Antibiotics

Classification of common antibiotics

Inhibition of cell wall synthesis o -lactams Penicillins Cephalosporins 1st, 2nd, 3rd & 4th generation Carbapenems Monobactams Glycopeptides Bacitracin Cycloserine (anti-TB)

o o o

Inhibition of protein synthesis o Aminoglycosides o Tetracyclines o Chloramphenicol o Macrolides o Lincosamides o Streptogramins o Oxazolidinones o Fusidic acid Inhibition of nucleic acid synthesis

Quinolones 1st, 2nd, 3rd & 4th generation o Rifamycins Inhibition of metabolic pathways that affect nucleic acid synthesis o Sulphonamides o Trimethoprim (& co-trimoxazole) Damaging DNA o Nitroimidazoles Inhibition of cell membrane function o Polymyxins

Resistance Bacteria can be inherently resistant, develop resistance (via mutation) or acquire resistance (via plasmids or
conjugation) o E.g. Gram negatives have an outer lipopolysaccharide layer (LPS) which means that they are less permeable to large molecules than Gram positives o Many Gram negatives have -lactamases inherently

Some bacteria more prone to developing resistance via mutation than others, e.g. Pseudomonas, which only requires one point mutation to become resistant to many antibiotics o Most bacteria require a lot of mutation to become resistant, so most of the resistance we see is because the bacteria is inherently resistant or acquires it Mechanisms of resistance o Target site altered o Decreased permeability of cell wall or pumping drug out of cell (efflux)

Enzymes that modify/destroy antibiotic (drug inactivation), e.g. -lactamases, aminoglycoside modifying enzymes, chloramphenicol acetyl transferase

Resistance is driven by the antibiotics given, so it is best to give the simplest antibiotic that the bacteria is susceptible to in order to prevent selecting out resistant strains or causing the development of resistance e.g. meropenem shouldnt be 1st line for Acinetobacter, vancomycin shouldnt be first line for Enterococcus for fear of VRE developing

-lactams
Action Bactericidal Contain a -lactam ring in structure Different groups distinguished by structure of ring attached to -lactam ring & side chains Inhibit cell wall (peptidoglycan) synthesis by binding to penicillin binding proteins (PBPs)

PBPs are membrane proteins that are responsible for the final stages of cross-linking of peptidoglycan structure so if inactivated by -lactams, precursor peptidoglycan units accumulate and the cell undergoes autolysis Most are parenteral (IMI or IV) Most only get into CSF if meninges are inflamed Generally not effective against intra-cellular organisms (e.g. Brucella, Legionella & Chlamydia), those that lack a cell wall (e.g. Mycoplasma) or those with impenetrable walls (i.e. Mycobacteria) All excreted in urine can be issue if patient in renal failure Probenecid can be administered concurrently to slow down excretion & maintain higher blood & tissue concentrations for a longer period of time Type 1 hypersensitivity reactions occur in 0.5-2% of patients Most people allergic to penicillins are also allergic to cephalosporins (less with 3rd generation) only aztreonam (a monobactam) shows no cross-reactivity

Resistance Alteration of target site

o o o o

Synthesis of an additional PBP which has a lower affinity for -lactams than normal PBPs bacteria able to continue cell wall synthesis The altered PBPs encoded by mecA gene E.g. MRSA, MR S. epidermidis (MRSE), penicillin resistant Streptococcus pneumoniae, Neisseria gonorrhoea & Haemophilus influenzae These are thus is resistant to all other -lactams (since they have same mechanism of action)

Reduced permeability o -lactams diffuse through a porin channel in the outer membrane of Gram negative bacteria

o o o

Mutation of porin genes decrease permeability E.g. carbepenem resistance of P. aeruginosa

Strains resistant by this mechanism may exhibit cross resistance to other unrelated antibiotics that use the same porins Production of -lactamases o Catalyse the hydrolysis of the -lactam ring o Genes encoding these enzymes widespread, found on chromosomes & plasmids Chromosomes:

Intrinsic resistance to penicillin G & ampicillin in Bacteroides fragilis, Klebsiella pneumoniae ESCaPPM organisms (Enterobacter spp., Serratia spp., Citrobacter freundii, Acinetobacter spp.,
Proteus vulgaris, Providencia spp. & Morganella morganii) Plasmids:

E. coli, H. influenzae, M. catarrhalis, N. gonorrhoea, S. aureus ESBLs (plasmid mediated mutant -lactamases)
Most are Class A or C Class A enzymes are penicillinases, and some also have cephalosporinase (1 st & 2nd generation) activity, while a few have carbapenemase activity -lactamase inhibitors such as clavulanic acid are effective against this class

Many different -lactamases classed A D

o
o

However, point mutations can make the enzyme inhibitor ineffective or extend the spectrum of activity to include 3rd generation cephalosporins and monobactams extended spectrum -lactamases (ESBLs) Class C -lactamase are cephalosporinases not inhibited by clavulanic acid Class B -lactamases have the broadest-spectrum, are inhibited by chelating agents, and are able to hydrolyse all -lactams except monobactams

The -lactamases of Gram positives released into extracellular environment so resistance will only manifest when a large population of cells is present The -lactamases of Gram negatives remain inside periplasm so that they hydrolyse the -lactams before they even bind to the PBPs

Penicillins

Narrow spectrum (natural penicillins) against non--lactamase producing Gram positives (streptococci, enterococci, Corynebacterium, Bacillus), anaerobes (Clostridia, Actinomyces, Peptostreptococcus), some Gram negatives (Neisseria, Pasturella), syphillis

Benzathine penicillin IMI slowly absorbed into circulation and hydrolysed to benzylpenicillin For when prolonged low concentrations of benzylpenicillin required (2-4 week action) Specific indications: rheumatic fever prophylaxis, early/latent syphillis Benzylpenicillin (penicillin G) Gold standard penicillin IV since it is destroyed by stomach acid Can cause neurotoxicity if given in high doses, esp. in patients with renal impairment seizures, unconsciousness, myoclonic spasm & hallucinations Specific indications: endocarditis, meningitis, aspiration pneumonia, lung abscess, community acquired pneumonia (CAP), syphilis, septicaemia in children Phenoxymethylpenicillin (penicillin V) Orally active penicillin For when high tissue concentrations arent required Specific indications: infections caused by Strep. pyogenes (tonsillitis, pharyngitis, skin infections), prophylaxis of rheumatic fever, moderate-severe gingivitis (with metronidazole) Procaine penicillin Combination benzylpenicillin with procaine (a LA)

IMI similar to benzathine penicillin in that it is for low prolonged doses The LA diminishes the pain of large IMI Specific indications: syphilis, RTIs where compliance with orals unlikely, cellulitis, erysipelas, adjunct in anthrax

Narrow spectrum -lactamase (penicillinase) resistant o Methicillin o Not used due to resistance mainly for laboratory antibiotic sensitivity testing Dicloxacillin/Flucloxacillin Oral or parenteral Diclox has fewer hepatic adverse effects and higher renal adverse effects than fluclox Less potent than penicillin G against non--lactamase producing Gram positive bacteria Less active against Gram positive rods & anaerobes

Specific indications: staph skin infections and cellulitis (impetigo, otitis externa, folliculitis, boils, carbuncles, mastitis), adjunct in CAP, osteomyelitis, septic srthritis, septicaemia, empirical treatment for endocarditis, surgical prophylaxis

Moderate spectrum (aminopenicillins) activity similar to penicillin with increased activity against Gram negative cocci & enterobacteriacae (which produce low levels of -lactamase) o Ampicillin IMI/IV

Specific indications: UTIs (good against enterococci), otitis media, CAP, H. influenzae, invasive Salmonella, Listeria meningitis, in combo with fluclox for cellulitis (covers strep while fluclox covers staph), surgical prophylaxis (along with gentamicin & metronidazole) Amoxicillin Oral Equivalent to ampicillin if given IV

Specific indications: UTIs, LRTIs, otitis media, sinusitis, skin infections/cellulitis, gonorrhoea, part of triple therapy for H. pylori Broad spectrum o Amoxicillin + Clavulanic acid (Augmentin) Extended spectrum (carboxypenicillins & ureidopenicillins) anti-Pseudomonas (but should also be used with another anti-Pseudomonas antibiotic such as an aminoglycoside to prevent resistance developing) o Ticarcillin IV

Combined with -lactamase inhibitor clavulanic acid Augmentin/Co-amoxiclav

Lesser Gram positive cover than aminopenicillins, greater anaerobic cover, anti-Pseudomonas, antiESCaPPM Combined with clavulanic acid Timentin active against high producers of -lactamase For severe infections Specific indications: septicaemia, LRTIs, bone & joint infections, skin & soft tissue infections, UTIs, gynaecological infections, intra-abdominal infections e.g. peritonitis

Can be used as a single antibiotic or with an aminoglycoside in empirical therapy Since its such a good drug, it is best to use it only when bacteria are proven or strongly suspected of being susceptible, otherwise if resistance develops, there is one less drug we can use that may have been very useful Piperacillin IV Similar activity against Gram positives & anaerobes as aminopenicillins, enhanced Gram negative spectrum similar to ticarcillin

Similar indications as ticarcillin for severe infections o Azlocillin - IV o Mezlocillin - IV o Carbenicillin IV, can cause platelet dysfunction & sodium overload General adverse effects of penicillins

Combined with tazobactam (another -lactamase inhibitor) Tazocin

o o

Immune mediated: hypersensitivity, serum sickness, allergic vasculitis, haemolytic anaemia, interstitial nephritis, neutropaenia Non-immune mediated: platelet dysfunction, GIT upset, hepatitis, electrolyte disturbances (Na+ overload, hypokalaemia), seizures (only with massive doses or renal failure)

Cephalosporins First generation (moderate spectrum) o For Gram positive cocci & some enterobacteriacae but poor activity against anaerobes & ESCaPPM o Most activity against -lactamase producing methicillin susceptible staph & strep o Activity against some E. coli, Klebsiella pneumoniae & Proteus mirabilis (similar to aminopenicillins) o No activity against Bacteroides fragilis, enterococci, MRSA, Pseudomonas, Acinetobacter, Enterobacter, Listeria monocytogenes, indole-positive Proteus or Serratia o Cephalothin (Keflin) IV/IMI/intraperitoneal o Not really ideal since its metabolised & excreted very fast frequent dosing is needed Cephazolin IV/IMI Longer half life than cephalothin

Specific indications: skin & soft tissue infections, more serious staph infections (e.g. endocarditis), surgical prophylaxis (cardiac/vascular surgery, orthopaedic, head & neck surgery that crosses the oropharyngeal mucosal barrier, vaginal & abdominal hysterectomy, high-risk caesarean sections, and high-risk gastroduodenal and biliary tract procedures but not to be used alone when surgery involves intestines) Cephalexin (Keflex) Oral Specific indications: skin & soft tissue infections, uncomplicated UTIs Used mainly to complete an antibiotic course after an IV cephalosporin has been used

Second generation (moderate spectrum, anti-Haemophilus) o Variable activity against Gram positives o Greater Gram negative spectrum o No activity against ESCaPPM

o
o

More resistant to -lactamases Cefamandole (Mandol) IV Specific indications: LRTIs, UTIs (unless due to Enterococcus), peritonitis, septicaemia, skin & soft tissue infections, bone & joint infections Cefuroxime (Zinnat/Ceftin) Oral

Lower serum protein binding and higher CNS penetration than cefamandole Specific indications: RTIs, otitis media, sinusitis, skin & soft tissue infections, UTIs, acute uncomplicated gonococcal urethritis & cervicitis, early Lyme disease o Cefaclor Oral Specific indications: otitis media, RTIs, UTIs, skin & soft tissue infections Second generation cephamycins (moderate spectrum, anti-anaerobes)

For anaerobes especially Bacteroides fragilis, enterobacteriacae but poor against staph o Specific indications: intra-abdominal, pelvic, and gynaecological infections, infected decubitus ulcers, diabetic foot infections, mixed aerobic-anaerobic soft tissue infections o Used in combo with doxycycline for PID o Better for prophylaxis in GIT surgery involving intestines than cephazolin o Cefoxitin IV, every 6 hours o Cefotetan IV, half life of 3-4 hours so can be administered twice daily Adverse effects: hypoprothrombinaemia (thus bleeding), disulfran like reactions Third generation (broad spectrum)

o
o o

o o
o o

Greater Gram negative activity, less Gram positive (but better against Gram positives than 2nd generation) Good activity against enterobacteriacae Resistant to some -lactamases, some activity against ESCaPPM but risk of inducing -lactamase with large inoculum size, no activity against ESBLs Good strep activity, modest staph activity Not as good against Bacteroides fragilis as 2nd generation cephamycins Particularly good for hospital acquired infections Better penetration into CNS effective against meningitis Cefotaxime IV/IMI Specific indications: LRTIs, UTIs, gynaecological infections, septicaemia, skin & soft tissue infections, intra-abdominal infections, bone & joint infections, CNS infections Ceftriaxone IV/IMI Long half life (once daily administration) Often used in combo with a macrolide &/or an aminoglycoside for CAP Drug of choice for meningitis

Specific indications: LRTIs, otitis media, skin & soft tissue infections, UTIs, uncomplicated gonorrhoea, PID (in combo with doxycycline), septicaemia, bone & joint infections, intra-abdominal infections, meningitis, surgical prophylaxis for potentially contaminated surgery (e.g. cholecystectomy)

Third generation broad spectrum with anti-Pseudomonas activity o Ceftazidime IV/IMI Minimal activity against staph & strep

Specific indications: LRTIs, skin & soft tissue infections, UTIs, septicaemia, bone & joint infections, gynaecological infections, intra-abdominal infections, CNS infections

Fourth generation (broad spectrum, resistant to -lactamases, anti-Pseudomonas)

o o
o o o o

Activity against Gram positives & wide range of Gram negatives (including ESCaPPM) Much less likely to induce chromosomal -lactamases than 3rd generation Minimal anaerobic activity Not active against ESBLs For severe nosocomial infections Cefepime (Maxipime) IV/IMI

Specific indications: moderate-severe pneumonia (especially due to multi-resistant Pseudomonas), empirical therapy for febrile neutropenia, UTIs (including pyelonephritis), complicated intra-abdominal infections, skin & soft tissue infections o Cefpirome IV/IMI Similar to cefepime Adverse reactions o Hypersensitivity less common than with penicillins o Cefaclor more commonly associated with serum sickness in children o Neutropenia, eosinophilia o GIT upset (diarrhoea, hepatitis, ceftriaxone induced biliary sludging), interstitial nephritis

Carbapenems Action

o o
o

Bind to PBPs of both Gram positives & negatives Broadest spectrum of all -lactams, although still not active against organisms that have altered PBPs e.g. MRSA & Enterococcus faecium Activity against enterobacteriacae, Gram positives, anaerobes, nocardia

Not hydrolysed by most -lactamases drug class of choice for ESBLs o First line drugs in empirical therapy of severe infections o Good for polymicrobial infections Resistance

Most frequent mechanism of acquired drug resistance is loss of outer membrane protein important for drug transfer into cell, e.g. P. aeruginosa develops resistance with monotherapy o Little cross-resistance with other -lactams Adverse reactions o Seizures (especially if underlying CNS pathology, drug accumulation) o Others similar to the other -lactams (e.g. abnormal LFTs and leucopaenia) Imipenem (Primaxin) o Combined with cilastatin which prevents renal dehydropeptidase metabolising imipenem

o o

Active against Gram negatives (including Pseudomonas), Gram positives (including some enterococci), anaerobes including Bacteroides fragilis Intrinsically resistant organisms include Enterococcus faecium, MRSA, coagulase negative staph, Chlamydia trachomatis and Stenotrophomonas maltophilia

Potent inducer of -lactamase production - may be important if therapy subsequently changed from imipenem to an antibiotic destroyed by this enzyme o IV o Specific indications: serious infections such as LRTIs, intra-abdominal infections, gynaecological infections, bone & joint infections, skin & soft tissue infections, septicaemia, endocarditis, polymicrobial infections o Can cause CNS effects such as seizures & somnolence o Degradation products nephrotoxic Meropenem (Merrem) o Stable to renal dehydropeptidase o Crosses BBB o Reduced potential for causing seizures compared with imipenem

Active against Gram-negatives (including Pseudomonas), Gram-positives (including some enterococci), anaerobes including Bacteroides fragilis o Greater Gram negative and lesser Gram positive activity than Imipenem o IV o Specific indications: serious infections such as LRTIs, complicated UTIs, febrile neutropenia, intra-abdominal infections, gynaecological infections, dermatological infections, meningitis, septicaemia Ertapenem o Also stable to renal dehydropeptidase

o
o o o o o o

Not active against Pseudomonas & Acinetobacter thus shouldnt be used empirically Similar anti-anaerobe activity to imipenem & meropenem Reserved primarily for ESBL-producing and high level AmpC-producing Gram-negative bacteria Poor penetration of BBB IV Long half life so can be given once daily Specific indications: intra-abdominal infections, obstetric and gynaecological infections, CAP, complicated skin & soft tissue infections, UTIs

Monobactams Aztreonam (only one used) Not really active against Gram positives or anaerobes

Highly active against most aerobic Gram-negatives (including -lactamase producing H. influenzae, enteric Gramnegative rods & Pseudomonas) Not active against ESBL or ESCaPPM Good tissue penetration, including CSF Same resistance mechanisms as other -lactams No hypersensitivity cross-reactivity with other -lactams as structure slightly different

Glycopeptides
Action

Very large so cant get into Gram-negatives for Gram positives only Bactericidal Interfere with peptidoglycan synthesis by binding to terminal amino acids at the end of the polypeptide chains inhibits transglycosylation reaction prevents incorporation of new subunits into growing cell wall Works at an earlier stage of cell wall synthesis than -lactams no point in combining the drugs in treatment Used for MRSA, MRSE, multi-drug resistant pneumococci, relapsing Clostridium difficile infections Dont cross BBB unless meninges inflamed Modest tissue penetration Highly protein bound, excreted renally Vancomycin o IV infusion slowly to avoid red man syndrome due to histamine release o Need to measure levels daily

Oral used for treatment of antibiotic related pseudomembranous colitis due to Clostridium difficile overgrowth

Teicoplanin

o o o

Natural Can be given by IV bolus or IMI as less toxic than vancomycin Long half life

Resistance Gram negatives naturally resistant

Some organisms have altered target: Erysiplothrix, Leuconostoc, Lactobacillus, Pediococcus, Enterococcus gallinarum, Enterococcus casseliflavus Inducible via chromosome or acquired via plasmids, e.g. VRE genes vanA, vanB & vanD

o o o

vanA (plasmid or chromosome) causes resistance to vancomycin & teicoplanin vanB (plasmid or chromosome) causes resistance to vancomycin only (although teicoplanin resistance can be induced by prior exposure to vancomycin) vanD is chromosomal (thus non-transferable) resistant to high levels of vancomycin & low levels of teicoplanin

Staph can become resistant to glycopeptides via mutation or acquisition from enterococci e.g. vanA gene on staph plasmid

Adverse effects Potentially ototoxic & nephrotoxic, but rarely severe or permanent Teicoplanin less toxic than vancomycin Hypersensitivity, leucopaenia, thrombocytopaenia

Bacitracin
Toxic, difficult to use antibiotic Doesnt work orally Effective topically Interferes with the dephosphorylation of a molecule that carries the building blocks of peptidoglycan As bacitracin zinc salt, and in combination with other topical antibiotics (usually polymyxin B and neomycin), it is used in ointment form for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections Sometimes given by IMI in infants for pneumonia

Aminoglycosides
Action Bactericidal

Bind to specific proteins in the 30S ribosomal subunit prevent protein synthesis Also cause misreading of mRNA codons & break up functional polysomes into non-functional monosomes Activity against aerobic Gram negatives (including P. aeruginosa), especially enterobacteriacae Not active against strep or anaerobes Active against some staph, including S. aureus in combination with -lactam therapy Generally not used alone for Gram positives Has therapeutic synergy with some -lactams e.g. against Pseudomonas, staph/strep/enterococcal endocarditis Best outcome for endovascular infections (not good tissue penetration) not used for skin & soft tissue infections No penetration of CNS Have a significant post-antibiotic effect Renal excretion Indications: empirical therapy for severe infections when Gram negatives are suspected, surgical prophylaxis, usually used in combo with lactams (especially those -lactams that have anti-Pseudomonas activity) Gentamicin, Tobramycin, Amikacin, Netilmicin, Streptomycin o All IV/IMI/eye drops

o o
o o

Tobramycin slightly more active than gentamicin against P. aeruginosa Amikacin & netilmicin are both less active than gentamicin against P. aeruginosa but may be active against strains resistant to gentamicin & tobramycin Streptomycin used mainly for mycobacterial infections Netilmicin less toxic than others

Neomycin not used systemically, used only orally in gut decontamination regimens in neutropaenic patients

Resistance Relatively uncommon Alteration of 30S ribosomal target protein Alterations in cell wall permeability Most important acquired mechanism of resistance is production of aminoglycoside-modifying enzymes o Genes often plasmid mediated, located on transposons and transferable to other bacterial species

Alter structure of aminoglycoside molecule inactivation

Adverse effects

Nephrotoxic, ototoxic (vestibular & cochlear) causing deafness or loss of equilibrium blood levels need to be measured daily Neuromuscular blockade (myasthenia gravis) in rare cases Hypersensitivity rare

Tetracyclines
Action Bacteriostatic

Bind to 30S ribosomal subunit inhibit protein synthesis Broad spectrum Used against intracellular organisms e.g. Mycoplasma, Chlamydia, Rickettsia, Brucella, Q fever spirochaetes, etc. Niches uses malaria (doxycycline is a blood schizonticide so is used in prophylaxis), cholera, plaque, acne (due to anti-inflammatory effects) Moderate activity against staph, strep, non-Bacteroides anaerobes & respiratory pathogens (e.g. Strep pneumoniae & H. influenzae) Poor activity against Gram negative rods Common uses: PID, peridontal disease, CAP, brucellosis, Lyme disease, soft tissue infections usually reserved for more minor infections Usually orally administered Good tissue penetration, low concentration in CSF, prostate Renal & biliary excretion Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline, Demeclocycline, Tigecycline

o
o o o

Doxycycline & minocycline more completely absorbed than tetracycline, oxytetracycline & chlortetracycline higher serum concentrations, lower GIT concentrations less GIT upset Tetracycline & demeclocycline need to be given on an empty stomach Minocycline & doxycycline have longer half life and absorption not affected by presence of food Minocycline active against some tetracycline resistant bacteria including staph Doxycycline generally preferred due to once daily dosage washed down with water and patient needs to stay upright for at least 30 min afterwards to prevent oesophagitis

Resistance Common, widespread Increased efflux from cell (plasmid encoded) most common form of resistance Occasional resistance due to altered ribosomal targets, reduced permeability or enzymatic destruction

Cross resistance occurs across the class, but not for new drugs (tigecycline)

Adverse effects Hypersensitivity, photosensitivity, pigmentation (minocycline)

Dental discolouration/skeletal growth inhibition contraindicated in children < 8 y.o. and in pregnancy after 18 weeks when babys teeth are developing GIT: overgrowth of resistant and pathogenic bacteria & fungi, oesophageal ulceration, fulminant hepatitis contraindicated in pregnancy & renal failure Renal: increases uraemia from potentiation of catabolism Neurological: benign intracranial HT, minocycline induced vestibular dysfunction Drug interactions: cimetidine, anticonvulsants, anticoagulants, OCP

Chloramphenicol

Bacteriostatic Nitrobenzene nucleus toxicity limits its use (inhibitory activity on human mitochondrial ribosomes)

o o
o o

Bone marrow suppression dose dependent (if given for long periods, reversible) or idiosyncratic aplastic anaemia (dose independent, irreversible, rare) Toxic to neonates, especially premature babies whose liver enzymes arent developed grey baby syndrome serum concentration should be monitored in neonates Optic neuritis Thus rarely used if alternatives are available

Binds to large 50S subunit of the 70S ribosome prevents peptide bond synthesis Well absorbed orally, but can be given IV if patient unable to swallow Also given topically Well distributed in body, including CSF Metabolised in liver microbiologically inactive form excreted renally Active against a variety of organisms, including bacteria, spirochetes, rickettsiae, chlamydiae, and mycoplasmas Common uses: meningitis (especially H. influenzae), eye infections (topical), Salmonella typhi infections Resistance o Inactivation by plasmid mediated enzymatic mechanism which is easily transferred between Gram negatives o Chloramphenicol acetyl transferases produced by resistant bacteria are intracellular, but are capable of inactivating all chloramphenicol in immediate environment o Once chloramphenicol is acetylated it cannot bind to ribosomal target

Macrolides
Action Bacteriostatic

Bind to 23S ribosomal RNA in 50S ribosomal subunit prevents release of transfer RNA after peptide bond formation inhibits protein synthesis Activity against Gram positive & negative cocci (but not enterococci), H. influenzae, Legionella, Bordetella, Corynebacteria, Mycoplasma, rickettsiae & to a lesser extent Chlamydia, anaerobes No activity against Gram negative rods Newer drugs have longer half lives (less frequent dosing) & high intracellular concentrations azithromycin > roxithromycin > clarithromycin > erythromycin Major indications: CAP (especially if penicillin resistant), atypical pneumonia, chlamydial infections Hepatic metabolism & biliary excretion (some small renal excretion) Diffuse into most tissues and phagocytes carry to sites of infection

Resistance Decreased permeability enterobacteriacae, Pseudomonas, Acinetobacter innately resistant Esterase inactivation of erythromycin enterobacteriacae innately resistant

Efflux (plasmid encoded mef gene) Altered target site

o o

50S (chromosomal) cross resistance with all macrolides, lincomycin, clindamycin 23S (plasmid encoded erm gene) cross resistance with all macrolides, lincosamides, stretogrammins (MLS macrolide-lincosamide-streptogrammin resistance)

Adverse effects Nausea, vomiting after oral administration, especially with erythromycin Cholestatic hepatitis Torsade de points (from potentiation of serum concentration of arrhythmic drugs) The newer drugs have fewer adverse effects and fewer drug interactions Erythromycin Oral, topical or parenteral Variable oral absorption, frequent GIT side effects Phlebitis with IV administration Potent cytochrome P450 inhibition (CYP3A4) Roxithromycin Oral

Similar to erythromycin but with greater activity against some Gram negatives, including Leigionella pneumophila

Clarithromycin Oral Has a microbiologically active metabolite unlike the other macrolides twice as active Used for Mycobacterium avium complex (MAC) infections in combo with other drugs Also used to eradicate H. pylori in combo with other drugs

Azithromycin Oral Less active than erythromycin against Gram positives but has activity against some Gram negatives, anaerobes, non-tuberculous mycobacteria including MAC, and against some parasites e.g. Toxoplasma gondii Used for chlamydial infections, trachoma, donovanosis, cerebral toxoplasmosis, MAC prophylaxis

Lincosamides
Action Bactericidal Similar mechanism to macrolides

Overlapping binding site on ribosomal 50S subunit to macrolides cross resistance common Active against most Gram positive cocci (but not enterococci) and anaerobes Activity against some parasites e.g. toxoplasmosis, malaria Good bioavailability, extensive tissue penetration, poor CSF penetration Hepatically metabolised, active metabolites concentrated in bile, minor urinary excretion Carried in phagocytes similar to macrolides Common uses: mixed anaerobic infection/abscesses, major hypersensitivity to -lactams

Resistance Increasing resistance to pneumococci & Group A strep Enterobacteriacae, Pseudomonas, Acinetobacter intrinsically resistant (poor permeability) Similar resistance mechanisms to macrolides (hence MLS resistance)

Adverse effects

Antibiotic associated diarrhoea, especially since C. difficile more resistant to lincosamides than macrolides pseudomembranous colitis Rare cases of abnormal LFTs, transient leucopaenia May potentiate neuromuscular blockade Dose reduction only required with concomitant renal & hepatic failure

Clindamycin Oral, topical or IV/IMI IV doses should be administered slowly to avoid producing serious arrhythmias

Penetrates well into bone but not CSF even when meninges are inflamed excellent for osteomyelitis IV clindamycin more expensive than lincomycin Cream for intravaginal treatment of bacterial vaginosis, gel/lotion for acne & rosacea

Lincomycin Similar to clindamycin

Streptogrammins

Synercid (quinupristin + dalfopristin) Bacteriostatic individually but bactericidal in combo Bind to 23S in 50S ribosomal subunit bind at different stages and together interfere with elongation & extension of peptide chains Resistance relatively uncommon but occurs by alteration of binding site (MLS resistance - makes it bacteriostatic), inactivation or efflux Active against Gram positive cocci (including MRSA), Enterococcus faecium but not Enterococcus faecalis Limited activity against respiratory pathogens including atypicals No activity against enterobacteriacae, minimal activity against anaerobes Used for glycopeptide resistant MRSA and VRE infections IV, hepatic metabolism, biliary excretion Adverse reactions: arthralgia, myalgia, infusional hypotension, phlebitis, hyperbilirubinaemia, abnormal LFTs

Oxazolidinones
Linezolid Bacteriostatic Inhibits initiation of protein synthesis by targeting 23S ribosomal RNA in 50S subunit which prevents formation of functional 70S complex Active against wide range of Gram positives, including multi-resistant strains Used for VRE/MRSA/GISA infections where other agents not tolerated or unavailable Resistance rare due to unique mechanism of action, seen only in E. faecium (due to altered target) Oral/IV, hepatic metabolism, renal excretion Adverse reactions: reversible myelosuppression with prolonged administration (> 3 weeks) including thrombocytopaenia/red cell aplasia, MAO inhibition (causing HT when used with dopamine, adrenaline, tyramine containing foods & serotonergic drugs), CNS including headache, dizziness, peripheral neuropathy Expensive

Fusidic acid

Bacteriostatic Forms a stable complex with elongation factor EF-G (bacterial equivalent of human EF-2), guanosine diphosphate & the ribosome inhibits protein synthesis Active against Gram positive cocci, used especially in treatment of staph infections resistant to -lactams or in patients allergic to other antibiotics should be given in combo with another anti-staph drug to prevent resistance developing (mutants with altered EF-G) Common use: in combo with rifampicin as oral treatment of MRSA Good activity against Neisseria and most anaerobes (mainly Gram positive anaerobes)

Not active against Gram negative rods Oral/topical/IV Well absorbed & penetrates into tissues and bone (good for osteomyelitis), but not into CSF Topical not encouraged due to resistance Metabolised by liver, excreted in bile Few adverse effects, occasionally GIT upset & jaundice

Quinolones
Action Bactericidal

Inhibit activity of DNA gyrase and topoisomerases prevent uncoiling of DNA prior to transcription Oral administration (parenteral for more serious infections) Good distribution throughout body Renal excretion mainly, small faecal excretion All but the 1st generation are fluroquinolones

Resistance No plasmid mediated resistance Spontaneous chromosomal mutations o Altered target enzyme o Changes in cell wall permeability May lead to cross resistance with other antibiotics with same mechanism of action Adverse effects GIT upset most frequent Photosensitivity Interstitial nephritis

Arthropathy/chondropathy & tendonitis (mainly in children) not recommended for children, pregnant or lactating women Hepatitis especially with trovafloxacin Thrombocytopaenia CNS: dose related organic psychoses/encephalopathy, seizures, rarely BIHT Should be used in lower doses in patients with renal failure

First generation Nalidixic acid

Activity against Gram negatives (especially enterobacteriacae) except Pseudomonas Occasionally used for UTIs Doesnt achieve antibacterial systemic concentrations

Second generation Ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin

Activity against Gram negatives including H. influenzae, enterobacteriacae, Pseudomonas, some intracellular organisms including Legionella and some Gram positives (S. aureus, but not strep), no activity against anaerobes Norflox used to treat UTIs & GITIs (only therapeutic in urinary tract & GIT) Oflox available as eye drops only Extensive tissue penetration superior to -lactams, including anterior chamber of eye, biliary tree, bone & prostate Fair CNS penetration Specific indications: pyelonephritis/prostatitis, meningococcal prophylaxis (2nd line), oral treatment of resistant Gram negative infections including P. aeruginosa & ESCaPPM, Gram negative osteomyelitis, diabetic foot infections, Salmonella typhi

Third generation Levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin Extended spectrum

Slightly less activity against aerobic Gram negatives & Pseudomonas than cipro

Greater Gram positive cover including strep (e.g. penicillin resistant pneumococci), extensive anaerobic cover, minimal enterococcal cover Highly active against intracellular respiratory pathogens including Legionella, Mycoplasma & Chlamydia Greater anti-mycobacterial activity Moxi has mixed hepatic & renal excretion so doesnt require dose adjustment in renal failure Lower chance of developing adverse reactions Once daily dosage (unlike earlier drugs which have twice daily dosage) Specific indications: severe CAP with immediate hypersensitivity to penicillin, Chlamydia psittaci pneumonia, perhaps best for COPD exacerbations

Fourth generation Trovafloxacin

rd

As for 3 generation but greater activity against anaerobes Associated with cases of acute liver failure reserved for life threatening situations Rifamycins

Bactericidal Bind to DNA-dependent RNA polymerase blocks synthesis of mRNA Activity against staph, Neisseria, Legionella & Mycobacterium tuberculosis Good anaerobic activity, moderate activity against strep Used with vancomycin for penicillin resistant pneumococcal meningitis No activity against enterobacteriacae Rifampicin, Rifabutin, Rifapentine Oral Hepatic metabolism, biliary excretion with minor urinary excretion Turns urine, sweat, saliva & tears orange measure compliance! Inducer of cytochrome P450 (rifampicin >> rifabutin) decreased drug levels of steroids (OCP), cyclosporin, warfarin, oral hypoglycaemics, sulphonylureas, anticonvulsants, etc. Newer agents (rifabutin & rifapentine) excreted more slowly than rifampicin less frequent dosage Good tissue penetration (greater than serum concentration) hence used when a ward is found to have MRSA etc. so that all staff members secrete rifampicin on skin to kill MRSA that have colonised there (also has an affinity for plastics good for cleaning equipment, prostheses) High intracellular levels, moderate CNS penetration Rifabutin used mainly for treatment & prophylaxis of MAC Rifampicin used mainly for TB, MRSA, prophylaxis of H. influenzae type b & meningococcal disease Resistance o Chromosomal mutations develop rapidly that alter RNA polymerase target o Rifampicin resistant TB an increasing threat o Best used in combo with other drugs Adverse effects o Self limited rash in 5% o Asymptomatic LFT abnormality common (especially increased bilirubin), hepatitis rare o Nephrotoxicity, flu-like illness, lupus-like syndrome, thrombocytopaenia

Sulphonamides

Bacteriostatic Compete with para-aminobenzoic acid (PABA) for active site of dihydropteroate synthetase inhibition of folate synthesis inhibition of nucleic acid synthesis Sulphamethoxazole Oral, often in combo with trimethoprim as co-trimoxazole Hepatic metabolism, renal excretion

Activity against Gram negatives, except Pseudomonas useful for UTIs Not really used alone nowadays Resistance widespread with plasmid mediated genes Adverse effects: rashes, bone marrow suppression, rarely Stevens-Johnson syndrome

Trimethoprim (and co-trimoxazole) Dihydrofolate reductase inhibitor inhibition of folate synthesis (at a later stage than sulphonamides)

Less toxic than sulphonamides Specific use in UTIs orally or by IV infusion Renal excretion

Co-trimoxazole used for Burkholderia cepacia, Pneumocystis carinii pneumonia (PCP) prophylaxis & treatment, S. maltophilia, Nocardia (brain/lung abscesses in Immunocompromised), Listeria monocytogenes if penicillin allergic Mainly used for treatment & long term prophylaxis of UTIs Resistance from plasmid encoded dihydrofolate reductase Trimethoprim & co-trimoxazole can cause neutropaenia, nausea & vomiting Immunocompromised people more susceptible to side effects

Nitroimidazoles

Bactericidal Reduced nitro-groups at reduction potentials only created in anaerobes Effective against anaerobes & some protozoa (Giardia Lamblia, Entamoeba histolytica, Trichomonas vaginalis) Oral or rectal (equivalent to parenteral) twice daily Hepatic metabolism, renal excretion Extensive tissue penetration, including CNS Resistance rare, becoming increasing problem in Helicobacter and parasites Adverse reactions: encephalopathy/seizures, peripheral neuropathy if used for > 2 weeks, disulfiram-like reaction with alcohol, leucopaenia Metronidazole, tinidazole Metronidazole also used as hypoxic cell sensitiser in radiotherapy

Polymyxins
Bactericidal Cyclic polypeptidases that disrupt cell membrane structure (like detergents) Poor distribution, neurotoxic & nephrotoxic so not used systemically Mainly used topically but are also used for GIT decontamination, wound irrigation & as a bladder washout Active against Gram negatives except Proteus Polymyxin B & E (colistin) Colistin may be used against MRAB if all other drugs fail

Miscellaneous
Nitrofurantoin & methenamine o Oral o Excreted in urine in high enough concentrations to inhibit urinary pathogens o For treatment & prophylaxis of LUTIs o Adverse effects: hypersensitivity, polyneuropathy, haemolysis, chronic active hepatitis o Action reduced by alkaline urine Mupirocin o Topical anti-staph & strep o High level mupirocin resistance in MRSA readily selected with prolonged & widespread use Spectinomycin o For syphilis and gonorrhoea Anti-TB

First line: isoniazid, ethambutol, rifampicin, pyrazinamide & streptomycin (to prevent resistance)

Isoniazid kills only mycobacteria via inhibition of mycolic acid synthesis neurological side effects prevented by co-administration with pyridoxine

Ethambutol causes optic neuritis regular eye checks necessary Pyrazinamide causes hepatotoxicity Second line: capreomycin, cycloserine, streptomycin, kanamycin, ciprofloxacin