Key Facts

AMR is one of the greatest threats to global health. Without action, AMR could cause 10 million deaths/year by 2050 (O'Neill Report). Antimicrobial stewardship programmes are central to the UK response.

Epidemiology

• 1.27 million deaths directly attributable to AMR globally (2019)
• UK: ~5,000 deaths/year from drug-resistant infections
• MRSA bacteraemia: reduced by >80% in UK since 2007 through IPC measures
• C. difficile: reduced by >70% through antibiotic stewardship
• CPE: increasing in UK — national surveillance programme

Aetiology

• Intrinsic resistance: naturally occurring (e.g. Pseudomonas inherently resistant to many antibiotics)
• Acquired resistance: horizontal gene transfer (plasmids, transposons, integrons), spontaneous mutation
• Key mechanisms: enzyme production (beta-lactamases, ESBLs, carbapenemases), target modification (PBP alteration in MRSA), efflux pumps, reduced permeability

Pathophysiology

• Selective pressure from antibiotic use drives resistance evolution
• Inappropriate prescribing accelerates resistance development
• Biofilm formation provides protected environment for resistant organisms
• Healthcare settings act as reservoirs for MDR organisms

Presentations of Resistant Infections

• MRSA: wound infections, bacteraemia, pneumonia, osteomyelitis — often nosocomial
• ESBL/CPE: UTIs, intra-abdominal infections, bacteraemia — often in patients with prior antibiotic exposure
• VRE: UTIs, bacteraemia, intra-abdominal infections — immunocompromised/ICU patients
• MDR TB: prolonged cough, weight loss, night sweats — failure of standard regimen
• Resistant gonorrhoea: persistent urethral/cervical discharge despite treatment

Risk Factors for Resistant Infection

• Recent antibiotic use
• Recent hospitalisation/healthcare contact
• ICU admission
• Indwelling devices (catheters, central lines)
• Immunosuppression
• Travel to endemic areas

Red Flags

• Treatment failure despite appropriate-seeming antibiotics
• Sepsis not responding to empirical therapy
• Known colonisation with MDR organism plus new infection

Bedside

• Clinical review: assess response to current antibiotics at 48–72 hours

Bloods

• Blood cultures: before antibiotic changes — identify organism and sensitivities
• FBC, CRP: trending to assess treatment response

Microbiology

• Culture and sensitivity testing: essential for all suspected resistant infections
• ESBL/CPE screening: rectal swab for at-risk patients (recent travel, hospitalisation)
• MRSA screening: nasal swab (admission screening in many UK hospitals)
• Rapid molecular diagnostics: PCR for mecA (MRSA), carbapenemase genes — results within hours

Special Tests

• Antibiogram: local resistance patterns to guide empirical therapy
• MIC (minimum inhibitory concentration): quantitative susceptibility for serious infections
• Whole genome sequencing: outbreak investigation, resistance gene characterisation

Prevention and Stewardship

• Antimicrobial stewardship: Start Smart — Then Focus; review at 48–72 hours (stop, switch IV→oral, narrow, change, OPAT)
• Infection prevention and control: hand hygiene, barrier precautions, isolation of colonised patients
• MRSA decolonisation: mupirocin nasal ointment TDS 5 days + chlorhexidine body wash
• Surveillance: mandatory reporting of MRSA/MSSA bacteraemia, C. difficile, CPE

Pharmacological — Treatment of Key Resistant Organisms

MRSA:

• Bacteraemia: vancomycin 15–20mg/kg BD IV (trough target 15–20 mg/L) or daptomycin 6–10mg/kg OD IV
• Skin/soft tissue: oral options — doxycycline 100mg BD, co-trimoxazole 960mg BD, linezolid 600mg BD

ESBL-producing organisms:

• Serious infection: meropenem 1g TDS IV
• UTI: based on sensitivities — nitrofurantoin, fosfomycin, or pivmecillinam may retain activity

CPE:

• Ceftazidime-avibactam (KPC-producing); colistin-based regimens; meropenem-vaborbactam
• Consult microbiology/infectious diseases

VRE:

• Linezolid 600mg BD (oral or IV) or daptomycin

Referral Criteria

• Microbiology/ID consultant: all serious resistant infections
• PHE: mandatory reporting of CPE, outbreak situations
• Infection prevention team: colonised/infected patients

• MRSA bacteraemia: mortality ~20–30% (vs ~10–15% for MSSA)
• CPE bacteraemia: mortality ~40–50%
• ESBL bacteraemia: mortality ~30% if treated with inactive agent initially; reduced with carbapenems
• Appropriate empirical therapy: key determinant of survival — delays increase mortality by 10–20%
• UK MRSA bacteraemia rates have fallen dramatically with IPC interventions

Key Resistance Mechanisms

O'Neill Report (2016) Key Recommendations