�THE ANTIBIOTIC TREATMENT GUIDE

Dani Brewster-O’Brien

Introduction

• To teach you a basic framework from which to guide your clinical decision making
• Always follow local ID guidelines or the Therapeutic Guidelines (eTG)
• eTG has great educational resources for antimicrobial prescribing
• ALWAYS check before prescribing as guidelines are continuously updated.

Severity of Infection

• Systemic Inflammatory Response Syndrome (SIRS) - An exaggerated defence response of the body to a noxious stressor (infection, trauma, surgery, acute inflammation, ischemia or reperfusion, or malignancy); SIRS Criteria must meet 2/4 of the following:
• Temperature <36.0 C OR >38.0 C
• Tachycardia >90 bpm
• Respiratory rate >20 breaths/min or PaCO2<32mmHg
• WBC <4.0 OR >12.0; or presence of immature forms neutrophils >10%
• Sepsis (generally SIRS + evidence of infection) – Life threatening organ dysfunction in response to infection, with organ dysfunction indicated by: impaired consciousness, RR ≥22 or hypoxaemia, hypotension (SBP<90), lactate >2; also poor peripheral perfusion/mottled skin, acute oliguria or creatinine above baseline, low platelet count, elevated serum bilirubin
• Septic Shock – Sepsis and despite adequate fluid resuscitation have EITHER:
• Inability to maintain MAP 65 (or SBP 90mmHg) without vasopressors, OR
• Blood lactate >2.0mmol/L

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Severity of Infection

• There are many factors that may affect the choice of antibiotic and it’s route of delivery - ALWAYS consult local ID guidelines about appropriate treatments. Some conditions have own criteria, e.g. CURB-65 in CAP.
• The classification between a ‘Non-Severe’ and ‘Severe’ within this document, is artificial and treatment will require the guidance of a senior clinician and guidelines to the specific condition, patient factors, and previous treatment.
• IV Therapy – If unable to tolerate PO therapy, immunocompromised, or with comorbidities that increase risk of rapid disease progression (e.g. Diabetes), even if not meeting SIRS criteria
• ‘Non-Severe’ (non-SIRS criteria, e.g. does not have 2/4 of the SIRS criteria)
• Generally uncomplicated, with only localised infections, and no signs of sepsis, or septic shock
• Generally no systemic involvements, e.g. no/low fevers, no vomiting or changes in level of consciousness
• ‘Severe’
• Meet 2/4 SIRS criteria, evidence of systemic effects, or complications such as perforation

Basic Antibiotic Guide

*Gram Negatives – Gentamicin is the standard empiric therapy however in many infections Ceftriaxone may be used to concomitantly cover gram positives or for target tissue penetration (eg of the meninges).

Gram Positive vs Gram Negative

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Gram Positive vs Gram Negative

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• Gram Positive bacteria have a thick peptidoglycan layer and no outer lipid membrane 🡪 retain crystal violet dye
• Gram Negative bacteria have a thin peptidoglycan layer and have an outer lipid membrane (composed mainly of lipopolysaccharides (LPS)) 🡪 can be decolourised to accept counterstain (safranin)

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Bacterial Classification

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• Toronto Notes 2020

Normal Human Flora

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• Mims Medical Biology 5th Ed

Beta-lactam: Mechanism of Action

• Beta-lactam antibiotics are bactericidal and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. They act as a suicide substrate for D,D-transpeptidases (eg the PBPs).
• It inhibits the last step in peptidoglycan synthesis by acylating the transpeptidase (Penicillin Binding Protein) involved in cross-linking peptides to form peptidoglycan. Inducing loss of viability and lysis of the bacteria.

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Beta-Lactamase Inhibitors: MoA

• Beta-lactamase Inhibitors: Work primarily by inactivating Beta-Lactamases, which are enzymes that hydrolyze and inactivate the beta-lactam ring (especially in gram-negative bacteria).
• Amoxycillin + Clavulanate/Clavulanic Acid = Augmentin; Piperacillin + Tazobactam = Tazocin (Pip-Taz)

Cephalosporins

• Bactericidal beta-lactam antibiotic (binds PBP, inhibiting transpeptidation, hence peptidoglycan synthesis in actively growing cells).
• Typically don’t cover ‘LAME’ bacteria: Listeria, Atypicals, MRSA, Enterococcus
• 1^st Generation – Cefazolin, Cefalexin, Cefalothin
• GPC (not Enterococcus), minimal GNB coverage, covers ‘PEcK’ (Proteus, E. coli & Klebsiella)
• Cefazolin 1^st line for surgical wound prophylaxis; Cephalexin for simple UTI
• 2^nd Generation – Cefuroxime, Cefaclor, Cefoxitin
• GPC (not Enterococcus), less GPB activity and more GNR coverage: ‘PEcK HENS’ (H. influenzae, Enterobacter, Neisseria & Serratia)
• 3^rd Generation – Ceftriaxone, Cefotaxime & Ceftazidime
• Serious GNB infections, less GPB activity; Ceftazidime is anti-pseudomonal (VAP); Ceftriaxone covers H. influenzae, Neisseria & S. pneumoniae (encapsulated bacteria - meningitis)
• Use Cefotaxime instead of Ceftriaxone in infants <3mo (esp neonates <28days of age)
• 4^th Generation – Cefepime
• Cefepime is anti-pseudomonal, also good GNB (beta-lactamase coverage) and GPB coverage
• 5^th Generation – Ceftaroline
• Ceftaroline has broad GNB & GPB (including MRSA), but not anti-pseudomonal

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Antibiotic: Mechanisms of Action

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Treatment Examples

• In all instances the ‘example’ EMPIRIC antibiotics are ONLY one possible OPTION given to the clinician, and will not suit all scenarios/patients.

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• ALWAYS consult the most current Infectious Disease (ID) guidelines and consult with a senior clinician/ID Specialist to establish the most appropriate empirical antimicrobial therapy, before MCS can guide directed therapy.

Gram Positive Bacteria: Cocci

• Gram Positive Cocci (GPC) - “coccus”
• Staphylococcus (MSSA)
• Non-Severe: Dicloxacillin PO OR Cefalexin OR Cefazolin
• Severe: Flucloxacillin IV
• Staphylococcus (MRSA)
• Non-Severe: Trimethoprim + Sulfamethoxazole (TMP+SMX) (Bactrim) or Clindamycin PO
• Severe: Vancomycin IV (trough levels required)
• Streptococcus
• Non-Severe: Amoxycillin PO or Phenoxymethylpenicillin PO or Procaine Benzylpenicillin IM
• Severe: Benzylpenicillin IV
• Enterococcus faecalis
• Non-Severe: Amoxycillin PO
• Severe: Ampicillin IV
• Vancomycin Resistant Enterococcus (VRE): Daptomycin OR Linezolid
• Enterococcus faecium: Vancomycin (as inherently resistant to penicillin's)

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Gram Positive Bacteria: Rods

• Gram Positive Rods (GPR) (just here for completeness)
• Bacillus (spore-formers)
• B. cereus (diarrhoea + vomiting): Don’t normally treat but Vancomycin if indicated
• B. anthracis (anthrax): Fluoroquinolone (Ciprofloxacin)
• Clostridium (spore-formers) (anaerobic)
• C. perfringens (necrotising skin infection/gas gangrene): Benzylpenicillin/Metronidazole IV + Clindamycin IV
• C. botulinum & C. tetani: Anti-toxin is mainstay of treatment
• Listeria (or gram-variable) (meningitis and transplacental/neonatal infections)
• Acquired from fruit (rock melons) and un-pasteurised dairy products
• Cause of meningitis in neonates and the elderly
• L. monocytogenes: Benzylpenicillin IV
• Corynebacterium (also club-shaped)
• C. diphtheriae (pharyngitis): Benzylpenicillin IV ± Azithromycin IV
• Diphtheria anti-toxin is mainstay of treatment

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Gram Negative Bacteria

• Gram Negative Cocci (GNC)
• Neisseria meningitis (Meningococcal meningitis) & Neisseria gonorrhoeae (Gonorrhoea = the ‘Clap’)
• Moraxella catarrhalis
• Haemophilus influenza (cocco-bacilli) - Encapsulated (typeable) (H. influenzae type b - Hib) and non-encapsulated (non-typeable) (NTHi)
• Bordetella pertussis (cocco-bacilli): Whooping Cough: *Azithromycin PO (if <3wk of Sx onset)
• Gram Negative Rods (GNR)
• Proteus
• Escherichia coli
• Klebsiella
• Enterobacter *different to = Enterobacterales = Enteric GNB: E. coli, Klebsiella & Enterobacter etc.
• Serratia
• + Salmonella, Shigella, Legionella, Yersinia, Campylobacter & Pseudomonas and others
• Empiric Treatment
• Acute Cystitis (UTI): Trimethoprim (TMP) PO, Cefalexin PO or Nitrofurantoin PO
• Non-Severe Pyelonephritis: Augmentin (Amoxicillin and Clavulanate) PO or IV
• Pyelonephritis: Gentamicin IV (maximum 2 doses (48h) then Ampicillin IV), or Ceftriaxone IV

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Anaerobic Bacteria

• Anaerobes: Live in devitalised/hypoxic tissue and smell foul
• Peptostreptococcus (GPC): oropharynx, GIT & genito-urinary tract
• Actinomyces (GPR): oropharynx, GIT & genito-urinary tract
• Clostridium (GPR): GIT & female lower reproductive tract
• Lactobacillus (GPR): major vaginal microbiota
• Cutibacterium (GPR): skin commensal
• Bacteroides (GNR): major GIT microbiota
• Fusobacterium (GNR): Oral pathogen/?commensal (periodontal disease)
• Empiric Treatment
• Metronidazole PO (Flagyl) (if GIT intact, PO absorption equals IV absorption)
• *Aminoglycosides (Gentamicin) are not active against anaerobes, because to be taken up across the cell membrane they need energy from aerobic metabolism; they do not function well in low pH or low oxygen (e.g. in an abscess).
• 2^nd line: Clindamycin, Beta-lactams with clavulanate or carbapenems

Atypical or ‘Adventure’ Bacteria

• Obligate Intracellular
• Chlamydophila/ia, Chlamydia trachomatis, Mycoplasma, Coxiella burnetii (Q Fever) & Rickettsia (R. australis: QLD Tick Typhus/Australian Spotted Fever)
• Facultative Intracellular
• Legionella, Listeria, Salmonella, Neisseria, Brucella, Mycobacteria
• No Cell Wall
• Mycoplasma
• Spirochaete *different treatment
• Treponema pallidum (Syphilis): *Benzathine Benzylpenicillin IM (long-acting) or Procaine Benzylpenicillin IM
• *Atypical Pneumonia Bacteria (due to clinical presentation – ‘walking pneumonia’)
• Mycoplasma pneumoniae, Chlamydophila pneumoniae & Legionella spp. (L. pneumophila & L. longbeachae) + viruses – interstitial ‘atypical’ disease
• Empiric Treatment
• Non-Severe: Doxycycline PO (tetracycline)
• Severe: Azithromycin IV (macrolide)

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Pseudomonas aeruginosa (GNR)

• Pseudomonas is a common coloniser especially of the oropharynx; only treat if in the blood (bacteraemia)
• Creates biofilms
• High mortality and can be causal pathogen in febrile neutropoenia.
• Considered opportunistic in cystic fibrosis, traumatic burns and immunocompromised patients (as well as immunocompetent).
• Ubiquitous soil, water, hospital equipment and human colonisation.

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• Empiric Treatment
• Non-Severe (non-severe Bronchiectasis + P. aeruginosa carriage): Ciprofloxacin PO (only PO antibiotic available)
• Severe (Pneumonia): Piperacillin + Tazobactam (Tazocin) IV or Ceftazidime (3^rd Gen Ceph) IV or Cefepime IV (4^th Gen Ceph) or Ciprofloxacin IV or Meropenem IV (PLUS give Gentamicin IV)

Mycobacterium: Acid Fast Bacilli

• Mycobacterium tuberculosis (MTB)
• Non-Tuberculosis Mycobacterium (NTM): M. leprae, M. bovis & Mycobacterium Avium Complex (MAC)
• Ziehl-Neelsen Stain (AFB – they are Acid-fast Bacilli)
• Tuberculosis (M. tuberculosis) Treatment:
• 2mo Rifampicin, Isoniazid, Pyrazinamide & Ethambutol, then:
• 4mo Rifampicin & Isoniazid

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• RIPE (+ common side effects)
• Rifampicin (RIF): Ri-‘fanta’-cin 🡪 Orange secretions (urine + tears)
• Isoniazid (INH): Peripheral Neuropathy
• Pyrazinamide (PZA): ‘pyramid’ deposits 🡪 Gout
• Ethambutol: E for eyes 🡪 Optic Neuritis and ↓Visual Acuity

Application of the Principles!

• Location?
• Likely Pathogen/s?
• Severity of Infection? (is it Non-Severe or is there systemic features?)
• IV/PO – Patient, Infection & Medication Factors
• This is for empirical therapy, ALWAYS take cultures (site and blood) for MCS (microscopy, culture and sensitivity) to guide directed therapy.
• ALWAYS consult local hospital ID Guidelines/eTG as these are continuously updated based on the most recent evidence.

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Basic Antibiotic Guide

*Gram Negatives – Gentamicin is the standard empiric therapy however in many infections Ceftriaxone may be used to concomitantly cover gram positives or for target tissue penetration (eg of the meninges).

Treatment Examples

• In all instances the ‘example’ antibiotics are ONLY one possible OPTION given to the clinician, and will not suit all scenarios/patients.

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• ALWAYS consult the most current Infectious Disease (ID) guidelines and consult with a senior clinician/ID Specialist to establish the most appropriate empirical antimicrobial therapy, before MCS can guide directed therapy.

Abdominal Infection

• Pathogen
• Gram Negative Rods (Enterobacteriaceae: E.coli & Klebsiella), Enterococcus & Anaerobes
• Empiric Treatment: Diverticulitis, Appendicitis & Peritonitis (perforated viscus)
• GNR: Gentamicin IV
• Enterococcus: Ampicillin IV
• Anaerobes: Metronidazole PO/IV
• eTG

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Pneumonia: CAP

• Pathogens
• Streptococcus pneumoniae (Pneumococcus) (5-15%) (declined due vaccines), Haemophilus influenzae (H.inf) (COPD) (5%), Moraxella catarrhalis & Staphylococcus aureus (2º to viral)
• Viruses (30%) – Influenza, RSV, Adenovirus, Rhinovirus, Parainfluenza
• Atypical (3-15%): Mycoplasma (young adults) , Chlamydophila & Legionella (environmental sources, outbreaks);
• Severity (Empiric Treatment)
• Non-Severe: Amoxycillin PO (Pneumococcus + H.inf) ± Doxycycline PO (Atypicals)
• Moderate: Benzylpenicillin IV (Pneumococcus + H.inf) + Doxycycline PO
• Severe: Ceftriaxone + Azithromycin ± Vancomycin (MRSA) ± Metronidazole (anaerobes)

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Pneumonia: CAP – eTG severity scale

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Pneumonia: HAP

• Pathogen (>48h in hospital)
• Most commonly S. pneumoniae, but GNB increase as the oropharynx gets colonised over the length of hospital admission
• Recent broad-spectrum antibiotic therapy select MRSA, MDR-GNB (Enterobacteriaceae, Pseudomonas and Acinetobacter)
• Empiric Treatment
• Non-Severe-Mod: Augmentin (Amoxycillin + Clavulanate) PO/IV or Ceftriaxone IV (GPC+GNB)
• Severe: Piperacillin + Tazobactam (Tazocin) IV ± Gentamicin (MDR-GNB) ± Vancomycin (MRSA)
• eTG

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Acute Cystitis (UTI) & Pyelonephritis

• Pathogen: UTI
• Escherichia coli (75-95% of cases) also Klebsiella, Proteus and Staphylococcus saprophyticus (5-10%) (young, sexually active females)
• If HAI: Pseudomonas, other GNR, Enterococci, Staphylococci & Candida
• Pathogen: Pyelonephritis
• E. coli (20-50%); but a wider range of bacteria: Klebsiella & Proteus (staghorn struvite stones) and Enterococci
• Flank pain, vomiting, fever ≥38C or costovertebral angle tenderness
• Empiric Treatment
• Non-Severe (Cystitis): Cephalexin or Trimethoprim; or Augmentin (if non-responsive)
• Non-Severe Pyelonephritis: Augmentin (Amoxicillin + Clavulanate) PO
• ‘Severe’ Pyelonephritis: Gentamicin IV (one or two doses) + Amoxicillin/Ampicillin IV

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Acute Cystitis (UTI) & Pyelonephritis

• eTG

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Septic Arthritis

• Pathogen
• Most commonly Staphylococcus aureus (MSSA & MRSA); also Streptococcus; Neisseria gonorrhoeae in sexually active adults. Also can be MTB (rare).
• Empiric Treatment
• MSSA: Flucloxacillin IV
• MRSA risk: Vancomycin IV or Clindamycin IV
• If streptococcal or GNB (Neisseria) suspected: Ceftriaxone/Cefotaxime IV
• eTG

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Osteomyelitis

• Pathogen
• Most commonly Staphylococcus aureus (MSSA & MRSA); also coagulase negative Staphylococcus, GAS, GBS, Enterococci, GNB (E. coli) (20%)
• In children: Kingella kingae (GNeg) and (Hib rarely) (esp <4yo)
• Empiric Treatment
• K. kingae suspected: ADD Cefotaxime/Ceftriaxone IV
• MSSA: Flucloxacillin IV
• MRSA: Vancomycin IV
• eTG – In adult osteomyelitis 4/6wks of therapy is IV

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Cellulitis & Erysipelas

• Pathogen
• Most commonly Streptococcus pyogenes (GAS) (β-haemolytic) for non purulent, recurrent cellulitis; other Streptococcus spp (Group B, C or G) also.
• Also, Staphylococcus aureus with penetrating trauma, ulceration or abscess.
• Empiric Treatment
• Non-Severe: Phenoxymethylpenicillin PO
• Severe: Benzylpenicillin IV
• Non-Severe MSSA: Dicloxacillin PO
• Severe MSSA: Flucloxacillin IV
• eTG
• Non-Severe:
• Severe:

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• Staph:

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Meningitis - Adult

• Pathogen: Streptococcus pneumoniae (most common bacteria), Neisseria meningitidis, Haemophilus influenzae (all encapsulated) & if >50yo, immunocompromised or high EtOH: Listeria monocytogenes.
• Viral ‘aseptic’ (enterovirus) meningitis is overwhelmingly (82-97%) more common than bacterial meningitis. Also consider fungal (Cryptococcus gattii & neoformans).
• Empiric Treatment
• Neisseria meningitidis (GNC) (Meningococcal): Ceftriaxone IV
• Streptococcus pneumoniae (GPC) (Pneumococcal): Benzylpenicillin IV or Ceftriaxone IV; ADD Vancomycin due to resistant strains S. pneumoniae
• Haemophilus influenzae (GNeg cocco-bacilli): Ceftriaxone IV
• Listeria monocytogenes (GPR): Benzylpenicillin IV
• Dexamethasone (continue if H. influenzae or S. pneumoniae identified)
• eTG
• Ceftriaxone covers Streptococcus, Neisseria & Haemophilus; ADD Benzylpenicillin if Listeria suspected; ADD Vancomycin if S. pneumoniae suspected (GPos diplococci on gram stain)

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Meningitis - Adult

Meningitis: 0-3 months old

• Pathogen
• Group B Streptococcus (GBS) (Streptococcus agalactiae), Enteric GNR (E. coli & Klebsiella) & Listeria monocytogenes; also Herpes Simplex Virus
• Empiric Treatment
• Group B Streptococcus (GBS) (S. agalactiae): Benzylpenicillin IV
• Enteric GNR (E. coli & Klebsiella): Cefotaxime
• Listeria monocytogenes: Benzylpenicillin/Ampicillin
• Paediatric Guidelines (NSW Bacterial Meningitis)
• Severe: Benzylpenicillin IV + Cefotaxime IV ± Aciclovir IV (HSV)
• Give Dexamethasone IV if >2mo old (eTG) (before or with 1^st ABx dose, but can be given up to 4h after ABx).

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Meningitis: 0-3 months old

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• NSW Bacterial Meningitis Guideline

Infective Endocarditis (native valve)

• Pathogen
• Staphylococcus aureus (31%) (ABE) (bacteraemia w/o focus is IE until proven), coagulase-negative staph CoNS-S. epidermidis) (highest in IVDU & PVE), Viridans streptococci (17%) (SBE), GAS & GBS (ABE), Strept. bovis (bowel malignancy), enterococcus (IE until proven) & oro-pharynx HACEK GNR (<5%) (Haemophilus, Aggregatibacter (prev Actinobacillus), Cardiobacterium, Eikenella & Kingella; Culture Neg (8%) (C. burnetii, Bartonella (cat scratch), Brucella, C. psittaci (birds), fastidious GPC)
• Treatment (if vegetations 6wk IV; if bacteraemia 2wk) (Duke Criteria) (3xBC sites)
• Staphylococcus aureus: Flucloxacillin IV ± Vancomycin (MRSA)
• Streptococcal/Enterococcal: Benzylpenicillin IV ± Gentamicin IV (synergistic)
• HACEK (GNR): Ceftriaxone IV
• Coxiella burnetii (Q Fever): Doxycycline + Hydroxychloroquine (>18mo)
• eTG

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Septic Shock (un-identified source)

• Septic Shock – If you have sepsis AND despite adequate fluid resuscitation have EITHER of the following: inability to maintain a mean ABP of 65 (or SBP 90) without vasopressors, with a blood lactate >2mmol/L
• If arrival at hospital is going to be delayed by >1hr start fluid resuscitation, take blood samples for MCS and give ABx – Ceftriaxone 2g IV/IM
• Pathogen
• The most common community acquired sepsis or septic shock without an identified source is Escherichia coli. Other important causes are staphylococcus aureus, Streptococcus pneumoniae and Neisseria meningitidis. If acquired in hospital then MRSA, MDR-Enterobacteriaceae and Pseudomonas aeruginosa are more common (also Candida spp).
• Empiric Treatment (based on risk assessment):
• Staphylococcus aureus: Flucloxacillin IV ± Vancomycin (MRSA)
• Escherichia coli (+GNB): Gentamicin IV
• Neisseria meningitidis: Ceftriaxone/Cefotaxime IV
• Streptococcus pneumoniae: Benzylpenicillin IV (not actually in empirical Rx though)
• eTG (following slide)

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Septic Shock (un-identified source)

C. difficile: Pseudomembranous Colitis

• Pathogen: Due to overgrowth of Clostridium difficile.
• Due to treatment with broad spectrum ABx such as cephalosporins, quinolones, penicillins (Augmentin) & lincosamides (Clindamycin) (strongest link), cancer therapy and use of PPI. It can cause Toxic Megacolon.
• Empiric Treatment
• Non-Severe: Metronidazole PO (or IV)
• Severe/Recurrent: Vancomycin PO
• eTG

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Surgical Prophylaxis

• Treatment
• Cefazolin as very minimal cross-reactivity with penicillin allergy, has adequate gram negative cover, but use Gentamicin if broader GNeg cover needed; Good cover (Staph, Strept & gram negatives), low risk of allergy and cheap.
• Use Vancomycin IV + Gentamicin IV if severe penicillin hypersensitivity
• Cefazolin prophylaxis needed before incision (<60min from), re-dose if >4h surgery.
• ADD Metronidazole if colorectal surgery/appendicitis (<120min of incision)
• Penicillin Allergy (from eTG)
• Penicillin IgE-mediated (allergic) immediate hypersensitivity was thought to be due solely to the beta-lactam ring structure that is common to all beta-lactam antibiotics (penicillins, cephalosporins, carbapenems and monobactams) however it appears to be a response to antigenic molecules in the R1 side-chain that distinguishes individual penicillins and cephalosporins
• Carbapenems:1% cross-reactivity with penicillins
• Cephalosporins: 1-2% (previously thought to be 10%) cross-reactivity with penicillins

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Basic Antibiotic Guide

*Gram Negatives – Gentamicin is the standard empiric therapy however in many infections Ceftriaxone may be used to concomitantly cover gram positives or for target tissue penetration (eg of the meninges).

Summary

• Location?
• Likely Pathogen/s?
• Severity of Infection? (is it Non-Severe or is there systemic features?)
• IV/PO – Patient, Infection & Medication Factors
• This is for empirical therapy, ALWAYS take cultures (site and blood) for MCS (microscopy, culture and sensitivity) to guide directed therapy.
• ALWAYS consult local hospital ID Guidelines/eTG as these are continuously updated based on the most recent evidence.
• Questions?

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