BETA LACTAM ANTIBIOTICS [4]: Penicillins, Cephalosporins, Monobactams, Carbapenems.

MOA- competitively inhibit transpeptidases of cell membrane thus preventing release of Dalanine of pentapeptide for formation of peptide linkages between NAM & NAG, resulting in cell wall deficient forms [giant protoplasts/ bizare, filamentous] whcich either lyse in hyperosmotic medium or do not multiply.

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NATURAL PNENICILLIN [PnG or Benzyl Pn] : benzyl side chain with amide link to Pencillanic acid [betalactam ring + thiazolidine ring]  Single dose 0.5 – 5 MU (1MU = 0.6gm)

Narrow spectrum: Gm+ [pneumococcus, aerobic & anaerobic rods], Gm- [neisseria, E.coli, proteus], spirochetes, actinomycetes.

Bactericidal even in acidic pus & more active against Gm+[more proteoglycan] than Gm-[lipoprotein barrier]

Acid labile so no oral; poor CSF & synovium – penetrates only in inflammation; t1/2 is 30min, increased in renal disease/infants/elders/probenecid.

• CRYSTALLINE PnG  : Na+/K+ to thiazolidine; stable in dry form, aq sol freshly prepared for i.m/i.v; rapid plasma levels.
• REPOSITORY PnG: insoluble salt given only i.m (never i.v since microemboli, convulsions, hallucinations); sustained plasma levels.
  • PROCAINE PnG: sustained
  • FORTIFIED(Na+) Procaine PnG: rapid & sustained
  • BENZATHINE PnG: extremely slow release   [USES- early/latent syphilis 2.4MU/1-3wk; late syphilis 2.4MU/wk for 4wks; rh fever prophylaxis 1.2MU/4wk till 5yrs after/ 18yrs age; gonorrhoea/syphilis prophylaxis 2.4MU single dose within 12hrs]

USES OF PnG:

• strep pharyngitis, otitis media, scarlet fever, rh fever.
• [high dose + gentamycin] strep viridans/faecalis  SABE.
• drug of choice for syphilis.
• rare infs like anthrax, actinomycosis, trench mouth, rat bite fever, listeria, pasteurella.
• [hig dose] meningitis [rifampin for prophylaxis]
• ophthalmia neonaturum
• adjuvant in diphtheria, tetanus, gas gangrene.
• prohylaxis for endocarditis in valvular heart disease, rh fever, syphilis, gonorrhea, agranulocytosis, surgery/ invasive procedures.

Pn resistance:

1. inherant by location of transpeptidase deeper to lipoprotein barrier.
2. high resistance acquired primarily by production of Pn destroying penicillinase [used to destroy PnG in blood culture smaples]- Gm+[staph] produce large amounts which even diffuse into surroundings & also inducible by methicillin, unlike Gm-betalactamase [gonococci, E.coli, H.inf]
3. [low resistance] Pn tolerant by acquisition of low affinity transpeptidase [MRSA, Pneumococci], low penetrability [Gonococci, H.inf], altered porins [Gm-]

ADRs- [most non-toxic drug]

• pain on inj.
• thrombophlebitis.
• >20MU/renal disease causes convulsions & coma.
• intrathecal inj causes spinal cord degeneration.
• major problem: natural/semisynthetic Pn causes hypersensitivity rxn esp with parenteral procaine which unpredictably  can be mild rash/urticaria/wheeze/ exfoliative dermatitis or it can be life threatening (stop use)angioneurotic edema/anaphylaxis [intradermal test with BENZYL PENICILLINOYL POLYLYSINE/ hyposensitize IDinj/hr with increasing amounts].
• not used topically since contact sensitization except for gonococcal ophthalmia.
• JARISCH HERXHEIMER RXN in syphilitic due to sudden release of spirochetal lytic products after 12-72hrs causing exacerbation of lesions, myalgia, fever, shivering, vascular collapse.

SEMISYNTHETIC PENICILLINS – benzyl side chain substitutes on betalactam ring. aim-

1. acid stable/ oral use
2. pnicillinase resistant
3. broad spectrum
4. non-allergic

PnV – oral acid stable, used only for less serious strep pharyngitis,sinusitis, otitis media, prohylaxis for rh fever, trench mouth.

Pnase resistant: oral Cloxacillin, Oxacillin, Dicloxacillin, Flucloxacillin, [parenteral Methicillin,Nafcillin]- used only for Gm+ staph except MRSA.

Extended spectrum Pn – against Gm- also without any Pnase resistance.

AMINO Pns: acid stable; Gm+ [strep viridans, enterococci, pneumococci] Gm- [gonococci, meningococci, Hinf, E.coli, shige, salm, prot]

AMPICILLIN [ADRs- incomplete absorption causes diarrhoea, rashes with allopurinol/AIDS/EBV/LL. Interactions- failure of oral contraceptives] USES-

• resp infs – bronchitis, sinusitis, otitis media.
• one of the first line drug for NPPNG urethritis.
• alt to cipro for typhoid.
• shigella dysentry
• cholycystitis [high conc in bile]
• [with gentamycin] SABE
• [with gentamycin/3rd ceph] septicaemias, mixed infs
• [3rd ceph] meningitis.

AMOXICILLIN -ADV:complete absorption, higher plasma levels, no diarrhoea, preferred over ampicillin for typhoid, bronchitis, SBAE, gonorrhoea.

CARBOXY Pns: parenteral CARBENICILLIN < TICARCILLIN :

• against pseudomonas & indole+ proteus;
• USE -serious burns,UTI, septicaemia;
• ADRs- bleeding, fluid retention, CHF.

UREIDO Pns:

• parenteral PIPERACILLIN,MEZIOCILLIN : most potent anti-pseudomonal & serious Gm- Klebsiella inf in immunocompromised/burns with cocurrent gentamycin/tobramycin.
• parenteral MECILLINAM[AMDINOCILLIN]: Gm- kleb, salm, E.coli, enterobacter [not pseudomonas] – USE: typhoid, dysentry, UTI.

BETALACTAMase(except 2nd & 4th cephalosporinase) INHIBITORS: CLAVULINIC ACID>SULBACTAM/TAZOBACTAM

• MOA- progressive inhibitor [with time] :betalactam ring binds betalactamase of Gm+&-
• combined with amoxicillin/piperacillin respectively since t1/2 is similar.
• USE: empirical Rx of mixed nosocomial inf, PPNG.

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CEPHALOSPORINS : 4 generations; bactericidal; MOA- bind to different traspeptidases so no cross resistance with Pn.
FIRST GEN : high activity against Gm+
CEPHALOTHIN i.v- primary indication for Pnase producing staph[not MRSA]
CEPHALEXIN, CEPHADROXIL>CEPHRADINE oral- commonly used ceph; less active on Pnase staph & Hinfl.
CEPHAZOLIN i.v- more active against kleb & E.coli; preferred parenteral first gen ceph esp for surgical prophylaxis.

SECOND GEN: more active against Gm- & anaerobes.
CEFOXITIN i.v- serratia, indole+ prot, bact.fr : anaerobic & mixed surgical/obstetric infs, lung abscess.
CEFUROXIME i.m- PPNG, meningitis form Hinf, meningococci, pneumococci.
CEFUROXIME AXETIL oral- incomplete absorption.
CEFACLOR oral- significant absorption.

THIRD GEN: higher activity against Gm-enterobacteriaceae & highly resistant to betalactamases.
CEFOTAXIME, CEFTIZOXIME i.m/i.v- aerobic Gm- infs: PPNG, meningitis[high CSF], nosocomial, septicaemias, in immunocompromised.
CEFTRIAXONE i.m/i.v- longer t1/2 but ADRs hypoporthromb & thrmbcytopenia; serious infs- meningitis in children, MDR typhoid, complicated UTI, septicaemias, PPNG, chancroid.
CEFTAZIDIME i.m/i.v- high activity against pseudomonas, used in burns, hematological malignancies in immunocompromised. ADR- hypoprothrmb.
CEFOPERAZONE i.m/i.v- high activity against pseudomonas, used in severe infs of urinary,resp, biliary, skin, soft tissue, meningitis, septicaemias. DAR- thrmcytopenia, disulfiram like rxn with alcohol.
CEFIXIME oral- highly active against enterobacteriaceae, Hinf, strep; used for rsp, urinary, biliary infs. ADR-diarrhoea.
CFEPODOXIME PROXETIL oral- highly active against entero,strep & also staph; used for resp, urinary, skin, soft tissue infs.
CEFDINIR oral- most resp Gm+ cocci are succeptible : pneumonia, chr bronchitis, ENT & skin infs.
CEFTIBUTEN oral- active against both Gm+&-; used in resp, urinary, GIT infs.

FOURTH GEN:
CEFEPIME i.v- 3rd ceph spectrum + highly resistant to betalactamases so pseudomonas & staph are also inhibited : serious nosocomial pneumonia, febrile neutropenia, bacteremia, septicaemia.
CEFPIROME i.m/i.v- zwitterion penetration thr Gm- porins, more potent than 3rd ceph against Gm+ & some Gm-, used for serious resistant nosocomial infs

ADRs- pain, thrombophlebitis, diarrhoea esp with cephradine & cefoperazone, hypersensitivty – mostly rash [cross reactivity with Pn, so CI in H/O immediate hypersensitivity rxn], nephrotoxicity with cephalothin/aminoglycoside/loop diuretics, bleed ing with cefoperazone & ceftriaxone due to hypoprothrmb, neutropenia & thromcytopenia with ceftazidime, disulfiram like with cefoperazone+alcohol.

USES-

• alt to PnG delayed hypersensitivity – 1st ceph
• Gm-[kleb,prot,serratia, enterobacter] resp, urinary, soft tissue infs – cefuroxime[2]/ceftaxime[3]/ceftriaxone[3]
• Pnase staph – cephalothin
• Gm- septicaemia – aminoglycoside+ceph
• surgical prophylaxis – cefazolin[1]
• Hinf & enterobacteriaceae meningitis – cefuroxime/cefotaxime/ceftriaxone.
• pseudomonas meningitis – ceftazidime+gentamycin
• PPNG, chancroid – ceftriaxone is first choice.
• alt to FQ for typhoid – ceftriaxone/cefoperazone
• mixed infs in cancer, colorectal surgery, obstetric complications – [3]cefotaxime,ceftizoxime,..
• prophylaxis in neutropenia – [3]ceftazidime,…

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MONOBACTAMS:
AZTREONAM – use in Pn/Ceph allergy; spectrum: enterobacteriaceae, Hinf, Pseudomonas – used for nosocomial urinary/biliary/git/genito infs

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CARBAPENEMS:
IMIPENEM [+cilastatin to inh renal hydrolysis]- spectrum: Gm+cocci, enterobacteriacea, Pseudomonas, anaerobes -used in seroius nosocomial infs & also in immunocompromised.
ADR- induce seizures.

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MRSA [methicillin resistanat Staph.aureus]

[through acquisition of low affinity transpeptidase to drug]resistant to

1. betalactams
2. erythromycin
3. aminoglycosides
4. tetracyclines

sensitive to

1. ciprofloxacin
2. vancomycin
3. linezolid

QUINOLONES synthetic antimicrobials.

NALDIXIC ACID [low potency, limited spectrum, rapid resistance]

MOA- inhibit DNA gyrase.

Bactericidal to Gm- coliforms: E.coli, Kleb, Prot, shigella, enterobacter.

• second line drug in recurrent UTI [lethal urine conc >20 times plasma/tissues]
• diarrhoea by prot, E.coli, salmonella, ampicillin resistant shigella.

ADRs- infrequent git upset, rashes, neurological toxicity [headache, vertigo, drowsy, seizures esp in children] prolonged use causes parkinsonism like, leucopenia, biliary stasis.

CI- infants.

FLUOROQUINOLONES [high tissue penetrability except in CSF & eye]

First generation- 1Fsubstitution [Gm + & -]- pef,cipro,o,nor.

Second generation- >1F [resp Q active even against Gm+ cocci & anaerobes; long t1/2] – levo, lome, spar, gati, moxi.

Ciprofloxacin [oral drug]

Bactericidal -most potent First gen FQ [rapid acting = MBC~MIC], active against beta lactam & aminiglycoside resistant strains, low resistance.

Broad spectrum

highly succeptible – [aerobic Gm-]

• enterobacteriaceae [E.coli, Kleb, S.typhi, shigella, prot, enterobacter]
• Neisseria
• Hemophylus
• V.cholera

modrately succeptible – hiher MIC

• Gm+ :Staph. aureus & epidermidis, anthracis, listeria
• Gm- :pseudomonas, brucella
• brnhm/morax, legionella
• Mycob.t

variable succeptibility – strep, mycoplas, chlamydia, MAC

resistant – anaerobes [protective intestinal flora spared - no diahrroea ADR]

MOA- inhibit DNA gyrase(Gm-) & topoisomerase4(Gm+) which nick & introduce negative supercoils to prevent excess positive supercoiling that damage dsDNA during separation for transcription/replication.

ADRs- safe & better tolerability: mild nausea, impaired conc & dexterity[caution while driving], high dose/predisposition cause seizures mild hypersensitivity, tendonitis.

Interactions- inhibit metabolism of warfarin, NSAIDs enhance CNS toxicity, anatcids iron reduce absorption.

USES-

• UTI even in complicated/cath/prostatitis.
• Gonorrhoea [both]
• chancroid
• bacterial gastroenteritis – EPEC, shige, salm,camp, reduce stool vol in cholera.
• first choice in typhoid
• resist staph & Gm- :bone,soft tissue, gynec inf. [add clindamycin/metronidazole for anaerobes]
• resp inf [not primary drug] : Gm- & mycoplasma,legionella, Hinf, Brnhm
• MDR TB
• i.v for Gm- septicaemia
• [though poor CSF] bacterial meningitis esp in immunocompromised & CSF shunts
• prophylaxis in neutropenic
• topical for conjunctivitis

NORFLOXACIN - only urinary & genital inf.

PEFLOXACIN -derivative of norfloxacin; higher CSF conc – preferred for meningeal inf; longest t1/2 repeat doses accumulate & so effective in systemic infs also; reduce dose in liver disease.

OFLOXACIN - more potent for Gm+; dose reduc in renal disease; USES: Chr bronchitis & ENT inf, alt for cipro in systemic inf esp chlamydial urethritis & cervicitis, atypical[mycoplasma] pneumonia, MDR TB, leprosy alt regimen.

LEVOFLOXACIN - improved action against strep pneu; primary indication – community acquired pneumonia & exacerbations of chronic bronchitis, sinusitis, pyelonephritis.

LOMEFLOXACIN - more active against Gm- & chlamydia.

SPARFLOXACIN - more active against Gm+[strep,staph], anaerobes, mycobact; primary indication: pneumonias, exacerbations of chr bronchitis, sinusitis & ENTinf, TB,MAC,leprosy; no interaction with warfarin; ADR- phototoxic, QTc prolongation with cisapride/TCA/phenothiazines/1A & 3 antiarrhyth.

GATIFLOXACIN - excellent against many resp : strep,chlamydia,anerobes : community acq pneu, exacerbations of chr bronchitis, other upper/lower resp infs; CI- hypokalaemia/drugs that prolong QT.

MOXIFLOXACIN - topoisomerase4 of Gm+ is major target; high activity against strep,etc, including beta lactam/macrolide resistant & anaerobes: primary indication for pneumonias, bronchitis, sinusitis, otitis media. CI- seizure predisposition, with proarrhyth drugs.

SULFONAMIDES

[used against pyogens but now limited to malaria [trimethoprin+pyrimethamine] because of resistance & ADRs]

bacteriostatic – both Gm + & -; bactericidal conc in urine.

• sensitive organisms- Strep.pyo, H.infl, H.ducreyi, Calymm.granulomatis, V.cho, chlamydia, actinomyces, nocardia, tox.
• prominent resistant organisms- gonococci, pneumococci, meningococci, Staph.aureus, Strep.pyo, E.coli, shigella.

MOA- inhibits replication by competively inhibiting PABA incorporation in bacterial folic acid synthesis. [unlike bacteria, humans utilize preformed FA in diet]

• cross resistance among all sulfonamides
• pus & tissues are rich in purines,thymidine,PABA, & antagonize sulfonamide action
• wide distribution even into CSF & placenta.
• acetylated metabolite is inactive but contributes to ADRs since it is less soluble in acidic urine & ppt causes crytalluria. CI- renal failure.

ADRs [common]- nausea, crystauria [Rx- alk/ dillute urine], hypersensitivity – photosensitization/ exfoliative dermatitis/ stevens jonson syndrome, hepatitis, kernicterus by protein displacement, hemolysis in G-6PD deficiency, contact sensitization.

short acting [less lipid soluble, 6hrs]- SULFADIAZINE - preferred for meningitis & urinary cath with analgesic phenazopyridine.

intermediate acting [10hrs]-

SULFAMETHOXAZOLE - preferred combination[COTRIMOXAZOLE] with trimethoprim since similar t1/2 for

• UTI[acute, chronic, recurrent] [trimethoprime concentrates in prostratitis],
• resp inf by H.inf 7 Gm+ cocci, alt to FQ for typhoid,
• ampicillin resistant dysentry from cam/E.coli/ shigella,
• one of the drugs of choice for chancroid,
• alt to doxy/eryth for granuloma inguinale,
• Pneu.carinii

ADRs- stomatitis, nausea, trimeth is anti-folate causes teratogenic effects & megaloblastic anaemia in alcoholics & pregnancy, uremia in renal disease, marrow hypoplasia in AIDS & elders, thrombocytopenia with diuretics.

MOA- combination becomes bactericidal  by sequential block of folate metabolism & max synergism is at plasma conc 20sulf:1trim which is obtained by dose 5:1 since trim has larger distribution in tissues.

SPECTRUM – S.typhi, serratia, kleb, , P.carinii, sulf resistant staph,strep,shigella, E.coli, H.inf, gonococci, meningococci.

SULFAMOXOLE- sole sulfanamide therapy for chronic UTI, resp inf [strep pharyngitis & gum inf].

long acting [high protein bound,7days, low plasma conc so not used for acute pyogenic inf]]- SULFADOXINE, SULFAMETHOPYRAZINE - supra additive synergistic combination with pyrimethamine [sequential block] for single dose treatment of chloroquine resistant falciparum, Pneu.carinii, toxoplasmosis. ADR- prolonged use causes severe cutaneous rxns.

SPECIAL PURPOSE-

1. SULFACETAMIDE- topically for ocular chlamydial/bacterial inf. [eradication requires sytemic azith/tetracycline]
2. SULFASALAZINE -ulcer colitis, rh arthritis.
3. MEFENIDE [atypical sulfonamide with action in pus & against pseudomonas, clostridia] – topical prophylaxis for <20% burns to prevent septicaemia. ADRs- severe pain, systemic absorption causes carbonic anhydrase inhibition – acidosis & hyperventilation.
4. SILVER SULFADIAZINE [antimicrobial action from slow release of silver ions]- topical prophylaxis in burns & nosocomial bacterial/fungal inf resistant to other sulfonamides.

TETRACYCLINE ANTIBIOTICS

oral broad spectrum except fungi& viruses [now many Gm+ cocci are resistant, Mycobacteria are naturally resistant but most Gm+ bacilli are sensitive, enterobact(pseudo,prot,kleb,s.typhi, b.frag) are resistant but some Gm- bacilli like Calymm.granulomatis, V.cholerae, yersinia, brucella, F.tularensis are sensitive, anaerobes & entamoeba,plasmodia  require higher MIC other misc sensitive ones are spirochetes, borrelia, ricketsiae, chlamydia]

MOA - bacteriostatic; inhibit bacterial protein synthesis by binding to 30s ribosomal subunit & preventing binding of aminoacyl tRNA to A site.

high intracellular penetration hence accumulate & penetrate even non-inflamed meninges & secreted in milk.

only doxycycline is metabolised so enzyme inducers reduce its t1/2.

most potent is minocycline.

ADRs-

• irritant [esophageal ulceration esp wiht doxy],
• liver damage [tetra & oxyt are safer],
• reversible faconi like syndrome [since all except doxy accumulate] in preexisting renal disease,
• phototoxicity on exposed parts [esp with demeclo & doxy so CI in malaria prophylaxis],
• brown discolaration & tooth caries & temporary bone growth suppression if given during late pregnancy & children<6yrs,
• inhibit protein synthesis & increased urea so CI with diuretics,
• demeclo causes Dinsipidus, mino causes vestibular toxicity,
• high doses [except completely absorbed mino & doxy] cause Cl.dificile pseudomembranous enterocolitis superinf,
• contact sensitization so not to be used topically except for ocular.

USES- only when more selective & less toxic antibiotic is not available [for empirical treatment of mixed infs combination of penicillin + aminoglycoside/3rd cephalosporin/FQ is preferred]

first choice in venereal diseases[lymphogranuloma, granuloma inguinale], atypical[mycoplasma] pneumonia, reduce stool vol in cholera, brucellocis, suspected cases in epidemic plague, borrelia relapsing fever, riskettsia – typhus/rocky mt spotted/Q fever.

second choice to

• ampicillin for tetanus, anthrax, actinomycetes, listeria.
• Pn allergy/cipro/ceftr for gonorrhoea/syphilis
• azithr for chlamydial[urethritis, trachoma, pneumonia]
• cotimox for chancroid & E.coli.
• strptomycin for tularemia.

misc uses- chr intestinal amoeb, adj in falciparum resistant malaria, severe acne, prophylaxis of  meningitis epidemic.

AMINOGLYCOSIDE ANTIBIOTICS

[produced from soil actinomycetes, not absorbed orally- given i.v, extracellular distribution -crosses placenta but  not BBB, excreted unchanged in urine, bactericidal to (coliforms)aerobic Gm- bacilli esp in alkaline pH, narrow safety margin]

MOA-[cidal unlike other inhibitors of protein synthesis since additional mechanism]- inhibit bacterial protein synthesis by binding to 30s-50s interface & causing mRNA codon misreading, / freezing initiation & polysome fromation.  +  altering cell membrane permeability.

single inj of the total daily dose is more effective & less toxic.

ADRs-

• ototoxicity [cochlear -initial tinnitus & later permanent frequency loss starting with high freq, vestibular -initial headache & later vomiting, vertigo, nystagmus, ataxia],
• nephrotoxicity- reversible tubular damage causing low urine concentration & enhancing ototoxicity,
• apnoe from NM block after appling to peritoneal/pleural cavities.
• [CI- pregnant, ototoxic drugs (high ceiling diuretics, minocycline), nephrotoxic drugs (amphotericinB, vancomycin, cephalothin, cyclosporin, cisplatin), caution - old age & muscle relaxants]

STREPTOMYCIN- low potency & narrow spectrum but lowest nephrotoxicity.

• tuberculosis with Ethambutol when hepatitis develops from H/R/Z [acts only on rapidly multiplying extracellular] [rapid resistance & streptomycin dependence if used alone]
• confirmed cases of plague [tetracycline for epidemics]
• drug of choice for tularemia [tetracycline for mild cases]

GENTAMYCIN- cheapest, more potent, broad spectrum but more nephrotoxic.

• First line amynoglycoside  for serious acute Gm- bacillary infections – [combined with pencillin/cephalosporin]
• resp infs in immunocompromised & implants.
• pseudomonas/proteus/klebsiella inf in burns,UTI, pneumonia/abscess, otitis media, osteomylitis(acrylic beads), septicaemia. [topical use is permissible in burns & conjunctivitis]
• meningitis
• SABE

KANYAMYCIN - more toxic, similar to S – second line drug in resistant TB.

TOBRAMYCIN - more potent & less toxic, reserve alternative to gentamycin.

AMIKACIN - widest spectrum since resistant to bacterial inactivation, higher dose required, reserve drug in nosocomial genta/tobra resistant Gm- bacillary infs.

NETILMICIN - widest spectrum since resistant to bacterial inactivation, possibly less toxic so preferable in immunocompromised & nosocomial genta resistant infs.

NEOMYCIN & FRAMYCETIN – only topical use since high systemic toxicity. [combined with polymyxin,bacitracin], wide spectrum including some Gm+ cocci.

• topically for wounds, ulcers,burn, ext ear, conjunctivitis.
• orally for bowel surgery preparation, hepatic coma(lactulose preferred) for inhibiting intestinal flora NH3.
• ADRs- prolonged oral use causes malabsortion by damaging villi & candida superinf by suppressing flora, small amounts are sytemically absorbed so CI in renal impairment.

MACROLIDE ANTIBIOTICS- erythromycin, spiramycin, roxithromycin, clarithromycin, azithromycin

MOA-  [bacteriostatic at low conc] inhibits bacterial protein synthesis by binding to 50s subunit of ribosome & preventing translocation of aminoacyl tRNA from acceptor to peptidyl site, thus terminating peptide chain elongation. [link to animation]

Bactericidal at high conc, depends even on organism & its multiplication rate.

[SPIRAMYCIN - toxoplasmosis & recurrent abortion in pregnant]

ERYTHROMYCIN-

Spectrum – narrow overlaping with PnG [most Gm+, few Gm-]  Str.pyo, Str.pneu, N.gono, C.diphth, Clostridia, Listeria, B.pertussis; in addition campylobacter, legionella, branhamella/moraxella, gardenella, mycoplasma are highly sensitive.

cocci develop rapid resistance & cross resistance with other macrolides.

widely distributed except BBB.

ADRs- safe drug -abdominal cramps, very high dose reversibly impairs hearing, hypersensitivity to estolate[enteric coat] causes hepatitis esp in pregnant, inhibits CYP3A4 causing arrhythmias from terfenadine/astemizole/cisapride.

USES-

1. alternative to penicillin for strep pharyngitis/Rh fever/SABE, resp inf by pneumococci & H.infl, carrier & acute stage of diphtheria, adjuvant in tetanus.
2. first choice in atypical[mycoplasma] pneumonia, whooping cough [effect depends on stage], chancroid [~ cotrimox/ceftria].

limitations of erythromycin – narrow spectrum, acid labile, short t1/2, interactions.

ROXITHROMYCIN - long t1/2 & acid stable – alt to erythro for resp inf.

CLARITHROMYCIN -  better gastric tolerability & more active on sensitive Gm+ cocci & also MAC & other atypical Mycobact & M.leprae – used in first line regimen for MAC, second line in other atypical mycobact & leprosy, H.pylori triple regimen, Strep resp/ear/skin inf.

AZITHROMYCIN - acid stable, better gastric tolerability, no interaction with CYP3A4, intracellular penetration, long t1/2, more potent than other macrolides on resp pathogens & chlamydia. first choice in legionnaires & chlamydial pneumonia, Ch.trachomatis [urethritis,trachoma], MAC, strep resp/ear/skin inf, gonorrhoea.

Anthelmintics

GIT is the abode of many helminths, but some also live in tissues or their larvae migrate into tissues.They harm the host by depriving him of food, blood loss, organ injury, itestinal or lymphatic obstruction, secreting toxins.But rarely fatal.

MEBENDAZOLE -preferred drug for multiple infestations & trichuriasis.

• Broad spectrum – ascaris, ancylostoma, necator, enterobius, trichuris.
• MOA- Slow action [2-3days] by blocking glucose uptake, depleting glycogen stores, loss of microtubules.
• ADRs- nausea, abbnormal expulsion of ascaris due to slow death, high doses -allergic rxns, hair loss, granulocytopenia.
• CI-pregnancy.

ALBENDAZOLE - single dose. superior over mebendazole in hydatid disease, ancylostoma, necator. drug of choice for neurocysticercosis.

• Broad spectrum – ascaris, ancylostoma, necator, enterobius, strongyloidis & taenia & trichinosis [3day course],  hydatid [4wk, repeat after 2ks if needed], neurocysticercosis & other tissue except occular[1mos], filariasis [adjuvant].
• MOA- similar to mebendazole + absorbed fraction is alos converted to active metabolite so effective in tissues as well.
• ADRs- nausea, prolonged use causes fever, hair loss, neutropenia, jaundice.
• CI- pregnancy, hepaic & reanl disease.

PYRANTEL PAMOATE – remarkably free of ADRs [nonirritant]

• Efficacy comparable to mebendazole against  ascaris, ancylostoma, enterobius [singloe dose] but lower in necator & strongyloides [3day].
• MOA- activates N[Ach] receptors causing depolarization & spastic paralysis. [antagonist - piperazine]
• ADR- occasional GIT symptoms & dizziness, safety in pregnancy not established.

PIPERAZINE - safe in pregnancy.

• MOA- GABA agonist causing hyperpolarization & flaccid paralysis [so preferred in ascaris intestinal obstruction].  Worms get expelled but recover in piperazine free medium, so purgative is given.
• ADRs -occasional GIT symptoms, high doses – dizziness.
• CI- renal disease, epileptics.

LEVAMISOLE -restricted[second choice] to ascaris[1dose] & ancylostoma[2doses].

• MOA- stimulates ganglia causing tonic paralysis.
• ADRs -low & well tolerated with 1or2 doses.

DIETHYL CARBAMAZINE CITRATE- highly selective action on Mf in peripheral blood [7days] – Filariasis & tropical eosinophilia.

• MOA- alteration of Mf membranes so that they are readily phagocytosed by tissue monocytes + hyperpolarization by piperazine moiety.
• ADRs- common. starting with a low dose minimises allergic rxns to mass destruction of Mf / for already occured rxns[fever,rash,puritus, lymphadenopathy, fall inBP] temporarily hold DEC & antiH/steroids given then subsequently DEC is administrated.

IVERMECTIN - drug of choice for onchocerciasis & strongyloidosis – single dose.

• MOA- acts on glutamate gated Cl- channels causing tonic paralysis.
• Filariasis – single dose along with albendezole
• Scabies & Pediculosis – only oral drug.
• ADRs- mild so preferred for loa loa & onchocerciasis

NICLOSAMIDE- higly effective against cestodes [Tsaginata, D.latum, H.nana]

• MOA- inhibits oxidative phosphorylation & anaerobic resp.
• REGIMEN- 1g after breakfast, then 1g after 1hr, then saline purge after 2hrs. H.nana -repeat fro 5days since cysticerci develop by 4days. [T.solium -ova released from digested segments develop into larvae in  intestine, so thorough purge required]
• ADRs- nonirritant, no sytemic absorption, safe in pregnancy.

PRAZIQUANTEL - Broad spectrum : drug of choice for schistosomes & other  trematodes[except Fasciola hepatica], cestodes & their larvae [hence T.solium]. [Single dose even in H.nana]

• MOA- leakage of intracellular calcium causing paralysis.
• ADRs- nausea, sedation. visceral flukes destruction causes urticaria, fever.
• Interactions- therapeutic failure from induction by phenytoin, carbamazepine use in neurocysticercosis.

Anti-amoebic drugs

Endemic in developing countries due to poor sanitation & low socio-economic status [faecal contamination of food & water]

TISSUE AMOEBICIDES-

1. for both intestinal & extraintestinal – metronidazole, secni-,  satrani-, emetine, dehydroemetine.
2. for extraintestinal – chloroquine.

LUMINAL AMOEBICIDES-

• diloxamide furoate
• 8-hydroxyquinolines [QUINIODOCHLOR, IODOQUINOL-least absorbed so safer]
• tetracyclines

METRONIDAZOLE -[tinidazole- once daily,higher cure rates, low ADRs;  secnidazole -single dose;  satranidazole -no metallic taste/ CNS/ disulfiram like rxns/carcinogen]

• broad spectrum cidal activity – protozoa [entamoeba, trichomon, giardia], anaerobic bacteria [bacteroides, fusobact, clostridium, Cl.difficle, H.pylori, streptopepto].
• MOA- anerobes’ redox proteins reduce nitro group to reactive nitro radical which damages DNA.
• ADRs- metallic taste, anorexia, glossitis, rash, neutropenia, chronic use causes neuropathy.
• CI- CNS disorders, blood disorders, pregnancy[carcinogen], intolerance in some alcoholics.
• USES-

1. Amoebiasis – first line drug for all froms : invasive dysentry, liver abscess, mild intestinal [almost complete absorption so less effective on luminal cysts]
2. other protozoal – giardiasis, trichomonas vaginitis.
3. anaerobic bacterial infections – colorectal & pelvic surgery, brain abscesss, endocardiits, pseudomembranous enterocolitis, ulcerative gingivitis, trench mouth, H.pylori(triple regimen).

EMETINE -potent, direct amoebicide, reserve drug for severe intestinal/extraintestinal amoebiasis or intolerance/resistance to metronidazole.

• kills only trophozoites, not cysts by inhibiting protein synthesis.
• rapid symptomatic relief in 1-3 days, but not curative.
• s.c/i.m inj till acute dysentry subsides/not more than 10 days & since it accumulates, second dose given after 6wks.
• ADRs – pain, vomiting, diarrhoea, stiff muscles, tachycardia & hypotension[ strict bed rest for 2mos] DIHYDROEMETINE is less toxic to heart.

CHLOROQUINE – only in hepatic/extraintestinal amoebiasis.

• complete absorption [so luminal amoebicide always given to abolish luminal cycle]-highly concentrated in liver & kills only trophozoites.
• as effective as emetine & less ADRs but long[2-3wks] treatment & more relapses.

DILOXANIDE FUROATE- directly kills luminal trophozoites, drug of choice given after tissue amoebicide to cure asymtomatic cyst carriers [chronic intestinal amoebiasis], ADRs- flatulence, nausea, itch.

8-HYDROXYQUINOLINES- kills cyst forming luminal trophozoites [also girdia, trichomonas, dermatophytes, candia, some bacteria], ADRs- nausea, green stools, itch, chronic use causes goitre, iodism[furunculosis, inflamed mm, angioedema, cutaneous hmrrhg], myelo-optic neuropathy. CI- children [blindness] & not more than 14days.

high doses of OLDER TETRACYCLINES- by incomplete absorption inhibit flora with which entamoebae live symbiotically, used as adjuvant in chronic amoebiasis.

Rx:

1. Dysentry/ invasive intestinal amoebiasis – tinidazole [severe cases -dihydroemetine till acute symptoms get controlled in 3 days]
2. chronic/ asymptomatic cyst carriers – diloxanide furoate(2 or more courses are needed) second choice is tinidazole esp for latent hepatic inf; thrid choice hydroxyquinoline for not >2wks; adjuvant is older tetracycline.
3. hepatic amoebiasis – tinidazole [alt dihydroemetine if intolerant]; after that chloroquine to ensure eradication of motile forms; then a luminal amoebicide to eradicate intestinal reservoir of infection.

Anti-Malarial drugs.

Causal prophylaxis - targets the liver preerythrocytic phase.

1. PROGUANIL for P.falciparum. [not used since daily dose]
2. PRIMAQUINE for all species. [not used since toxic]

Suppressive prophylaxis – targets erythrocytic phase. limited to short term use in special risk groups like nonimmune travellers to endemic areas for fixed periods & pregnant women.. .

1. CHLOROQUINE is the drug of choice, but not given for >3yrs since cumulative toxicity.
2. PROGUANIL with CHLOROQUINE for low ressistant falciparum.
3. MEFLOQUINE for resistant falciparum.
4. DOXYCYCLINE for mefloquine intolerance [CI in pregnant & <8yr]

Clinical cure - target erythrocytic phase. radical cure for falciparum, but ralpses of vivax/ovale continue.  fast acting  high efficacy drugs [chloroquine,quinine,artemisinin] articularly for deadly falciparum. slow acting low efficacy drugs [proguanil,pyrimethamine,sulfonamide,doxycycline] are used only in combination.

1. CHLOROQUINE is drug of choice.
2. PYRIMETHAMINE+SULFONAMIDE for chloroquine intolerant /resistant.

Clinical cure for chloroquine/multi-resistant falciparum – mefloquine,quinine,pyremethamine+sulfonamide,artemisinin.

Clinical cure for severe/complicated falciparum – parenteral  quinine, artemisinin.

Antirelapse/Radical cure – target exoerythrocytic phase in relapsing vivax/ovale, used only in very low transmission nonendemic areas, during epidemics after effective vector control measures. .

1. PRIMAQUINE given immediately after erythrocytic schizontocide.

Gametocidal – to reduce disease transmission to mosquito.

1. PRIMAQUINE for all species, a single dose immediately after clinical cure of falciparum.
2. CHLOROQUINE,QUININE for vivax.
3. PROGUANIL,PYRIMETHAMINE make gametes sterile.

CHLOROQUINE - faster high efficay erythrocytic schizontocide for all species.

• MOA- weak base, accumulates in intraerthrocytic plasmodia acidic vesicles, no nontoxic hemozoin, heme-chloroquine complex damages membrane. [analogous MOA- mefloquine,quinine]
• ADRs -cumulative toxicity since high tissue affinity so not >3yrs, low frequent sideeffects -anorexia,itching,headache; chronic use causes loss of hearing, rash, photoallergy, myopathy, gray hair, neuropsychiatirc rxns;  rapid i.v causes arrhythmia & convulsions in children; chronic high dose for RA&DLE causes retinal damage.
• USES- drug of choice for suppressive prophylaxis[1wk before -10wks after] & clinical cure[not antirelapse] of all types of sensitive malaria [safe in pregnancy]. [oral for uncomplicated, i.v in adults only for sever/complicated] ; extraintestinal amoebiais, RhArthritis, DLE, lepra rxn.
• clinical cure for chloroquine resistance in falciparum – sulfa-pyrimethamine, in vivax – mefloquinine/quinine+primaquine.

AMODIAQUINE - faster, more palatable than chloroquine for clinical cure of uncomplicated falciparum.

MEFLOQUINE - intermediate acting erythrocytic schizontocide.

• ADRs – vomiting, diarrhoea, sinus bradycardia, neuropsychiatric rxns.
• limitations – long t1/2 [enterohepatic circulation & high tissue affinity] increases the chances of resistant strains selection & restricts wider use, cannot be given parenterally in complicated cases.
• USES- reserve drug for uncomplicated multiresistant falciparum [suppressive prophylaxis & clinical cure].

QUININE - fast acting erythrocytic schizontocide for all species, gametocide for vivax.

• ADRs – occasional hemolysis,HBuria,kidney damage; cinchonism [tinnitus, vertigo, perspiration,hypotension, respiratory depression, arrhyhtmia]] with higher doses, idiosyncratic -rash,itch,purpura, angioedema, bronchoconstriction.
• USES-  oral for uncomplicated chloroquine resistant, i.v for complicated falciparum[hypoglycemia sideeffect -5%dextrose]; noctornal muscle cramps, myotonia congenita, varicose veins, spermicidal.

PROGUANIL - slow acting erythrocytic schizontocide, sterilize gametes.

• MOA- active metabolite inhibits plasmodial DHFRase.
• limitations- no conversion to active metabolite in some, slow acting disadvantage in nonimmune, cannot be used in pregnancy, rapid resistance.
• USE- suppressive prophylaxis of low chloroquine resistance falciparum.

PYRIMETHAMINE - more potent than proguanil[slow acting erythrocytic schizontocide for falciparum & secondary tissue phase of vivax], directly inhibits DHFRase.

• limitaiotn – slow action so not used for clinical cure, rapid ressitance if used alone.
• USE- suppressive prophylaxis for vivax, given for 10wks after.

PYRIMETHAMINE-SULFONAMIDE/DAPSONE - faster acting due to supra additive synergistic sequential block.

• ADRs- more than sigle dose causes severe cutaneous rxns. CI- infants &hypersensitivity to sulf.
• USE- single dose for clinical cure of chloroquine resistant/intolerant falciparum; first choice for toxoplasmosis.

PRIMAQUINE - targets primary & secondary tissue phases, hypnozoites & gametocytes.

• ADRs- oxidant porperty causes hemolysis, tachypnoea..esp in G-6PD deficiency & RhArthritis,SLE, acutely ill.  CI- pregnancy since foetus is G6PD deficient.
• USE- single dose as gametocide in low trasmission areas after effective vector control measures.

BULAQUINE - better tolerated than primaquine esp in G6PD deficient.

DOXYCYCLINE -

• Clinical cure -always used in combination for chloroquine resistant falciparum [with quinine/pyrimeth-sulf/artimisinin]
• 2nd prophylatic for chloroquine resistant falciparum.

ARTEMISININ- potent & fastest blood schizontocide. some are gametocidic.

• MOA- heme cleaved endoperoxide releases free radicals cause parasite lysis.
• ADRs- safe but close monitoring required for ECG changes.
• USE- reseve drug for acute severe multiressitant falciparum. Recrudescence from short action can be prevented by extending the 3-5day artemisinin monotherapy with long acting mefloquine.