Chap 47: Antimycobacterials

INTRODUCTION
- mycobacteria intrinsically resistant to most abx

• grow slowly - abx act on dividing cells
• can be dormant - completely resistant or killed very slowly
• lipid rich cell wall - impermeable to many agents
• intracellular pathogen - organism residing in macrophages are difficult to be entered
• development of resistance is notorious

- combination >2 drugs needed + long term treatment


ANTUBERCULOUS DRUGS
Introduction
- 1st line agents - RIPES
- I+R - 2 most active drugs - 9 months of both will cure 95-98% of cases
- addition of pyrazinamide to above for 1st 2 mths --> reduce duration to 6 mths
- ethambutol and streptomycin

• does not reduce duration of rx
• for coverage of resistant bugs while culture pending

- prevalance of resistance

• INH resistance in US 10%
• both INH and R resistance (MDR) 3%

Isoniazid (INH)
- most active drug
- less effective for atypicals
- penetrates into macrophages --> extracellular and intracellular microbes
- MOA

• inhibit mycolic acid synthesis - components of mycobacterial cell wall - cell death

- resistance

• drug resistance happens in 1 x 10*6
• TB lesions has 1 x 10*8 bacilli - resistant mutants are readily selected
• adding rifampicin - resistance 1 x 10*6 x 10*6 - much higher

- pharmacokinetics

• po - well absorbed
• penetrates all tissue including CNS
• metabolised by liver, renally excreted
• don't need to adjust dose in renal pt

- SE

1. hepatitis - commonest, up 3-4x normal - dont need to stop drugs, if clinically symptoms occur (loss of appetite, n/v, jaundice, RUQ pain - stop drugs promptly (causes liver cell necrosis)
2. peripheral neuropathy - due to relative pyridoxine deficiency (INH promotes pyridoxine excretion) - hence higher risk for alcoholic/malnutrition/DM/AIDS/uremia
3. immunologic - rash, fever, SLE
4. blood disorders - pyridoxine def anemia, tinnitus, GI discomfort

Rifampicin
- semisynthetic abx of rifamycin, produced by Streptomyces mediterranei
- g+ve/-ve, enteric bacteria, mycobacteria (bactericidal), chlamydia
- readily penetrates tissues, phagocytes --> enters abscess and lung cavities
- MOA

• binds to B-subunit of RNA polymerase --> (-) RNA synthesis
• resistance - point mutation - reduction in binding to polymerase

- clinical uses

1. mycobacteria infection
2. others - meningococcal carriage, Hib in kids, + fusidic acid = against staph carriage

- SE

1. orange tinge to bodily fluid
2. hepatitis
3. allergic type - rash, fever, thrombocytopenia

Ethambutol
- synthetic agent
- inhibits mycobacterial arabinosyl transferases --> needed for polymerization of arabinoglycan (component of cell wall)
- resistance - due to mutation unable to bind to transferases
- SE - retrobulbar neuritis - loss of visual acuity, red-green color blindness --> C/I in children too young to allow visual assessment

Pyrazinamide
- exact mechanism unknown
- use - important as 1st line agent to reduce rx time 6mths - as 'sterilizing' agent
- SE - liver toxicity, hyperuricemia (may provoke gout)

Streptomycin
- aminoglycoside - see chapter 45
- penetrate into cells poorly - mainly against extracellular tubercle bacilli

ALTERNATIVE 2ND LINE AGENTS
Introduction
- considered only

1. resistance to 1st line
2. failure of lcinical response
3. serious drug reactions
4. expert guidance to deal with the SE of the agents listed

- examples

• Ethionamide - related to INH - blocks mycolic acid
• Capreomycin - peptide protein synthesis inhibitor
• Cycloserine - inhibit cell wall synthesis
• Aminosalicylic acid (PAS) - anti-folate exclusively against TB
• Kanamycin & amikacin
• Fluoroquinolone
• Linezolid
• Rifabutin
• Rifapentine

DRUGS FOR ATYPICAL MYCOBACTERIA
- 10% of clinical practice in US - not M tuberculosis or M tuberculosis complex

• M avium complex - M avium, M intracellulare

- characteristics of atypical mycobacteria

• special lab characteristic
• present in environment
• not communicable btw person
• less susceptible to normal antiTB drugs

- usually need atypicals - tetracycline, macrolide, sulfonamides
- M kansasii - INH, R, ethambutol
- M avium

• common - important in AIDS
• combination agents - azythro/clarithro + ethambutol +- ciprofloxacin

DRUGS USED IN LEPROSY
- M leprae
- dapsone + other sulfones

• closely related to sulfonamides - same MOA
• resistance issue - used in combination with 3 agents - dapsone, rifam, clofazimine
• NB: dapsone can be used for PCP
• SE: hemolysis (common, esp in thos with G6PD deficiency), metHb, erythema nodosum (can be rx with steroids/thalidomide)

- rifampicin - usually in combination
- clofazimine

• phenazine dye - alternative to dapsone
• MOA unknown - DNA binding
• SE: skin discoloration - red brown to nearly black

Chap 44: Bacterial protein synthesis inhibitors - tetracyclines, chloramphenicol

Tetracycline, macrolide, clindamycin, chloramphenicol, streptogramin - all inhibit protein synthesis

TETRACYCLINE
General
- bacteriostatic
- g+ve and g-ve
- anaerobes, rickettsia, chlamydia, mycoplasma, protozoa
- most tetracyclines has similar antibacterial activity --> resistant ones can use doxy
- differences in clinical efficacy are minor - only differences are due to pharmacokinetics
- MOA

• partly passive diffusion; partly active transport into cell
• binds reversibly to 30S subunit of bacterial ribosome
• inhibit protein synthesis

- resistance

1. reduced influx/increased efflux of drug by active transport protein pump
2. ribosomal protection
3. enzymatic inactivation

Pharmacokinetics
- differences in excretion

• minocycline excreted in tears - eradicate carrier state of meningococcal infection

- excreted mainly in bile and urine --> enterohepatic circulation may contribute to maintenance of serum concentration level
- classified by serum T1/2

• short acting - chlortetracycline, tetracycline, oxytetracycline
• intermediate - demeclocycline, methacycline
• long acting - doxy, minocycline

Clinical uses
- drug of choice in atypical infections - mycoplasma, chlamydia, rickettsia, spirochetes
- H. pylori - in combination with other regimens
- Vibrio - cholera
- combined with aminoglycosides --> to treat plague, tularemia, brucellosis
- protozoal infection - E. histolytica, Plasmodium falciparum

SE
- GIT - N/V/D
- Bony structures and teeth - binds to Ca in newly formed bone and teeth - enamel dysplasia + retardation in bone growth - hence never give in <8 yo
- Liver
- Nephrotoxic - renal tubular acidosis, renal injury
- Photosensitization
- Vestibular reaction - dizziness, vertigo, n/v

CHLORAMPHENICOL
- binds to 50S ribosomal subunit - inhibit protein synthesis
- bacteriostatic
- active against rickettsia, NOT chlamydia, also g+ve, g-ve aerobic and anaerobic

Clinical use
- rarely used due to resistance, other alternatives, toxicity
- serious rickettsial infection - typhus, rocky mountain spotted fever
- alternative to B-lactams for meningococcal meningitis for pt with serious allergy
- eye infections - cos of its broad spectrum, penetration of ocular tissue + aqueous humor (*ineffective for chlamydial infection)

SE
- BM suppresion - reversible, dose-related - aplastic anemia (idiosyncratic, irreversible)
- newborn infants lack effective glucoronic acid conjugation mechanism --> accummulate drugs in serum --> grey baby syndrome (vomit, flaccid, hypotherm, gray, shock, collapse)
- GIT - N/V/D

Chap 49: Antivirals

INTRODUCTION
- needs to block viral entry/exit from host cell
- or active inside host cell
- hence toxicity relates to intefering host cell function

- viral infection --> replication peaks at/before manisfestation of clinical symptoms
- hence the reason for early initiation of therapy OR prevention of infection (chemoprophylaxis for influenzae A using amantidine)

- stages of viral replication

1. adsorption --> enter host cell
2. uncoating of viral neucleic acid
3. systhesis of early regulatory proteins --> nucleic acid polymerases
4. systhesis of RNA/DNA
5. systhesis of late, structural proteins
6. assembly of viral particles
7. release from cell

AGENTS FOR HSV and VZV
- acyclovir, famvir, valacyclovir
- acyclovir the earliest hence most studied

Acyclovir
- acyclic guanosine derivative
- requires 3 phosphorylation steps for activation --> eventually inhibit viral DNA polymerase
- clinical uses

• primary genital herpes - shortens duration by 5 days
• recurrent genital herpes - shortens by 1-2 days
• VZV - needs higher dosage

- SE

• generally well tolerated
• minor GIT SE: N/V
• neurotoxic - tremor, deliriumm seizure

Valacyclovir
- L-valyl ester of acyclovir
- rapidly converted to acyclovir after po
- serum levels 3-5x higher than with aciclovir

Famcyclovir
Penciclovir
Trifulridine

Agents against CMV
Ganciclovir
- affinity against CMV 100x more than aciclovir
- active against CMV, HSV, VZV, EBV, HHV-8

Valganciclovir
- converted into ganciclovir
- for treatment of CMV retinitis for pt with AIDS

Cidofovir
Foscarnet
Fomivirsen

Chap 48: Antifungal agent

Introduction
- human fungal infection increasing
- advances in surgery, cancer treatment, ICU, AIDS
- divided into

1. Systemic drugs (oral/parenteral) for systemic infections
2. Oral drugs for mucocutaneous infection
3. Topical drugs for mucocutaneous infection

SYSTEMIC ANTIFUNGALS FOR SYSTEMIC INFECTIONS
Amphotericin B
- produced Streptomyces nodosus --> both A + B --> only B in use
- polyene macrolide
- poorly absorbed orally unless intestinal infection
- no effect with renal/liver/dialysis pt
- MOA

• difference in lipid composition of fungal and mammalian cell membranes
• human: cholesterol; fungi: ergosterol
• amp B binds to ergosterol only --> creates pores in cell membrane --> leakage of intracellular ions and molecules --> cell death

- Resistance

• ergosterol binding is impaired by decreasing membrane concentration of ergosterol/mutation by modification of sterol molecule

- SE

• infusion related toxicity: very common - fever, chills, m spasm, vomiting, headache, hypoTN - slow down infusion rate/reduce daily dose or use pre-meds (PCM, antiH1, steroids)
• slower toxicity: renal damage happens in all pt with clinically significant dose of drug, abnorm LFT

- Clinical uses

• broadest spectrum antifungal - drug of choice of all life-threatening mycotic infection
• against all clinically significant yeasts - Candida, Cryptococcus neoformans
• endemic mycoses - H capsulatum, Blastomyces dermatitidis, Coccidiodes immitis
• pathogenic moulds - Aspergillus fumigatus, mocor

Liposomal amphotericin B
- due to SE --> this aim to bind more selectively to fungal ergosterol by being morel lipid soluble
AZOLES
General
- synthetic compounds
- depending on number of N atoms in zole ring - divided into

1. imidazole: ketoconazole, miconazole, clotrimazole
2. triazole: itraconazole, fluconazole, voriconazole

MOA
- inhibit fungal c-P450 enzyme --> inhibit ergosterol systhesis
- more selective to fungal one than human c-P450 --> causes SE

Clinical uses
- Candida, C. neoformans, endemic mycosis, dermatophytes
- Itraconazole + voriconazole --> aspergillus

SE
- nontoxic
- minor GI upset, liver abnormalities, hepatitis

Ketoconazole
- 1st oral azole
- hepatitis - less selective to c-P450 than other azoles

Itraconazole
- oral and IV form
- needs gastric acid for better drug absorption --> take it with coke!
- used in dermatophytoses and onychomycosis
- azole of choice in dimorphic fungi histoplasma, blastomyces, sporothrix

Fluconazole
- high water solubility --> hence better oral absorption
- better GI and hepatic tolerance --> widest therapeutic index
- for mucocutaneous candidiasis
- no activity against aspergillus + filamentous fungi

Voriconazole
- similar to itraconazole in activity
- less toxic than amphotericin B --> drug of choice in invasive aspergillosis

ECHINOCANDINS (capsofungin)
- newest class --> inhibit fungal cell wall synthesis
- IV form - extremely well tolerated in GIT and hepatitis
- indicated for salvage therapy with invasive aspergillosis that failed to response with amphotericin B

- Horvath - advantage of capsofungin over amphotericin

• very narrow spectrum
• has best coverage for candida and aspergillus but nothing else
• not as nephrotoxic as amphotericin
• ampho has broader coverage but nephrotoxic is a problem
  

ORAL ANTIFUNGALS FOR MUCOCUTANEOUS INFECTION
Griseofulvin
- from penicillium
- very insoluble fungostatic --> only use in dermatophytoses
- exact MOA unknown --> deposited in newly forming skin --> binds to keratin --> protect skin from new infection
- hence to be given 2-6 wks for hair/skin infection to replacement of infected keratin
- nail infection --> longer

Terbinafine
- systhetic allylamine
- keratophilic medication like griseo; but unlike griseo: fungicidal
- inhibit fungal enzyme (squalene epoxidase) --> accummulate sterol squalene (toxic to fungi)
- cure rate up to 90% for onychomycosis for 12wks duration --> better than itroconazole/griseo

TOPICAL ANTIFUNGALS
Nystatin
- polyene macroline (like amphotericin B)
- too toxic for parenteral admin --> only orals
- active against candida ==> for suppression of local candidal infection

Topical Azoles
- clotrimazole, miconazole
- shampoo form of ketoconazole for seborrheic dermatitis, pityriasis versicolor

Topical allylamines (terbinafine)
- tinea cruris and corporis

Chap 51: Clinical use of antimicrobial agents

Empirical therapy
- presumptive therapy
- justification: early intervation = better outcome

Approach to empirical therapy
- get clinical dx
- specimen for lab exam
- formulate microbiologic dx
- is empirical therapy necessary?
- start treatment
- monitoring of treatment

Choice of antimicrobial agents
- host factor

• PMHx - liver, renal, AIDS
• drug allergy
• age
• pregnancy status

- pharmacologic factor

• pharmacokinetics
• delivery of drugs to site of action
• SE
• drug interaction

ABX OF KNOWN INFECTIOUS AGENTS
Interpretation of culture results
Reasons for -ve results

1. wrong sample - give abx first, contaminated
2. wrong request - bacterial vs viral culture
3. non-cultivable organism/slow growing stuff - H. capsulatum, bartonella
4. non knowing special needs of culture medium

Susceptibility testing
- measures MIC - minimum drug concentration to INHIBIT organism growth
- or MBC - minimal bacteriocidal concentration
- usually MIC is measured
- only in severe cases where MBC is measured - meningitis, endocarditis, neutropaenic sepsis

Specialised assay methods
- B lactamase assay
- synergy studies

Monitoring therapeutic response - duration of therapy
- 2 methods

1. microbiology - cultures/specimens should become sterile
2. clinically - symptoms, inflammatory markers, radiology

- duration depends on pathogen, site of infection, host factor

• generally determined empirically
• serious infection: 7-10 days after pt is afebrile
• recurrent infections: longer

Clinical failures
- check culture
- check host
- check abx

Bacteriostatic vs bacteriostatic activity
- generally, cell wall agents are bactericidal

• aminoglycosides
• B-lactams abx
• isoniazid
• metronidazole
• pyrazinamide
• quinolones
• rifampicin
• vancomycin

- protein synthesis inhibitors are bacteriostatic

• chloramphenicol
• clindamycin
• ehtambutol
• macrolides
• nitrofurantoin
• oxazolidinones
• sulfonamides
• tetracyclines
• trimethoprim

- which to choose?

• immunocompetent - doesnt matter it's the same
• immunocompromised - bactericidal
• severe infection like meningitis/endocarditis/neutropaenic - bactericidal

- bactericidal agents divided into 2 groups

• concentration dependent killing - aminoglycosides, quinolones
• time dependent killing - B-lactams, vancomycin; bactericidal activity continues as long as serum concentration > MBC

Postantibiotic effect
- persistant suppression of bac growth after limited exposure
- reason:

1. reversible non-lethal damage to cell structures --> needs time to recover
2. drug still at binding site within periplasmic space
3. then need to synthesize new enzymes before growth will resume

Route of administration
- many have similar pharmacokinetic properties po vs iv

• tetracycline
• trimethoprim-sulfamethoxazole
• quinolones
• chloramphenicol
• metronidazole
• clindamycin
• rifampicin
• fluconazole

- IV are for:

1. critically ill pt
2. bacterial meningitis/endocarditis
3. cannot swallow
4. abx that are poorly absorbed orally

Management of antimicrobial drug toxicity
- usually able to switch
- some no alternatives - eg neurosyphilis has anaphylaxis to penicillin - needs desensatisation
- penicillin + cephalosporin <10%>

- penicillin + imipenem cross reaction - >50%



ANTIMICROBIAL DRUG COMBINATION
Rationale
- seriously ill
- polymicrobial infections - intra-abdominal abscess
- reduce resistance (eg TB)
- reduce dose-related toxicity with single agent
- enhanced inhibition/killing



Synergism and antagonism
- 2 drugs together - MIC/MBC using 1/4th of the dosage compared to using single agent
- see text how to calculate synergism and antagonism

• FIC (fractional inhibition concentration) index <=0.5 = synergism
• FIC index >=4 = antagonism

- 3 mechanisms of synergism

1. Blockade of multiple steps in metabolic sequences - eg in bactrim as folic acid p/way - against PCP
2. Inhibit enzymatic inactivation - amoxyl-clavulanic acid, timentin, tazocin
3. Enhancement of antimicrobials uptake - cell wall agents (penicillin) increases aminoglycoside uptake by bacteria - eg Staph, enterococci, Pseudomonas, strep

- 2 mechanisms of antagonism

1. Inhibition of cidal agents by static agents - cell wall agents need dividing cells to act upon - if stopping cell division = cannot work; eg: tetracycline + chloramphenicol inhibit cell wall agents
2. Induction of enzymatic inactivation - g-ve (enterobacter, pseudomonas, serratia, citrobacter) if given imipenem, cefoxitin, ampicillin - can induce B-lactamase secretion --> hence B-lactams will lose activity

Antimicrobial prophylaxis
Surgical vs non surgical

• Surgical - needs to cover common pathogen - typically cefazolin/cefalothin
• Non-surgical - for suspected exposure or immunocompromised - depends on situation

National Research Council Wound classification
- clean

• infection rate <2%
• elective
• primarily closed procedure - respiratory, gastrointestinal, biliary, genitourinary, or
  oropharyngeal tract not entered
• no acute inflammation and no break in technique

- clean contaminated

• infection rate 10%
• emergency of an otherwise elective as above
• minimal spillage/minimal break

- contaminated

• Infection rate 20%
• Acute nonpurulent inflammation
• major technique break or major spill from hollow organ
• penetrating trauma <>
• chronic open wounds to be grafted or covered

- dirty

• Infection rate 40%
• Purulence or abscess present
• preoperative perforation of respiratory, gastrointestinal, biliary, or oropharyngeal tract
• penetrating trauma > 4 hrs old

Chap 50: Misc antimicrobial agents

METRONIDAZOLE
- antiprotozoal + antibacterial (anerobes) - bacteroides, clostridium
- well absorbed po - use as 1st line
- crosses BBB
- iv/pr/po
- metabolised by liver
- clinical uses

• anerobes - intra-abdominal infection
• vaginosis - can use topically
• clostridium
• brain abscess

- adverse

• GI - N/V/D
• peripheral neuropathy with prolonged use (never discharge someone on long term flagyl) - irreversible

MUPIROCIN
- produced Pseudomonas fluorescens
- inactived after po --> only topical
- MOA and uses

• g+ve cocci - MSSA and MRSA
• inhibit isoleucyl tRNA synthetase
• can induce resistance
• topical treatment for minor skin infection - impetigo
• intranasal elimination of MRSA
• NOT recommended for long term ulcers/surgical wound due to emergence of resistance

NITROFURANTOIN
- g+ve, g-ve bacteria
- well absorbed - rapidly metabolised and excreted --> no systemic antibacterial action, only in urine - renal impairment can cause systemic toxicity
- clinically - prophylaxis of chronic UTI - keep urine pH <5.5 (enhances activity)
- SE - N/V, G6PD def (neuropathy, hemolytic anemia)

DISINFECTANTS, ANTISEPTICS, STERILANTS
Disinfectants - strong chemicals that inhibit/kill microbes
Antiseptics - disinfectants with low toxicity to host cell - used on mucous membrane, skin
Sterilants - kills vegetative cells and spores

Alcohol
- disinfectant + antiseptic - denatures proteins
- NOT sporicidal hence not sterilant
- ethanol and isopropyl alcohol (isopropanol)
- quick - kills vegetative bacteria, mycobacteria, many fungi, lipophilic viruses
- optimal concentration - 60-90% by volume in water
- disadvantages

• lack residual action - evaporate quickly
• skin drying effect - can add emollient
• damages corneal tissue - tonometer has to be wait till completely evaporated/water rinsed
• flammable

Chlorhexidine
- active for vegetative bac, mycobacteria, moderate against fungi and viruses
- strongly binds to bac membranes --> leakage of small molecules + precipitation of cytoplasmic proteins
- slower action than alcohol --> but has residual activity hence similar to alcohol action if used repeatedly
- most effective - g+ve cocci, inhibit spore germination
- less irritating to skini
- no oral toxicity (poorly gut absorbed) - can cause ototoxicity and neurotoxicity (never used in such surgeries)

Halogens
- Iodine

• most active antiseptic for intact skin
• bactericidal in 1 min; kills spores in 15 mins
• problems: hypersensitivity reaction, stains clothing + dressings

- Iodophors

• complexes of I2
• retain activity as above
• less irritating to skin + producing less toxicity

- Chlorine

• universal disinfectant - oxidizing agent - must be kept in air sealed containers
• inactivated by serum/blood/feces/urine/protein containing stuff --> hence surfaced must be cleaned before using

Chapter 46: Sulfonamides, trimethoprim

SULFONAMIDES
General
- sulfonamides are antifolate drugs
- basic formula --> similar to p-aminobenzoic acid (PABA)
- some microbes require extracellular PABA to form dihydrofolic acid --> form purine and nucleic acid


- mechanism of action - competitively competes with PABA as above
- susceptibility: g+ve, g-ve, nocardia, chlamydia, protozoa, some enteric bacteria (e coli, klebsiella, salmonella, shigella, enterobacter)
- rickettsia NOT inhibited by sulfonamides - stimulated by it

Resistance
- some bac dont have enzymes for folate systhesis - nothing to block
- overproduction of PABA due to mutation
- production of enzyme that has low affinity to sulfonamides

Pharmacokinetics
- po/iv - metabolised by liver --> urinary excretion *reduce dose for renal pt

Clinical uses
- hardly used anymore alone
- needs combination

TRIMETHOPRIM
- inhibits bacterial dihydrofolic acid reductase --> see diagram
- binds 50,000 times more efficiently than same enzyme
- creates synergism with sulfanamides
- combination is bactericidal vs bacteriostatic alone

Resistance - due to plasmid encoded mutation
- reduced cell permeability
- overproduction of dihydrofolate reductase
- mutation of reductase - reduced drug binding

Pharmacokinetics
- po or iv
- absorbed well orally
- 1:5 preparation with sulfamethoxazole - peak concentration in serum 1:20 (due to increased lipid solubility)
- concentrates in prostatic fluid and vaginal fluid (more acidic) --> more antibacterial activity
- renal excretion

Uses
- UTI - prostatitis
- PCP
- GIT - shigellosis, salmonella infection
- respi - strep pneumoniae, haemophilus, M catarrhalis, K pneumoniae
- not mycoplasma

SE
- antifolate --> megaloplastic anemia, bone marrow suppresion
- can give folinic acid for prevention

Chapter 45: Aminoglycosides

General
- active ingredient - hexose ring attaching to amino sugars
- works in synergism with B-lactams + vancomycin
- MOA: irresible protein synthesis inhibitor - exact mechanism unknown

• passive diffusion via porin channel across outer membrane (see B-lactamase cell wall)
• actively transported into cytoplasm
• binds to 30S subunit ribosomal protein
• inhibit protein synthesis

- resistance - NO activity against anaerobes

1. production of transferase enzyme/enzyme that inactivate aminoglycoside
2. impaired entry into cell --> mutation/deletion of porin protein
3. receptor protein on 30S ribosomal subunit deleted/altered

- pharmacokinetics

• poorly absorbed po unless has ulcers
• IM or IV
• cencentration-dependent killing + has postantibiotic effects (several hours) --> hence can be given OD rather than traditional TDS in smaller doses

- aminoglycoside toxicity

• concentration and time dependent
• toxic threshold achieved --> once the concentration achieved --> the time above the threshold becomes critical
• usually look at trough - hence the monitoring of genta at 12hrs post abx
• with OD dosing - unncessary to measure serum level in 3 days

- SE

• ototoxic - neomycin, kanamycin, amikacin
• nephrotoxic - neumycin, tobra, genta
• vestibulotoxic - streptomycin and genta
• likely to be encountered for therapy >5 days
• loop diuretics --> potentiate kidney damage
• don't use with concurrent nephrotoxic abx (vancomycin, amphotericin B)

- water soluble, cannot mix with B-lactams with administration

Spectinomycin
- alternative rx for gonorrhoea allerg to penicillin

Gentamicin
- isolated from Micromonospora purpurea
- g+ve and g-ve - inhibit staph and coliform and g-ve
- synergistic with B-lactams against pseudomonas, proteus, enterobacter, klebsiella, serratia, stenetrophomonas
- resistance

• strep and enterococci - failure of drug to enter cell --> add vanco or penicillin (break down cell wall)
• ribosomal resistance is rare
• mostly from plasmid - encoded aminoglycoside-modifying enzymes --> this type of resistance will be susceptible to amikacin

- clinical use

• IM/IV
• topical - infected burns/wounds/skin lesion
• intrathecal - g-ve meningitis

Tobramycin
- similar to genta in dose, frequency, chemical
- slightly different

• genta covers serratia better
• tobra covers pseudomonas
• E. faecalis susceptible to both
• E. faecium only to genta
• otherwise can interchange

- can be given via neb for Pseudomonas rx

Amikacin
- works with g-ve that are resistant to genta and tobra --> proteus, pseudomonas, enterobacter, serratia
- MDRTB

Netilmicin
Neomycin & kanamycin
- paromomycin member of the group
- active g+ve and g-ve but not strep and pseudomonas
- widespread use in bowel prep --> resistance
- limited to topical (joint injection/infected surfaces) or oral use

Chap 43: B-lactam abx + other cell wall inhibitors

General
- active structure: B-lactam ring
- group of families: penicillins, cephalosporin, monobactam, carbapanem - hence cross reaction can occur
- all b-lactams are renally excreted --> reduce in renal impairment

PENICILLINS
- penicillins - g+ve, g-ve cocci, g-ve rods resistant (e. coli)
- antistahy penicillins - nafcillin
- extended spectrum

Mechanism of action
- histology - layers of bacterial cell wall (1st two constitute cell wall)

• outer membrane (only in g-ve, lipid layer)
• peptidoglycan (very thick in g+ve)
• periplasmic space - where b-lactamase work
• cytoplasmic membrane - where b-lactams bine
• - binds to protein PBP (penicillin binding protein) in cytoplasmic membrane in bac cell wall - inhibit cell wall synthesis

- timentin --> can cause bone marrow dysfunction --> neutropaenia/thrombocytopenia (think about used in febrile neutropaenia)
- antipseudomonal penicillins --> home IV on piperacillin not timentin due to stability of solution in the baxter pump

CEPHALOSPORIN
- more stable than penicillin
- not active against enterococci and Listeria
- 4 major groups of increasing g-ve cover
- 1st generation: cephalothin, cephalexin, cefazolin, cephradine, cephapirin
- 2nd: cefamandole, cefoxitin
- 3rd: ceftriaxone, cefotaxime

ID stuff
Ceftazidime vs cefepeme
- antipseudomonal
- similar to timentin but lacks g+ve cover as compared to cefepeme
- hence cefepeme is the abx of choice in neutropaenic pt - to cover g+ve
- but for pseudomonas alone - should use ceftaz but reserve as last agent

MONOBACTAMS
- aztreonam
- g+ve, pseudomonas, serratia cover

B-LACTAMASE INHIBITOR
- clavulanic acid, sulbactam, tazobactams
- resemble B-lactam, but weak antibacterial action
- active against Staphy, H influenzae, N gonorrhoea, salmonella, shigella, E. coli, Klebsiella

CARBAPENEM
- structurally similar to B-lactam abx
- covers everything but NOT

• Enterococcus faecium
• MRSA
• C. difficile (use flagyl)
• Burkholderia cepacia
• Stenotrophomonas maltophilia (use bactrim)

VANCOMYCIN
- glycopeptide
- produced by Streptococcus orientalis
- inhibit cell wall synthesis
- has VRE and vancomycin resistant S. aureus (VRE significance - transmit VR into SA)
- syngergistic with genta and streptomycin against E faecium and E faecalis
- given IV, only orally for C. dificcile enduced enterocolitis (but due to emergency of VRE - metronidazole is used instead)
- SE: phlebitis, 'red man'/'red neck' syndrome - antihistamine release (give phenergan/slow down infusion)

- if someone on vancomycin - no use doing MRSA swab - it will come back -ve --> still needs isolation

TEICOPLANIN
- similar to vanco, but given IM and IV
- allows once daily dosing due to long T1/2 --> hence easier for home IV

Quinolones

QUINOLONES
- nalidixic acid as prototype
- DNA gyrase inhibitor
- DNA gyrase - uncoil DNA to for replication
- nalidixic acid + flurinated group = fluoroquinolone - increases antibacterial spectrum

Antibacterial activity

• g-ve aerobic bacteria and atypical cover (mycoplasma, chlamydia, legionella, mycobacteria)
  
• limited g+ve (covers MSSA, not MRSA)
  
• development of fluoroquinolone aims to cover more g+ve
• cipro, lemo, levo, oflox, peflox = good g-ve, moderate to good against g+ve
• cipro best for P. aeruginosa
• gati, moxi, spar, trova (3rd group) - covers Strep pneumoniae
  

Resistance

• Staph, pseudomonas, serratia
• Cross resistance happens

Pharmacokinetics

• IV = oral administration = hence give oral

Clinical

• UTI - norfloxacin concentrated in urine
• bacterial diarrhoea

SE

• QTc prolongation
• damage growing cartilage --> not recommended <18>
• tendinitis
  

Antibiotics - macrolides, ketolids, streptogramins, clindamycin

MACROLIDES IN GENERAL

• Have similar activity
  
• Major differences in side effects, half lives (frequency of dosage), admin method
• Obtained from streptomyces erythreus
• Binds to 50s ribosomal DNA - bacteriostatic/cidal depending on dosage and susceptibility
  

Erythromycin
- Activity

• G+ve stuff - pneumococci, strep, staph, corynebacterium
• atypicals - chlamydia, mycoplasma, legionella, helicobacter, listeria
• mycobacteria

- Resistance

• Plasmid encoded
• Cross-resistance complete btw all macrolides

- Clinical uses + SE

• Stimulates gut motility - used in post operative gut surgery to promote gastric emptying - only for erythromycin NOT other macrolides
• Due to this SE - we don't use them a lot routinely
• Liver toxic
• Inhibit cP450

Clarithromycin

• increased activity with g+ve (Horvath)
  
• advantage over erythromycin - lower GIT SE, better gut absorption - hence used in eradication of H. pylori

Azithromycin

• Difference from above - penetrates tissue extremely well - [tissue] > [serum] - hence slowly released from tissue = longer T1/2 of 3 days
  
• hence once daily dosing
• 1g = 7 day of doxycycline

KETOLIDES

• semisynthetic macrolide
• 3-keto group added
• eg: telithromycin

CLINDAMYCIN AND LINCOMYCIN
Lincomycin - no longer used due to toxicity
Clindamycin
- like erythromycin in activity - binds 50s ribosomal subunit - reduce toxin production - hence used in necrotising fasciitis (reduces exotoxin produced by Strep)
- covers g+ve (strep, staph, pneumococci) and anaerobes
- doesn't cover: enterococci, g-ve aerobic, clostridium
- bacteriostatic --> hence if someone has staph bacteremia --> treat with fluclox first to kill, then use clindamycin orally --> if not use clindamycin + other agents eg rifampicin (never use this alone)
- has excellent oral bioavailability (one of those to use orally unless mechanical reason, like ciprofloxacin)

- clinical uses

• has the best oral bioavailability for staph (1st clindamycin, 2nd fluclox, 3rd augmentin, last keflex)
• severe anaerobic infection (bacteroides)

- SE

• diarrhoea - major SE leading to disuse
• colitis - usually pseudomembranous

OXAZOLIDINONES
Linezolid
- g+ve: staph, strep, enterococci, listeria, corynebacteria
- binds to 23S ribosomal RNA of 50S subunit - unique to linezolid - hence there's no cross resistance
- problem: hematologic toxic - low PLT most common (3%), neutropaenia
- use: VRE