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Case 8: Eczema & Psoriasis, Antibiotics that act on these are…
Case 8: Eczema & Psoriasis
The Skin
Describe the normal structure of skin
Epidermis
Most superficial layer
Made of stratified squamous epithelium
Contains keratinocytes, melanocytes, Langerhans cells, and Merkel cells
Keratinocytes - Produce keratin
Melanocytes - Produce melanin
Langerhans cells - Immune
Function:
Resists abrasion on skin's surface
Reduces water loss through the skin
Has 5 layers
Stratum basale:
Made of a single layer of cuboidal to low columnar cells that rest in a basal lamina
Contains stem cells, from which new keratinocytes arise
Has hemidesomosomes, and desmosomes
Hemidesmosomes:
Anchor the epidermis to the basement membrane
Desmosomes:
Hold keratinocytes together
Stratum spinosum:
8-10 cells thick
Made of keratinocytes, and Langerhans cells
Stratum granulosum:
2-5 layers of flattened, damond shaped cells with long axes that are oriented parallel to the surface of the skin
Keratinocytes of this layer contain conspicuous non-membrane bound protein granules of keratohyalin
Stratum lucidum:
Thin clear zone
Several layers of dead cells with indistinct boundaries
Present in only thick skin
Stratum corneum:
25 or more layers of dead anucleated squamous cells joined by desmosomes
Made of cornified cells (dead cells with a hard protein envelope, which is filled with keratin)
Dermis
Has 2 layers
Papillary layer:
Thin
Includes the substance of dermal papilla and epidermal ridges
Also contains nerve processes
Made of dense, loose connective tissues with thin fibers that are loosely arranged
Contains the blood vessels which suply the epidermis with nutrients, remove waste products, and aid in regulating body temperature
Reticular layer:
Deeper than the papillary layer
Has dense irregular bundles of collagen and coarse elastic fibers which are not randomly orientated, but form regular lines of tensions in the skin (Langer's line)
Hypodermis (Subcutaneous tissue)
Stores approximately half the body's stored fat
Source of energy, insulation, and padding
Varies with age, sex, and diet
Comprised of mainly fibroblasts, adipose tissue, and macrophages
Describe the structure and function of hair and sebaceous glands
2 types of hair
Terminal hairs:
Long
Coarse
Pigmented (scalp, eyelids, and eyebrow)
Vellus hairs:
Short
Fine
Unpigmented (the rest of the body)
Sebaceous gland:
Located in the dermis
Simple/compound alveoar glands that produce sebum
Oily white susbstance rich in lipids
Responsible for:
3d skin surface lipid organisation
Maintaining skin barrier integrity
Has antimicrobial properties
Transports antioxidants to skin surface
Has excess proinflammatory and anti-inflammatory properties
Anagen:
Active hair growth
1cm per month
Catagen:
Hair has stopped growing
Hair follicle shrinks and pushes upwards
Telogen:
Hair detaches and rests
Hair follicle sheds at some points
New hair grows at this position and cycle repeats
Exogen:
Extension of telogen phase, where the telogen hair sheds, and new hair starts to grow simultaneously (new anagen phase)
Describe the functional role of skin
Secretes hormones, cytokines, and growth factors and precursor molecules into active molecules
Excretion through exocrine secretion of sweat, sebaceous, and apocrine glands
Absorption of lipid-soluble substances that allows delivery of therapeutic agents
Staphs & Streps
Describe the classification of streptococci and staphylococci
Stretococci:
Gram-positive round bacteria
Arranged in chains or pairs
Catalase negative
Classified by their haemolytic properties and serological properties
Haemolytic properties
α-haemolytic streptococci cause haemoglobin to change colour
S. penumoniae:
Causes pneumonia, sinusitis, otitiis media, pneumococcal meningitis, and pneumococcal bacteremia
Meningitis - Inflammation of the protective membranes surrounding the brain and spinal cord
Gram positive diploccoci
Present in the nasopharynx of healthy individuals also
Viridans group:
Wide range of symptoms
Dental manifestations, endocarditis, brain abscesses, meningitis
β-haemolytic lyse red blood cells
Group A:
Example: S. pyogenes
Causes pharyngitis, skin and soft tissue infections, rheumatic fever, bacteremia, and sepsis
Group B:
Example: S. agalactiae
Causes Endometritis, UTIs, Neonatal bacteremia, and sepsis
γ-haemolytic cause no change
Staphylococci:
Gram-positive, round cocci
Arranged in clusters
Catalse positive
Describe the virulence factors of streptococci and staphylococci
Sweating and its regulation
Describe the composition and function of sweat and the regulation of sweating
Eccrine glands
Process of sweating begins with nerve stimulation
The sympathetic nerves mainly respond to M3 muscarinic receptor stimulation by acetylcholine, which leads to increase in Ca2+ levels
Isotonic secretion from secretory segments
High Ca2+ levels activates aquaporins, apical Cl- channels, K+ channels, and basolateral Na+/K+/Cl- cotransporter
Cl- and K+ will be actively transferred into lumens, followed by Na+ and water
Isotonic water is produced in the lumen
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Nicotinic receptors and sympathetic adrenergic receptors play a minor role
Apocrine glands
Mainly respond to sympathetic adrenergic nerves
Composition:
99% water
~1% electrolytes
No plasma proteins
May contain glucose and antibodies
pH 4.5-7.5
Regulation:
Climate
Hot climate:
Thermoreceptors detect high temp than set point, it inputs this to the CNS, which leads to the stimulation of sympathetic cholinergic stimulation, which causes eccrine sweating
Cool climate:
Skin temp decreases lower than set point, which prevents sweating
Exercise:
Body and skin temp gets higher, thermoreceptor or heat-sensitive neurones increase firing rate, leading to eccrine sweating
Emotions:
Fear, stress, anxiety activate the amygdala, which stimulates the activation of sympathetic and cholinergic activation, which stimulates eccrine and apocrine sweating
Describe the structure and function of sweat glands
Sweat glands are exocrine glands that are found deep in the dermis or hypodermis
There are 2 main types of sweat glands
Eccrine
It is a simple, coiled, tubular structure which can be divided further into 2 segments
Coiled/secretory segment - Secretes primary secretions
Comprised of:
Clear cells - secretes sweat
Dark cells - assists in mucin secretion
Myoepithelial cells - supports in secretion
Duct segment - Modifies the composition of primary secretion by reabsorption
Made of stratified cuboidal cells
Function:
Thermoregulation (secretes more watery and clear sweat to skin surface)
Found all throughout the body
Apocrine
Found in the armpits, pubic region, external genitalia, and perineum
Similar structure to eccrine, but:
Has a larger lumen
Found deeper in the dermis or adipose layers
Simple cuboidal cells
Function:
Secretes more viscous and cloudy sweat to hair follicles
When bacteria metabolise it, it produces odour
Acne & Cellulitis
Describe the pathophysiology and presentation of acne
Acne vulgaris - Chronic inflammatory skin condition, affects the face, back, and chest
Blockage and inflammation of pilosebaceuous unit, presents with lesions, can be non-inflammatory or inflammatory, or a mix
Causes:
Genetics
Race and ethnicity
Diet
Hormones
Medications
Anabolic steroids
Pathophysiology:
Main pathogenic factors:
Follicular hyperkeratinisation -> forms follicular plugs
Increased sebum production at hair follicles
Cutibacterium acnes found in hair follicles
Inflammation of pilosebaceuous unit
Presentation
Mild acne - Mostly non inflamed lesions, such as open and closed comedones, with few inflammatory lesions
Moderate acne - More widespread, more inflammatory papules and pustules
Severe acne - Widespread inflammatory papules, pustules, and nodules
Microcomedone - precursor for acne lesions, small invisible plug of keratin and sebum within a pilosebaceuous unit
Accumulation of sebum and keratinous material converts a microcomedone into a closed comedone
Follicular orifice is opened with continued distension, forming an open comedone
Densely packed keratin, lipids, and melanin contribute to the dark colour
Follicular rupture leads to inflammatory lesions
After rupture, proinflammatory lipipdsd and keratin are extruded into surrounding dermis, leading to papules or nodules
Describe the therapeutic approach in the treatment of acne
Treat pyschological and social effects, identify underlying cause.
Topical treatment is the standard of care, but both local and systemic treatments are needed for severe acne
Lifestyle advice:
Advise person to avoid over cleaning skin
use non alkalaine detergent products 2x daily on acne prone skin
avoid oil-based cosmetics and sunscreens
make-up should be removed at the end of the day
remind that over scratching lesions increase scarring risk
remind that treatment may irritate the skin, especially at the start
Drug Treatment:
Topical treatment
Encourage regular cleansing with soap and water
Benzoyl peroxide
Topical retinoids
Azelaic acid
Topical antibiotics
Cosmetic camouflage
Systemic treatment
Antibiotics:
Erythromycin has highest resistance, recommendation should be benzoyl peroxide or retionids
Tetracylcline can be used
Retinoids:
Isotretinoin
MOA is unknown, but it inhibits sebaceous gland function and keratinization
Risks: Venous thromboembolism, hyperlipidemia, intracranial hypertension
Hormonal treatment:
Works best with women with persistant inflammatory papules who report flares around their menstrual cycle
Co-cyprindiol - combined antiandrogen treatment
Reduces ovarian androgen synthesis
Reduces free testosterone levels and sebum production
Describe the pathophysiology and presentation of bacterial infections of the skin
Describe the therapeutic approach in the treatment of infections of the skin
Septic and Septic Shock
Bateraemia:
Bacteria in bloodstream
Alive and capable of reproducing
Systemic Inflammatory response syndrome (SIRS):
Overactive inflammatory response
Affects whole body
Caused by infection, trauma, surgery
Temp <36C or >38C
HR >90/min
RR >20/min
WBC <4x10^9/L
Sepsis:
Life threatening organ dysfunction caused by dysregulated host infection response
Septic shock:
Complication of Sepsis
Circulatory, cellular, metabolic abnormalities
Higher mortality risk than sepsis alone
Diagnosis:
Persistent hypotension (vasopressors needed to maintain MAP 65mmHg
Blood lactate level more than 2mmol/L after adequate vol resuscitation
Suspect when:
Signs indicate infection causing severe illness
Concern from carer/relative that there is change in appearance or behaviour
Suspected sepsis must be treated immediately
Diagnosis:
qSOFA score
Sys BP: < or = 100mmHg
RR: > or = 22 breath/min
Altered mental status
Pathophysiology:
Complex
Results from circulating bacterial products mediated by cytokines
Bacteria and components activate coagulation and complement system
Activates macrophages
They release cytokines
Activates platelets
Promote metabolism of arachidonic acid and eosinophil release
Endothelial damage
Tissue injury
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Activates neutrophils and T cells
Cause vasodilation and increased vascular permeability
Activation of coagulation system causes microthrombi
Blood flow to tissues can be reduced
Management:
Done in acute hospital
Follow UK Sepsis Trust "Sepsis Six" within the first hour
Give Oxygen therapy to ppl with reduced o2 saturation/increased o2 requirement
Maintain 94% saturation
Blood tests and microbiology samples
Blood gas
Blood culture
Identify primary bactaraemia, b4 antibiotic administered
Blood tests
FBC, CRP, Urea and electrolytes, etc.
Urinalysis and culture
Treatment
Broad spec antibiotics IV at max recommended dose
Do after culture
IV fluid bolus
Check serial lactate
Check urine output, fluid balance (/hr), and monitor clinical condition
Transfer to critical care may be needed
Skin and systemic diseases
Viral rash
Measles
Caused by measles virus
Prevented by vaccination
Signs
Cough
Coryza
Conjunctivitis
Prodromal
Malaise
Fever
Cough
Kopliks spots on buccal mucosa
Rash
Lasts 1 week
Erythematous
Maculopapular
Can become confluent with progression
Appears on:
Face
Behind ears
Body -> Trunk -> Limbs
Rubella
Occurs during childhood
Preventable by vaccination
Mild and resolved in a week
Maternal infection during pregnancy can be serious
Miscarriage, stillbirth, CRS
Signs
Rash
Face and neck -> Spreads down the body
Pink/light red
Maculopapular
Lasts 3-4 days
Lymphadenopathy
Coryzal symptoms
Varicella Zoster
Chickenpox
Vesicular rash
Fever
Malaise
Predominant in childhood
Self-limiting in healthy children
Prevented by vaccine
In pregnancy
Can lead to maternal chicken pox, and fetal varicella syndrome
Signs
Prodromal
Nausea
Myalgia
Anorexia
Headache
General malaise
Small erythematous macules
Scalp, face, trunk, limbs
Can progress to
Papules, clear vesicles, and pustules
Persists in sensory nerve ganglia of the dorsal root.
Reactivation years late can cause
Herpes Zoster
reactivation of varicella zoster
Incidence increase with age
Post-herpetic neuralgia is most common
Diagnosis
Unilateral vesicular rash in affected dermatome
Location depends on affected nerve
Herpes Simplex
Caused by HSV-1 (90% of cases)
Cold sores
Parvovirus B19
Slapped cheek syndrome
No vaccines
Ppl at risk
Pregnant women
Immunocompromised
Haematological disorders
Common in skool aged children
Mild, self-limiting
Signs
Children present with:
Diffuse, erythematous facial rash on one or both cheeks
Can be preceded by:
Prodromal symptoms
Erythematous maculopapular rash on trunk, back, and limbs
Adults present with:
Maculopapular ras on trunk, back, and limbs, but not face
Vasculitis
Inflammation of Blood vessels (autoimmune related)
Characterised by size of vessel affected
IgA Vasculitis
Most common systemic vasculitis
Causes
Upper respi infection
Drugs
Food
Insect bites
Cold weather
Genetics
Features
Joint manifestation
GI manifestation
Kidney manifestatiion
Self limiting
Rash
Symmetricall, erythematous macular rash
Kawasaki disease
Occurs in children
Viral/bacterial/genetic triggers
39C fever
Rash-red plams and soles and peeling skin
Conjunctivitis
Inflamed lips tongue and mouth
Aspirin, colchecine helps
PAN
Hep B and C, genetics, Bacterial/viral infection
Systemic and cutaneous forms
Systemic
Peripheral nerves
Kidney
GI Tract
Cutaneous forms
Tender nodules
Skin necrosis and ulceration
Livedo reticularis
Diabetes
Skin manifestation
Eruptive xanthomatosis
Diabetic dermopathy
red papules, on shins
Diabetic bullae
Necrobiosis lipoidica diabeticorum
Endocrine disease
Acanthosis Nigricans
Hyperpigmentation
Pretibial myxoedema
Associated with hyperthyroidism
Tumours of the skin
Types of skin tumours
Epidermal tumours
Most common
Non-melanocytic
Arise from Keratinocytes
Benign
Seborrheic keratosis
Formerly known as basal cell papilloma
Presentation
Common pigmented epidermal tumour due to melanin deposition
Round, coin like waxy plaques (geasy)
"Stuck on' appearance
Locations
Face
Shoulder
Behind ears
Rarely, can be a sign of an underlying condition (GI Tract)
Warts
Malignant
Basal cell carcinoma
Frequent in white and fair-skinned people
Pathogenesis
Major risk factor - Sun exposure
Causes mutation in PTCH1 (Tumour suppressor gene)
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Presentations
Clinical features
Rodent ulcers
Microscopic features
Nests of atypical basaloid cells within the dermis, separated from adjacent stroma by thin clefts
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Subtypes
Nodular
Scab/lumps/pearly papules with prominent dilated subepidermal blood vesssles
Most common
Superficial
Scaly erythematous plaques
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Infiltrative
Waxy, indurate plaque that resembles a scar
Grows slowly, never metastasis, locally invasive
Treatment
Surgical excision
Pharmacological intervention
Hedgehog pathway inhibitors
Squamous cell carcinoma
2nd most common type of skin cancer
Peak incidence in the 60-70 y/o range
Faster growing
Metastasis rare
Treatment
Non-invasive SCC
Surgical excision or other local therapies
Invasive SCC
Surgical excision for localised cases
Chemotherapy/immunotherapy for metastatic cases
Risk factors
Sun exposure
Immunocompromisation
Melanocytic
Arise from melanocytes
Benign
Melanocytic naevus (mole)
Proliferation of melanocytes
Mutation in BRAF or RAS
Acquired or Congenital
Acquired - Common in sun expoed areas
95% remain benign
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Malignant
Melanoma
Least common, most dangerous
Can develop from moles, or normal skin
Risk factors
Fair skin
Multiple moles
Family history of melanoma
Differentiate between typical moles and melanomas with ABCDE
Prognosis depends on depth the melanoma has penetrate below epidermal base
Treatment
Non-invasive melanoma
Surgical Excision
Invasive melanoma
Chemotherapy/radiotherapy not effective
Immunotherapy have improved outcomes
BRAF/MEK inhibitors for BRAF-mutant melanomas
Dermal tumours
Sweat glands (hidradenoma)
Sebaceous gland adenoma
Vascular tumour
Tumours of connective tissues (fibroma)
Nerve-sheath tumours (Neurofibroma)
Pathogenesis
UV rays from sun exposure causes 90-95% of skin cancers
UVC
Shortest wavelength
Mostly blocked by ozone
Rarely damages skin
UVB
Burning
Medium wavelength
Can damage skin surface and epidermis
UVA
Aging and wrinkling
Longest wavelength
All layers of skin can be damaged
Pathophysiology
UV Directly damages DNA
DNA forms covalent linkages between consecutive bases
Prevents proper replication and transription
Damage is usually repaired by nucleotide ecision repair pathway
Excess damage overwhelms pathway
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UV indirectly damages DNA
Free radical mediated
Antibiotics
Selective toxicity
Ability of drug to injure a target cell or organism
only
Antibiotics only harm bacteria, not human cells
Strategy depends on biochemical/structural differences btwn target and host cells
Why certain antibiotics work better towards certain bacteria, and not others?
Gram-positive and Gram-negative bacteria have many differences
Can make it easier/harder for antibiotics to act
Def: Substance produced by micro-organisms that kill/inhibit growth of other micro-organisms
Classifications of antibiotics
Based on MOA
Bactericidal - Kill organisms
Affects cell wall/membrane/DNA synthesis
Preffered when
Large bacteria load
Host immunocompromised
Bacteriostatic - Inhibit multiplication
Affects protein synthesis
Based on spectrum
Narrow spec - few bacteria
Broad spec - broad range of bacteria
What do antibiotics target?
Cell wall
Beta-Lactam antibiotics
Peniciliins
Cephalosporins
Monobactams
Carbapenems
Antibiotics can become resistant, and produce beta-lactam-ase
To counter, some antibiotics can be combined with beta-lactamase inhibitors
Beta-lactamase inhibitors:
Active against plasmid encoded beta-lactamases
Used in fixed combo with hydrolysable penicillins
Co-amoxiclav
(Amoxicillin + Clavulanic acid)
Tazocin
(Piperacillin + Tacobactam)
Penicillins
Works best against Gram-pos organisms
Types
Narrow spec:
Mostly against G(+) Cocci
B-lactamase resistant:
Against Sensitive staphylococci
Broad spec
Agaisnt G+ and G- bacteria
Not penicillinase-resistant
Combined with
beta-lactamase inhibitors
Extended spec
Agasint Pseudomonas sp
Cephalosporins
Used for sensitive organisms
Types
1st gen:
Good activity against G+, ok against G-
2nd gen
Good against G-
3rd gen
Good against G-, bad against G+
4th gen
Good against G+ and G-
Increased resistance to beta-lactamase
5th gen
Good against MRSA
Others
Bacitracin
Vancomycin - Inhibits transglycosylation and transpeptidation (last resort for MRSA)
Works better against Gram positive bacteria
MOA:
Normal bacteria growth cycle
Transglycosylase enzymes
forms the sugar backbone structure of the peptidoglycan cell wall
Vancomycin inhibits this
Transpeptidase enzymes
forms cross-links btwn polysaccharide backbones
Strengthens cell wall
Beta-Lactams target these, inhibiting cross-linking, weakening the wall, leading to lysis
Cell membrane
MOA:
Disrupts bacterial outer cell membrane, altering permeability
Affective against gram-neg bacili, MRSA, and Vancomycin resistant enterococci
Protein synthesis
Ribosomal subunits
30S:
Decodes mRNA by aligning it with tRNA
Tetracyclines:
Interfere with attachement of tRNA to mRNA-ribosome complex
Streptomycin:
Changes shape of 30S portion, mRNA read incorrectly
50S:
Contains peptidyl transferase center
Chloramphenicol:
Bind to 50S portion, inhibits forming of peptide bond
Broad spec for serious infections
Causes aplastic anaemia
Macrolides - Erythromycin, Clarithromycin:
Bind to 50S, prevents movement of ribosome along mRNA
Can cause GI disturbances
Active against G(+), but not most G(-)
Others
Clindamycin
Streptogramins
Linezolid
Metabolism
MOA:
Inhibits specific enzymes needed for folic acid synthesis, required for DNA synthesis in bacteria
Sulfonamides:
Acts on Dihydropteroate synthase
Trimethoprim:
Acts on Dihydrofolate reductase
Nucleic acid synthesis
Quinolones:
MOA:
Inhibits DNA gyrase
Prevents negative supercoiling of DNA
Broad spec
Metronidazole:
MOA:
Forms cytotoxic-intermediate particles, interacts with bacterial cell DNA, resulting in DNA strand breakage, and fatal destabilization of the DNA helix
Antibiotic susceptibility testing
Determines bacteria susceptibility to certain types of antibiotics
Determines minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC)
MIC:
Lowest conc of antimicrobial agent to cause inhibition of bacterial growth
MBC:
Lowest conc of antimicrobial agent to cause microbial death
Done with disc diffusion testing, or Broth dilution
Disc diffusion
Paper discs with antibiotics placed in agar plate with bacteria
Antibiotic diffuses, forming zones of inhibition
Suggests MIC
ZOI measured and compared to standard database to see if bacteria is susceptible, moderately susceptible, or resistant
Susceptible:
Isolates inhibited by usually achievable concentration of agent, when recommended dose is used
Resistant:
Isolates not inhibited by usually achievable concentration of agent, when recommended dose is used
Moderately susceptible:
Isolates with antimicrobial MIC wherer response rates are lower than susceptible isolates
Broth Dilution
Bacteria added to tubes of liquid medium in the presence of varying antibiotic concentrations.
If antibiotic inhibits bacterial growth, vials will not become turbid (cloudy)
Suggests MIC and MBC
Principles in choosing antibiotics
Consider patient and organism
Patient
history of allergy
renal and hepatic function
susceptibility to infection
ability to tolerate drugs by mouth
severity of illness
ethnic origin, age,
whether taking other medication
pregnant, breast-feeding or taking an oral contraceptive.
Organism
Based on culture/diagnostic tests
Empiric therapy - "best guess":
When identity and susceptibility of organism is unknown
Broad spec administed for broad coverage
Definitive therapy:
Targets specific agent from culture or rapid tests
Antibiotic Resistance
Causes of resisance
Inappropriate use
Easy public access
Misoconceptions (not finishing prescription)
Poor stewardship
Inadequate diagnosis
Use of broad spec
Prescribe for infection including viral
Over prescribing
Def: The effort of every party to measure and improve the prescription and usage of antimicrobials, including antibiotics, antivirals, and antifungals
Natural selection
Poor hygiene in hospitals
Over-use of antibacterial soap
Over-use of antibiotics in agriculture
Mechanisms
Intrinsic
Due to microbial natural defenses system
Act to reduce intracellular antibiotic level
Reduce uptake
G- are more resistant due to outer membrane forming a permeable barrier
Hydrophilic antibiotic can gain entry through porins
When down regulated, reduced entry
Increase efflux
Transport of intracellular antibiotics out of cell, involves pumps
Extrinsic
Metabolise/modify antibiotics
Bacteria produce enzymes that inacivates antibiotics
Change antibiotic target
Via mutation
Transformation:
Uptake of cell-free DNA that contains antibiotic resistance genes from a donor cell
Transduction:
Transfer of bacterial DNA containing antibiotic resistance by bacteriophage
Conjugation:
Transfer of plasmid DNA between mating bacterial cells
Propagation of resistance:
Mixed population of bacteria, some have acquired resistance
Addition of antibiotics kills non-resistant bacteria
Antibiotic resistant bacteria proliferate
Without mutation
Lesser binding and effects from antibiotics
E.g.: Ribosome protection proteins
Antibiotics that act on these are bactericidal
