Antibiotics

קדייח ןפוד הנבמ

קדיחה ןפוד תזתניס

Resistance mechanism

• Beta-lactamases (eg. ESBLs, Carbapenemase) • Target modifying enzymes (PBP) • Drug modifying enzymes • Porin loss • Efflux pump • VISA/VRSA • VANs

Resistance mechanism

Penicillin Binding Protein (PBP)

• Low affinity of beta lactam to penicillin binding proteins (transpeptidases) – – –

MRSA

- low affinity to PBP2a (mecA gene)

Pneumococci

- PBP2b, 2x

Enteroccoci

- PBP5 (also some of them have beta-lactamase)

Resistance mechanism

Beta-lactamase

• Enzymes produced by some bacteria, hydrolyzing the beta-lactam ring • Plasmid, chromosomal –

Class A

(all

inhibited

by calvulanate) • Penicillinase (SA, E.coli, KP, HI, NG) • penicillinase+cefalosporinase •

penicillinase+cefalosporinase+ cefalosporinase s 3 (ESBLS)

• carbapenemase –

Class B

(metalloenzymes,

not inhibited

by calvulanate)) • hydrolyse penicillins, cefalosporins, carbapenems –

Class C

(SPICE) -

Amp C

chromosomal, induced,

not inhibited

by calvulanate • Cefalosporinase 3 –

Class D

• oxacillanase (usually with penicillinase, sometimes carbapenemase)

Resistance mechanism

Beta-lactamase

•

ESBLs

- Augmentin-S, Cefotaxime-R, Ceftazidime-R, cefamycin-S – Most of them also resistance to AG, resprim and quinolones, and beta lactam+inhibitor – Members of

enterobacteriacea

commonly express plasmid encoded beta lactamases (TEM, SHV) or extended beta lactamases (CTX-M) •

AmpC- class C

- chromosomal inducible – Augmentin-R, Cefotaxime-R, Ceftazidime-R, Cefamycin-R •

Carbapenemase

– PA, acinetobacter •

KPC

- derived from class A and contains carbapenemase

Resistance mechanism

Beta-lactamase

Resistance mechanism

Beta-lactamase

Resistance mechanism

Staphylococcus aureus

• •

Beta lactamase-

resistance to penicillin

Low affinity to PBP2a

(MRSA) (mecA gene)- resistance to methicillin • •

VISA VRSA

- VANA from enterococcus

Resistance mechanism

-

enterococci

•

Intrinsic

resistance to

AG

• Modifying enzymes- acetyltransferase, adenyltransferase, phosphotransferase •

Intrinsic (relative)

resistance to

penicillin

through PBP5 (totally R to cefalosporins) • • Beta lactamase- rare, fecalis, IE

VRE-

– VANA– produced ligase which produces D-lactate end, resistance to vancomycin and teicoplannin – VANB- R to vancomycin

Beta lactams

• Penicillins • Beta-lactamase inhibitors • Cephalosporins • Cephamycins • Carbapenems • Monobactams

Beta-lactams

Penicillins

•

Penicillin G

•

Antistaphylococcal penicillins

– nafcillin, oxacillin, cloxacillin and dicloxacillin •

Broad spectrum penicillins

– Second generation (ampicillin, amoxicillin and related agents) – Third generation (carbenicillin and ticarcillin) – Fourth generation (piperacillin)

Beta-lactams

Penicillin G- spectrum of activity

•

Penicillin G

is highly active against: – Gram-positive cocci (except penicillinase-producing staphylococci, penicillin-resistant pneumococci, enterococci, and oxacillin-resistant staphylococci) – Gram-positive rods such as Listeria – Gram-negative cocci such as Neisseria sp (except penicillinase producing Neisseria gonorrhoeae) – Most anaerobes (with certain exceptions, such as Bacteroides)

Beta-lactams

Penicillin G- spectrum of activity

• Penicillin G is only

bacteriostatic for enterococci

–

Serious infections

with enterococci are generally treated with combination therapy of a

cell wall active antibiotic

penicillin, ampicillin, or vancomycin streptomycin

plus gentamicin

such as or • Penicillin G is not active against gram-negative bacilli because of poor penetration through the porin channel.

Beta-lactams

Antistaphylococcal penicillins

nafcillin, oxacillin, cloxacillin and dicloxacillin

• Inhibit penicillinase-producing staphylococci but are inactive against oxacillin-resistant staphylococci •

for strains of S. aureus sensitive to oxacillin, antistaphylococcal penicillins are preferable to vancomycin

• Antistaphylococcal penicillins have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria sp.

Beta-lactams

Broad spectrum penicillins (2

nd

, 3

rd

, 4

th

generations)

• • Activity against

gram-negative bacilli None

of the broad spectrum penicillins is effective against

penicillinase-producing staphylococci

• The third and fourth-generation penicillins are generally considered together as anti-Pseudomonal penicillins •

Second generation

–

Ampicillin

,

amoxicillin

– Can penetrate the porin channel of gram-negative bacteria but are not stable to beta-lactamases – Active against the majority of strains of Escherichia coli, Proteus mirabilis, Salmonella, Shigella, and Haemophilus influenzae – Active against non-type b hemophilus influenza.

Beta-lactams

Broad spectrum penicillins (2

nd

, 3

rd

, 4

th

generations)

•

Third generation (Carbenicillin and ticarcillin)

– Can penetrate the porin channel of gram-negative bacteria, but they are

less active than ampicillin

aeruginosa; – Ticarcillin is a disodium bleeding time.

salt

on a weight basis. – More resistant to the chromosomal beta-lactamases of certain organisms, such as indole-positive Proteus species, Enterobacter species, and Pseudomonas aeruginosa. – Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. (which may cause a problem in patients with volume overload) and may cause a bleeding diathesis by inhibition of platelet function and prolongation of the

Beta-lactams

Broad spectrum penicillins (2

nd

, 3

rd

, 4

th

generations)

•

Fourth generation (piperacillin)

–

Piperacillin

is a derivative of ampicillin . – The same spectrum as carbenicillin and ticarcillin but is more active in vitro on a weight basis. – .It is more active than carbenicillin or ticarcillin against enterococci and Bacteroides fragilis – Piperacillin is somewhat more active against Enterobacteriaceae than carbenicillin or ticarcillin and more active than ticarcillin against P. aeruginosa. – Piperacillin has less effect than ticarcillin on platelet function

Beta-lactams

Penicillins- pharmacology

•

Time dependent killing

• High therapeutic levels in pleural, pericardial, peritoneal and synovial fluids, as well as urine • • High bile level

Penetrate the CSF poorly

in the absence of inflammation but achieve therapeutic levels in patients with meningitis who are given high dose parenteral therapy

Beta-lactams

Beta lactamase inhibitors

• A drug given in conjunction with a beta-lactam antibiotics.

• The inhibitor does not have usually antibiotic activity • It inhibits activity of

plasmid mediated

beta lactamase – – –

Calvulanic acid Sulbactam Tazobactam

•

Amoxicillin-calvulanate (Augmentin)

– Oxacillin-sensitive SA and beta-lactamase producing HI in addition to the usual organisms inhibited by amoxocillin alone – Can be used orally for AOM, sinusitis, LRTI, UTIs and bite wounds

Beta-lactams

Beta lactamase inhibitors

•

Ampicillin-sulbactam (Unasyn)- IV

– Beta lactamase producing SA, HI and enterobacteriacea, anaerobes – Abdominal infections – Diabetic foot –

Sulbactam has activity against AB

•

Ticracillin-calvulanate and piperacillin-tazobactam (timentin and tazocin)

– Beta lactamase producing SA, HI, NG, enterobacteriacea and anaerobes – Not effective for ticracillin or piperacillin resistant strains of PA

Beta-lactams

Cephalosporins

•

First generation

(cefazolin) •

Second generation

– activity against Haemophilus influenzae (cefuroxime) – Cephamycin subgroup with activity against Bacteroides •

Third generation

– poor activity against Pseudomonas aeruginosa (cefotaxime, ceftriaxone) – good activity against Pseudomonas aeruginosa (cefoperazone and ceftazidime) •

Fourth generation

(cefepime)

Beta-lactams

Cephalosporins

•

First and second

generation

should not

be used to treat infections of the

central nervous system

•

The third

generation cephalosporins achieve much more reliable CSF levels in patients with meningeal irritation •

Cefotaxime

,

ceftizoxime

,

ceftriaxone

, and

ceftazidime

are approved for the treatment of bacterial meningitis

Beta-lactams

Cephalosporins Spectrum of activity

•

First generation- cefazolin

– Most gram-positive cocci (including penicillinase-producing staphylococci) – Does not have clinically useful activity against enterococci, Listeria,

oxacillin

-resistant staphylococci, or penicillin-resistant pneumococci – Active against most strains of Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, but has little activity against indole-positive Proteus, Enterobacter, Serratia, and the non-enteric gram-negative bacilli such as Acinetobacter spp and Pseudomonas aeruginosa.

– Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae are generally

resistant.

Beta-lactams

Cephalosporins Spectrum of activity

•

Second generation

– less active against gram-positive cocci than the first-generation agents but are more active against certain gram-negative bacilli – Two subgroups: • Activity against HI • Cephamycins- activity against bacteroides

Beta-lactams

Cephalosporins Spectrum of activity

•

Second generation

• Activity against HI cefuroxime – More active than cefamezine against HI –

Approved

for HI meningitis but

ceftriaxone preferred

– Active against Beta- lactamase producing Moraxella catarrhalis • Cephamycin subgroup (active against Bacteroides) – Cefoxitin, cefotetan – Active against gram negative the same as cefamezine – Stable to plasmid mediated beta-lactamase – prophylaxis and therapy of infections in the abdominal and pelvic cavities

Beta-lactams

Cephalosporins Spectrum of activity

•

Third generation cefalosporins

– stability to the common beta-lactamases of gram-negative bacilli – highly active against Enterobacteriaceae (E.coli, Proteus mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria and H. influenzae – Mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal beta lactamase, are

resistant

to these antibiotics

Beta-lactams

Cephalosporins Spectrum of activity

•

Third generation cefalosporins

– Less active against most gram-positive organisms than the first generation cephalosporins and are inactive against enterococci, Listeria, oxacillin-resistant staphylococci, and Acinetobacter – cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third generation cephalosporins as well

Beta-lactams

Cephalosporins Spectrum of activity

•

Third generation cefalosporins

– Poor activity against pseudomonas - Ceftriaxone, cefotaxime – Ceftriaxone- longest half life (6h), sludge – Activity against PA • Ceftazidime - stable to the common plasmid-mediated beta lactamases , highly active against Enterobacteriaceae, Neisseria, and H. influenzae, and against P. aeruginosa.

• Ceftazidime has

poor activity against gram-positive

organisms

Beta-lactams

Cephalosporins Spectrum of activity

•

Fourth-generation - cefepime

– Better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal beta-lactamases of gram-negative bacilli. – Similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and oxacillin-sensitive S. aureus. – Active against the Enterobacteriaceae, Neisseria, and H. influenzae (like cef3) – Greater activity against the gram-negative enterics that have a broad spectrum, inducible, chromosomal beta-lactamase (Enterobacter, indole positive Proteus, Citrobacter, and Serratia) – Cefepime is as active as ceftazidime for Pseudomonas aeruginosa, and is active against some ceftazidime-resistant isolates – increased all-cause mortality?

Beta-lactams

Cephalosporins Spectrum of activity

•

Fifth generation-

–

Ceftobiprole

• capable of binding to penicillin binding protein 2a, the protein conferring S. aureus resistance to beta-lactam antibiotics • It can also bind penicillin binding protein 2x in penicillin resistant S. pneumoniae • It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacteriaceae; it also has activity against enterococci

Beta-lactams

Cephalosporins Treatment indicators for 3

rd

or 4

th

generation drugs

• May be complicated by superinfection (particularly with enterococci or Candida) or by the emergence of resistance on therapy (particularly when used as single agents for Enterobacter, indole positive Proteus, or P. aeruginosa infections) • Therapy of choice for

gram-negative meningitis penicillin-resistant gonococcal ampicillin-resistant H. influenzae

due to Enterobacteriaceae. Ceftriaxone is a therapy of choice for infections and meningitis due to . Ceftriaxone is also one of the recommended therapies for

Lyme

disease involving the CNS or joints

Beta-lactams

Carbapenems

• Carbapenems are generally resistant to cleavage by most plasmid and chromosomal beta-lactamases and have a very broad spectrum of activity: • Gram negative organisms (including beta-lactamase producing H. influenzae and N. gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa), including those that produce extended spectrum beta-lactamases • Anaerobes (including B. fragilis) • Gram positive organisms (including Enterococcus faecalis and Listeria) – PA- resistance may emerge on therapy when used as single agent • Porins/membrane channels (not those used by other beta lactams)

Beta-lactams

Carbapenems

•

Imipenem -

– Inactivated in the proximal renal tubule by dehydropeptidase I, (prevented by co-administration of cilastatin) – Imipenem-cilastatin therapy has been associated with central nervous system (CNS) toxicity, especially evident in patients with underlying CNS disease or impaired renal function. – Imipenem should not be used for the therapy of meningitis. The dosing of imipenem should be carefully titrated; patients with glomerular filtration rates of <5 mL/min should generally not receive imipenem

Beta-lactams

Carbapenems

•

Meropenem

– Stable to dehydropeptisase1 – Can be administrated without cilastatin – Lower risk of seizures – Approved for bacterial meningitis •

Ertapenem-

– Enterobacteriacea and anaerobes

but less active against PA, AB,

gram positive bacteria particularly

enterococci and PRSP

•

Doripenem

Monobactams

•

Aztreonam

– Gram negative bacteria including PA – No activity against anaerobes or gram positive bacteria –

Similar to AG

– Absence of cross allergenicity

Macrolides/Ketolides

Azithromycin, Clarithromycin and Telithromycin

• Derivatives of erythromycin • Bind to the 50s ribosomal subunit • newer macrolides are more acid-stable than erythromycin, providing improved oral absorption, tolerance, and pharmacokinetic properties. • The newer macrolides have a broader spectrum of antibacterial activity than erythromycin • acquired resistance: – A

methylase

encoded by the

ermB/A gene

alters the macrolide binding site on the bacterial

ribosome

, usually confers a high degree of resistance

(MLSB)

– An active

macrolide efflux pump

encoded by the

mef

(macrolide efflux) gene, which confers a low to moderate degree of macrolide resistance (

msrA

in SA) – Pneumococcal resistance U.S-

15-20%

– Azithro, clarithro, telithro have enhanced gram negative activity compared with erythromycin

Staphylococcus aureus Erythromycin R Clindamycin S D test, induction of ribosomal methylation (erm gene). Do not use clindamycin.

No induction, macrolide efflux (msrA gene). Can use clindamycin

Azithromycin, Clarithromycin and Telithromycin

–

URT infections

: erythro-sensitive SP, Hemophillus sp., M. catarrhalis, legionella, chlamidophila pneumonia, Mycoplasma pneumonia – usually active against other

gram-positive organisms

including Staphylococcus aureus (except for MRSA), and Group A, B, C, G streptococcus – The

gram-negative spectrum

includes activity against Escherichia coli, Salmonella spp, Yersinia enterocolitica, Shigella spp, Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae, and Helicobacter pylori – MAC

Azithromycin, Clarithromycin and Telithromycin

• Tissue and intracellular penetration — All macrolides and ketolides distribute and concentrate well in most body tissues and phagocytic cells • Prolonged half life- azithro • Major adverse events: – Hepatotoxicity (telithro) – GI upset 2-5% (azithro, clarithro) – Long QT- erythro, clarithro (usually with other drugs)

Aminoglycosides

• Gentamicin, Aamikacin, Tobramycin • binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation • Treatment of serious infections caused by

gram negative bacilli

• Treatment of selected staphylococcal and enterococcal infections

in combination with beta lactams

• • Antiprotozoa (paromomycin), NG (spectinomycin), mycobacteria (streptomycin)

bactericidal

against susceptible aerobic

gram-negative bacilli

• The microbiologic activity of aminoglycosides is

pH dependent

Aminoglycosides

Two important pharmacodynamic properties of aminoglycosides

• Postantibiotic effect (PAE) – persistent suppression of bacterial growth that occurs after the drug has been removed in vitro or cleared by drug metabolism and excretion in vivo – described for gram-negative bacilli, also against Staphylococcus aureus (but not against other gram-positive cocci) – approximately 3 hours • Concentration-dependent killing – ability of higher concentrations of aminoglycosides (relative to the organism's MIC) to induce more rapid, and complete killing of the pathogen

Aminoglycosides Resistance

• •

Amikacin

is usually reserved for

serious gram-negative infections

due to a gentamicin or tobramycin-resistant organism or as part of combination therapy against atypical mycobacterial infection

Gram negative organisms

: (acquired resistance) – Inactivation of the drug by phosphorylation , adenylylation, or acetylation – Another mechanism is methylation of 16S ribosomal RNA, associated with high level resistance to all parenteral aminoglycosides in current use – Decreased accumulation of the drug

Aminoglycosides Resistance

•

Enterococci-

Intrinsic resistance to low-moderate levels of aminoglycosides • synergy exists when enterococci with low-level resistance, are exposed to a combination of the aminoglycoside with a cell wall agent • increasing reports of acquired high-level enterococcal resistance to aminoglycosides (MIC >2,000)

Aminoglycosides Spectrum

• Aaerobic gram-negative pathogens (Enterobacteriaceae, Pseudomonas, Haemophilus influenzae) • In vitro activity against Burkholderia cepacia, Stenotrophomonas maltophilia, and anaerobic bacteria is usually

poor or absent

• Activity in vitro against methicillin-susceptible S. aureus (MSSA) • Activity against pneumococci is generally considered

insufficient

• Empiric therapy of serious infections such as septicemia, nosocomial respiratory tract infections, complicated urinary tract infections, complicated intra-abdominal infections, and osteomyelitis caused by aerobic gram-negative bacilli.

Aminoglycosides Spectrum

• Combination (usually with a beta-lactam) for serious infections due to Pseudomonas spp, indole-positive Proteus, Citrobacter spp, Acinetobacter spp, and Enterobacter spp. • Combination therapy with gentamicin is frequently used for the treatment of invasive enterococcal infections not exhibiting high level aminoglycoside resistance and sometimes for serious staphylococcal and viridans streptococcal infections.

Aminoglycosides

Toxicity

• • •

Nephrotoxicity

– 10-20% (highly variable) – Mostly reversible

Ototoxicity

– Vestibular or cochlear

Neuromuscular blockadge

– MG

Aminoglycosides Monitoring serum concentrations

• Trough concentrations are measured within 30 minutes of the next dose and peak concentrations 30 to 45 minutes after the end of an intravenous infusion • Frequency • Target peak for genta/tobra: – Serious invasive infections 6-8 mcg/ml, life threatening 7-9 – Synergy (gram positive cocci) 3-4 • Trough – Less than 2

vancomycin (glycopeptide)

• Glycopeptide • Inhibition of cell wall synthesis in gram positive bacteria • Binds to D-alanyl-D-alanine in the NAM/NAG peptide • Invasive gram positive infections (MRSA, enterococci), penicillin allergy, PMC •

Should not be used for MSSA!!!

• AUC/MIC- best predictor of efficacy (time to MIC) • High clinical failure rate in patient infected with SA isolates with MIC ≥2mcg/ml

vancomycin (glycopeptide) Adverse events

• Mississippi mud • Rash • Red man syndrome- histamine mediated flushing ( no more than 500 mg/hr), sometimes angioedema and hypotension • Serum concentration monitoring: – Trough vs peak – Trough- at least 10mcg/ml – Serious infections: trough 15-20 – MIC >1, trough 15-20 – MIC≥2, daptomycin • Whom to monitor – Therapy longer than 3 days

vancomycin (glycopeptide) Resistance

• Staphylococcus aureus: VISA, VRSA • Enterococcus: VAN-A/B

• Streptogramins • Linezolide • Lipopeptides • Tigecycline • Doripenem • Glycolipopeptides • Ceftobiprole

New agents

Streptogramins- Quinpristin-dalfopristin (Synercid)

• Type B and A streptogramins • Target the late and early stages of bacterial protein synthesis • Synergistic • In vitro- MRSA, VRE- not fecalis!!

• Indicated for (FDA approved) – –

VRE faecium infections Complicated skin and skin-structure infections caused by MSSA ans S. pyogenes

• Not enough evidence for its use in VRE endocarditis • MRSA skin and skin structure infections- 70% clinical success (open labeled), less if bacteremia or RTI (40%) • Gram-positive nosocomial pneumonia- success rate comparable to vancomycin (55%) • Adverse events: high rate of phlebitis, myalgias or arthralgias, cholestasis • Resistance- low – MLSB (gram positive rods)

Linezolide

• Oxazolidinone, IV and PO • In vitro- gram positive cocci including MRSA and VRE • Bacteriostatic • Inhibiting bacterial protein synthesis • FDA-approved indications: – VRE faecium – Resistant SA, S.pypgenes, pneumococci, S. agalactiae – Nosocomial and community acquired pneumonia, uncomplicated or complicated skin and skin-structure infections, including diabetic foot but not those with osteomyelitis or decubitus ulcer • VRE faecium Endocarditis- not enough data. Acceptable to VRE with concomitant resistance to AG and penicillins

Daptomycin

• Cyclic lipopeptide • Gram positive pathogens, staphylococci and enterococci regardless of their resistance profile to methicillin or vancomycin • Rapidly bactericidal • Membrane depolarization • FDA approved indications: – Complicates skin and skin-structure infections caused by susceptible isolates of specific gram positive pathogens – SA bloodstream infections including right sided endocarditis • VRE. Faecium endocarditis- scarce data, may be considered • Should not be selected for pulmonary infections (inactivation by surfactant) • VISA- diminished susceptibility to daptomycin because of trapping of the drug in the thickened cell wall

Tigecycline

• Derivative of minocycline • Glycylcycline • Broad spectrum- aerobic and anaerobic gram positive and gram negative pathogens, atypical pathogens,

but not p. aeruginosa

• FDA approved indications: – Complicated skin and skin-structure infections – Complicated intra-abdominal infections – Community acquired pneumonia – Adverse events: mainly GI

Newer carbapenems

•

Ertapenem

- lacks in vitro activity against P. aeruginosa , other non fermentative gram negative bacteria, enterococci • Once daily administration • FDA approved for complicated abdominal infections, complicated skin and skin structure infections (including diabetic foot without osteomyelitis), CAP, complicated UTI, PID •

Doripenem

• FDA approved for complicated intra-abdominal infections and complicated UTIs • In comparison with tazocin and imipenem/cilastatin for nosocomial pneumonia and VAP was found favourable • No convulsions

colistin

• Reintroduced to clinical practice • Gram negative pathogens • AB, PA

New glycopeptides and lipoglycopeptided (not yet on clinical practice)

• Oritavancin- potent bactericidal against MRSA, VISA and VRE, mainly had been evaluated in clinical trials for csssi • Dalbavancin- MRSA, not against VRE with VANA, x1/w,csssi telavancin- MRSA, VRE, csssi, nosocomial pneumonia

When man extinct, micro organisms will rule the world, as they always did.

Quinolones

• Fluoroquinolones inhibit DNA gyrase and topoisomerase IV • • Bactericidal

Resistance

- mutation at DNA gyrase/topoisomerase gene or efflux pump, plasmid encoded qnr genes (kp, ecoli enterobacter) • Related to intensity and duration of therapy • Increasing resistant NG, c.jejuni, SP • Related to MRSA appearance in hospitals • Spectrum – Aerobic gram negative bacilli – Haemophilus sp – Gram negative cocci (neisseria and moraxella) – Non enteric GNR – Staphylococci – Atypical bacteria- chlamydophila pneumoniae, mycoplasma pneumonia, legionella pneumophila, chlamydia trachomatis, ureoplasma urealiticum, mycoplasma hominis

Quinolones

• Ciprofloxacin- the most potent against gram negatice bacteria • Levofloxacin, moxifloxacin- better acticity against gram positive cocci • Moxifloxacin- anaerobes • Mycobacteria – Pulmonary TB- Moxifloxacin vs ethambutol, Moxifloxacin vs INH • Levofloxacin and moxifloxacin have increased potency relative to ciprofloxacin and ofloxacin against SP • Gemifloxacin is the most potent against SP (rash) • Marginal activity against enterococci • High bioavailability • Use in pregnancy- safety has not been established • Use in children- not recommended for routine use <18y • Adverse events: GI (5-15%), CNS (1-10% ), rash-1%(gemi), arthropathy- rare and reversible, tendinitis and tendon rupture 3/1000 adults and dose related

Newer fluroquinolones

• Moxifloxacin, gemifloxacin • Enhanced invitro activity against gram positive pathogens, in comparison with ciprofloxacin (particularly SP, PRSP) • Activity against anaerobic and atypical bacteria • Less active than ciprofloxacin for P. aeruginosa • Good bioavailability • Main indication- CAP • Moxi is approved for sinusitis, skin infections and abdominal infections