol consumption * Development of lung abscess, empyema, necrotising pneumonia * Do not respond to initial empiric therapy

Answer 28

**Most common down** * Streptococcus pneumoniae * Mycoplasma * Influenza * Picornaviruses * Haemophilus * Legionella * rsv * Chlamydia species * Psuedomonas * Gram negative enteric bacilli * S. aureus * Moraxella catarrhalis

Answer 29

* SMART-COP * CORB

Answer 30

* Common cause of CAP in spring/summer in NZ (cover Sept → March) * Does not respond to beta-lactams * Can't distinguish from other causes of CAP * Suspicion raised based on time of year, exposure to potting mix, not improving on amoxicillin * Test if severe CAP in hospital * PCR of sputum * Urinary antigen not recommended → does not detect L. longbaechae - commonest cause in NZ (only detects L pneumophila serogroup 1)

Answer 31

* HECKY → Hafnia alvei, enterobacter cloacae, citrobacter freundii, Klebsiella aerogenes, Yersinia enterocolitica (Yersinia and Hafnia less well studied) * initially appear to be sensitive to beta-lactams but treatment failures seen due to an inducible cephalosporin/beta-lactamase - chromosomal AmpC (Amber class c) * Antibiotics that are poor substrates and weak inducers of AmpC → cefepime or meropenam

Answer 32

_CAMERA 2 study_ * RCT comparing flucloxacillin + standard therapy vs standard therapy alone for MRSA bacteraemia (standard therapy = vancomycin) * Ceased early due to nephrotoxicity in fluclox + vanc group → AKI even when vancomycin in therapeutic range * Nephrotoxicity also observed with co-administration of Tazocin

Answer 33

* Mechanism of resistance to penicillins and cephalosporins is via alteration of PBPs (addition of clavulanic acid will do nothing) * Pneumococci develop antibiotic resistance by transformation - acquisition of genetic material from other bacteria in close proximity **Macrolide resistance** * Either via mefA gene (efflux pump) or ermB gene (alteration of binding site) * Macrolide resistance cannot be overcome by higher doses (penicillin often can)