Antimicrobial resistance and stewardship

• Antimicrobial resistance (AMR) means an organism is no longer killed or inhibited by an antibiotic that used to work; it is driven by antibiotic use selecting resistant mutants and mobile resistance genes.
• MRSA, ESBL-producing Enterobacterales and carbapenem-resistant Enterobacterales (CRE) turn common infections (skin, urine, lung, blood) into difficult-to-treat illness with higher mortality.
• Antibiotics alone do not solve a resistance problem: the main levers are prudent antibiotic use (stewardship), reliable infection control, and source control.
• Stewardship means giving the right drug, dose, route and duration to the right patient, then narrowing or stopping as soon as cultures allow; de-escalation and the shortest effective duration are central.
• Every patient with a suspected resistant organism needs two things early: an adequate culture and the correct precautions, before the first antibiotic dose whenever it is safe.

By the end of this page you should be able to:

1. Define antimicrobial resistance, MRSA, ESBL production and carbapenem resistance, and explain the main mechanisms.
2. Recognise the patients and syndromes in which these organisms are likely, and take appropriate specimens.
3. Choose empiric and targeted therapy for an ESBL or CRE infection using a current guideline and a local antibiogram.
4. Explain the core elements of an antibiotic stewardship programme and how de-escalation works in practice.
5. Apply the standard and transmission-based precautions that prevent spread of resistant organisms.
6. Adapt management when the newest antibiotics or diagnostics are not available.

"Antibiotic stewardship" is, in the consensus wording used by IDSA, SHEA and the paediatric society, "coordinated interventions designed to improve and measure the appropriate use of [antibiotic] agents by promoting the selection of the optimal [antibiotic] drug regimen including dosing, duration of therapy, and route of administration".^[4] "De-escalation" is the reverse of escalation: once culture results are known, replacing a broad empiric regimen with a narrower, simpler or oral agent, or stopping antibiotics altogether if infection is excluded, without harming the patient.

The resistance patterns you must know:

• MRSA (methicillin-resistant Staphylococcus aureus). S. aureus carrying the mecA (or mecC) gene produces penicillin-binding protein 2a (PBP2a), whose low affinity for beta-lactams makes oxacillin, methicillin, flucloxacillin, cephalosporins and carbapenems ineffective. MRSA is divided clinically into community-associated (CA-MRSA) and healthcare-associated (HA-MRSA) disease.
• ESBL producers (extended-spectrum beta-lactamase-producing Enterobacterales). Enzymes, most often CTX-M in modern isolates, hydrolyse penicillins, most cephalosporins and aztreonam but spare carbapenems; the same isolates often carry resistance to fluoroquinolones and co-trimoxazole.^[2]
• CRE (carbapenem-resistant Enterobacterales). Enterobacterales that test above the carbapenem susceptible breakpoint, either because they carry a carbapenemase (KPC, OXA-48-like, NDM, VIM, IMP) or because porin loss combined with an ESBL or AmpC enzyme raises the MIC. They are usually resistant to several other classes as well.
• Other troublesome phenotypes on the same wards include AmpC producers, carbapenem-resistant Acinetobacter baumannii, difficult-to-treat Pseudomonas aeruginosa and vancomycin-resistant enterococci.

ESBLs are enzymes that inactivate most penicillins, cephalosporins and aztreonam, and ESBL-E generally remain susceptible to carbapenems.^[2] Carbapenem resistance matters most because the carbapenems are the reliable backstop for ESBL infection.

The burden is large and well documented. In the United States more than 2.8 million antibiotic-resistant infections occur each year and more than 35,000 people die as a result; when C. difficile is added the toll exceeds 3 million infections and 48,000 deaths.^[1] AMR pathogens caused more than 2.8 million infections and over 35,000 deaths annually in the US from 2012 through 2017.^[2] Worldwide, an estimated 1.27 million deaths were directly attributable to bacterial AMR in 2019.^[8]

• MRSA is a serious threat. Historically a hospital pathogen, it spread into the community; in the US, national healthcare-associated MRSA rates fell while community disease became prominent. People who inject drugs are about 16 times more likely to develop a serious invasive MRSA infection than people who do not.^[1]
• ESBL-E. The incidence of ESBL-E identified in bacterial cultures in the United States increased by 53% from 2012 to 2017, largely from community-acquired infections.^[2] CTX-M enzymes, particularly CTX-M-15, are the dominant ESBLs in the US, and most disease comes from E. coli, Klebsiella pneumoniae, K. oxytoca and Proteus mirabilis.^[2]
• Carbapenem resistance. Carbapenemases are largely plasmid-borne and mobile: IMP-1 was first described in Pseudomonas in Japan in 1991, KPC-1 in the US in 1996, OXA-48 in Turkey in 2003 and NDM-1 in 2008 in a patient transferred from India.^[3] Resistance is very uneven: rates differ between countries, hospitals and wards, which is why a local antibiogram outweighs any textbook.
• Costs. Treating infections caused by six resistant pathogens frequently found in healthcare can cost the US more than 4.6 billion dollars annually.^[1]

Resistant organisms are selected, not invented, by antibiotic pressure. Risk rises with:

• Prior antibiotics, especially broad-spectrum ones in the previous 30 days, and repeated courses.^[2]
• Healthcare exposure: hospitalisation within the last 6 months, long-term care residence, recent invasive procedures or indwelling devices.^[2]
• Previous organisms and their susceptibility results from the same patient in the last 6 months.^[2]
• Severity of illness, critical care, immunosuppression, renal failure and chronic disease.
• Travel to regions with high ESBL or CRE prevalence, and contact with a colonised household member.

MRSA is also tied to crowded settings, contact sports, military barracks, prisons, shared personal items and injecting drug use. ESBL-E is increasingly community-acquired and often begins as cystitis. CRE clusters in units with heavy carbapenem use and in hospitals that transfer patients between wards or institutions.

1. Selection on the normal flora. A broad-spectrum antibiotic clears susceptible organisms in gut, skin and mucosa and leaves the few that resist it. Repeated courses build a resistant population; plasmids and transposons move resistance genes between species.
2. MRSA. The mecA gene on the staphylococcal cassette chromosome mec (SCCmec) encodes PBP2a, a transpeptidase with low affinity for all beta-lactams, so the peptidoglycan assembly pathway bypasses oxacillin and cephalosporins. Community clones usually carry smaller SCCmec elements and more toxins; hospital clones carry bulkier cassettes.
3. ESBL. Plasmid enzymes, now dominated worldwide by CTX-M, break the beta-lactam ring of oxyimino cephalosporins such as ceftriaxone and of aztreonam, but not of carbapenems. Heavy carbapenem use then selects the next step (carbapenem resistance).
4. Carbapenem resistance. Carbapenemases (KPC class A, OXA-48 class D, and the metallo-beta-lactamases NDM, VIM and IMP) inactivate essentially all beta-lactams. Where no carbapenemase is present, loss of outer-membrane porins or up-regulation of efflux pumps can raise the carbapenem MIC above the susceptible breakpoint.
5. Biofilm and devices. Resistant staphylococci and gram-negative organisms on central lines, catheters, prostheses and wounds sit in biofilm, which shields them from both antibiotics and host defences; removing the device is often the real treatment.

The clinical result is the same in every case: empiric therapy may be inactive in the first critical days, resistance amplifies within the treated patient, and the organism spreads to neighbours on hands, equipment and the environment.

AMR is a laboratory property; the patient presents with an infection. Match the syndrome to the risk.

MRSA clinical picture. Skin and soft-tissue infection is the commonest presentation: a painful, red, warm, indurated lesion, often an abscess, sometimes necrotic, sometimes multiple. MRSA also causes necrotising pneumonia (often after influenza) with rapid progression, bacteraemia and infective endocarditis, osteomyelitis and septic arthritis, meningitis and brain abscess. Many people are only colonised, usually in the anterior nares; colonisation is not an infection that needs antibiotics. Red flags for severe disease are haemodynamic instability, rapidly spreading soft-tissue infection, post-viral pneumonia and infection in an injecting drug user.

ESBL-E picture. Most often a urinary tract infection: cystitis, pyelonephritis or catheter-related infection that does not respond to oral cephalosporins. Also intra-abdominal infection, hospital-acquired pneumonia and bloodstream infection, generally after healthcare contact or recent broad-spectrum antibiotic use.

CRE picture. Usually found in very sick, multiply exposed patients: intensive care, long stay, recent carbapenem use, transplant or immunosuppressed recipients. Typical infections are catheter-related bloodstream infection, pneumonia, complicated UTI and intra-abdominal sepsis.

Red flags that a resistant organism may be involved and that the plan should change: broad-spectrum antibiotic use in the last 30 days; hospitalisation or long-term care in the last 6 months; a resistant organism previously isolated from the same patient; severe sepsis or rapid worsening despite what should have been adequate empiric therapy; and a documented outbreak on the ward.

Take specimens before the first dose whenever the patient is stable enough, because once antibiotics are started yield falls.

• Blood cultures (two sets from separate sites) for fever, sepsis or suspected bacteraemia.
• Urine culture with microscopy for urinary symptoms, including in catheterised patients after removing or changing the catheter.
• Pus, tissue or deep aspirates for skin and soft-tissue disease; superficial swabs of purulent collections are often misleading. An abscess still needs surgical drainage.
• Respiratory samples (sputum, tracheal aspirate, bronchoalveolar lavage) for pneumonia, with attention to prior antibiotics and ventilation.
• Wound and device specimens when hardware is involved.
• Susceptibility testing on every isolate. Non-susceptibility to ceftriaxone (MIC at or above 2 mcg/mL) is widely used as the proxy for ESBL production.^[2] A carbapenem-resistant phenotype should be confirmed and, where possible, genotyped for the carbapenemase.
• Imaging to locate collections, infected prostheses and catheter-related collections; source control often matters more than drug choice.

ESBL-E is generally still susceptible to carbapenems, so a carbapenem-resistant phenotype changes the drug plan entirely.^[2]

There is no single scoring system or staging scheme that "diagnoses" resistance: resistance is determined in the laboratory. Severity is judged clinically, and a patient can be bacteraemic but well, or in septic shock with a susceptible organism. Use your local sepsis bundle and an early-warning score to decide the level of care and urgency; IDSA 2022 guidance assumes the organism has been identified and its in vitro activity is known before a specific agent is recommended.^[2]

• Obtain cultures first, then start empiric antibiotics without avoidable delay in a sick patient.
• Give source control the same priority as antibiotics: drain an abscess, remove an infected line, relieve obstruction, repair a leak.
• Start the correct infection-control precautions at the same time, not after the cultures return.
• Choose empiric therapy from the site of infection, likely organisms and local resistance data, plus the patient's individual risks: organisms identified from them in the last 6 months and antibiotic exposures in the last 30 days.^[2]
• Call microbiology or an infectious diseases clinician early for suspected CRE or deep-seated MRSA infection.

IDSA guidance (content current as of 24 October 2021) is the reference for the agents below and is aimed at the US; adapt for local epidemiology and drug availability.^[2][3]

• Uncomplicated cystitis. Nitrofurantoin or trimethoprim-sulfamethoxazole preferred; amoxicillin-clavulanate, a single dose of an aminoglycoside, and oral fosfomycin (for E. coli only) are alternatives. Carbapenems and fluoroquinolones are effective but discouraged when a safer option exists, to preserve their utility. Doxycycline is not recommended.^[2]
• Pyelonephritis or complicated UTI. Ertapenem, meropenem, imipenem-cilastatin, ciprofloxacin, levofloxacin or trimethoprim-sulfamethoxazole preferred; if a carbapenem was started and a fluoroquinolone or co-trimoxazole is susceptible, step down to the narrower agent. Nitrofurantoin and oral fosfomycin do not reach the renal parenchyma and should be avoided here.^[2]
• Infection outside the urinary tract (bacteraemia, pneumonia, intra-abdominal, skin). A carbapenem preferred; after clinical improvement, oral fluoroquinolone or trimethoprim-sulfamethoxazole may be considered if susceptible.^[2]
• Piperacillin-tazobactam and cefepime are not recommended for invasive ESBL-E infection: in the bloodstream infection trial, piperacillin-tazobactam had 30-day mortality of 12% versus 4% with meropenem (11% versus 4% in the MIC-limited reanalysis).^[2] If either was started for cystitis and the patient improves, no change is needed.
• Dosing for ESBL-E and other resistant gram-negatives follows IDSA Table 1: carbapenems are standard (for example, ertapenem 1 g IV every 24 hours; meropenem 1–2 g IV every 8 hours for ESBL disease; imipenem-cilastatin 500 mg IV every 6 hours), with extended (3-hour) infusions for CRE disease.^[2]

• Empiric treatment of CRE, or of ESBL-E before susceptibility is known, is not addressed by current guidelines; choose from local data and the patient's risk profile.^[3]
• Targeted therapy pivots on the type of enzyme: ceftazidime-avibactam, meropenem-vaborbactam or imipenem-cilastatin-relebactam for KPC; ceftazidime-avibactam for OXA-48-like; ceftazidime-avibactam plus aztreonam, or cefiderocol, for metallo-beta-lactamases (NDM, VIM, IMP).^{[3] [2]}
• For CRE urinary infection, IDSA lists aminoglycosides, cefiderocol and high-dose meropenem among options; for intra-abdominal infection, tigecycline or eravacycline.^[3]
• Where those agents are unavailable, older regimens still have a role: high-dose meropenem (2 g every 8 hours, infused over 3 to 4 hours) possibly combined with a second in vitro-active agent such as an aminoglycoside, colistin, fosfomycin or tigecycline, guided by susceptibility.^[3]
• Aminoglycosides, colistin and polymyxins are reserve options in IDSA's table, dosed with pharmacokinetic monitoring rather than fixed interval dosing.^[2]

IDSA's 2011 guideline on MRSA infections was its first and still defines the patterns used in practice; an independent review summarises its recommendations.^[7]

• Uncomplicated skin/soft-tissue abscess: incision and drainage is the treatment; antibiotics are added for severe, extensive or rapidly progressive disease, systemic illness, or an abscess in a difficult site.
• Cellulitis/abscess requiring drugs: oral or IV agents with MRSA activity (vancomycin, linezolid, clindamycin, doxycycline, trimethoprim-sulfamethoxazole) chosen by severity and local susceptibility.
• Pneumonia, bacteraemia/endocarditis, bone and joint, CNS: parenteral therapy, usually vancomycin, with linezolid as an initial or alternative agent; linezolid may be preferred when renal impairment makes vancomycin hard to dose, and it may reduce toxin production in pneumonia, though outcome benefit from that is not proven.^[7]
• Linezolid is recommended by IDSA 2011 as initial or alternative therapy for MRSA pneumonia, complicated skin infection, osteomyelitis, septic arthritis, meningitis, brain abscess, subdural empyema, spinal epidural abscess and cavernous or dural venous sinus septic thrombosis.^[7]
• Newer lipoglycopeptides and other anti-MRSA agents are used in specialist practice; their dosing and combination regimens are beyond the sources cited here.

The benefits of a working stewardship programme are improved patient outcomes, fewer adverse events including C. difficile infection, better susceptibility of targeted organisms, and better use of resources.^[4] CDC's Core Elements for hospital programmes (2019 revision of the 2014 version) describe the minimum structure: leadership commitment, accountability, pharmacy expertise, action, tracking, reporting and education.^[5] IDSA/SHEA recommend that programmes are best led by infectious disease physicians with stewardship training and combine preauthorization and/or prospective audit and feedback as a core component.^[4]

Key interventions worth memorising:

• Preauthorization (approve restricted drugs before use) and prospective audit with feedback (review started therapy and steer changes); PAF is the route that classically handles de-escalation and duration.^[4]
• Facility-specific guidelines and care pathways based on local epidemiology.^[4]
• IV-to-oral conversion and timely transition off intravenous therapy.^[4]
• Reducing antibiotic therapy to the shortest effective duration.^[4]
• Rapid diagnostics (blood-culture panels, MALDI-TOF, respiratory viral tests) work best when paired with active stewardship support, because a test without an action changes nothing.^[4]
• Antibiotic "time-outs" or stop orders that prompt the prescriber to revisit the regimen during the admission.^[4]
• Pharmacy-led pharmacokinetic monitoring for aminoglycosides and vancomycin, and dose optimisation of broad-spectrum beta-lactams.^[4]
• Antibiograms stratified by ward or unit to inform empiric choice.^[4]
• Selective or cascade reporting of susceptibility results.^[4]
• Allergy assessment and penicillin skin testing to remove false labels and return first-line drugs to use.^[4]

De-escalation is a daily discipline, not a single dramatic act. A workable sequence:

1. Start with the smallest adequate empiric regimen guided by the local antibiogram, the syndrome and the patient's risks.^[2]
2. Review every patient on antibiotics within the first 48 to 72 hours (an antibiotic time-out): do they have an infection at all; is the drug active; what do the cultures say; is the source controlled.^[4]
3. Narrow, stop or switch, species by species, as results return: MRSA cover if all staphylococci are methicillin-susceptible; drop the carbapenem if an ESBL is absent; IV-to-oral if the drug is bioavailable, the patient is stable, source control is done and absorption is not a concern.^[2][4]
4. Fix the duration from the diagnosis, not from the admission: most infections have an evidence-based short course, and continuing "until further orders" wastes drug and breeds resistance.^[4]
5. Document the indication and planned stop or review date in the chart at the start.

Stopping an antibiotic that is no longer needed is the single highest-value stewardship act.

• Device bundles: line insertion and maintenance care, urinary catheter use and prompt removal, and ventilator-associated pneumonia prevention.
• Source-control surgery for deep collections, necrotising soft-tissue infection and infected prostheses.
• Education in antimicrobial principles during training, plus patient-facing messages about unnecessary antibiotics.
• Non-antimicrobial prevention of infection: vaccination programmes where indicated, alongside the infection-control measures below.

• Review every course at culture return and at discharge, checking length, route and a stated indication.
• Refer early to microbiology or infectious diseases for CRE, carbapenemase producers, bacteraemic MRSA, endocarditis, deep-seated infection, and any outbreak.
• Invasive MRSA and CRE disease, and patients who are immunocompromised or pregnant, should be managed by a team.

Infection control stops the resistant organism reaching the next patient; stewardship works on the prescriber, control works on the environment.

• Standard precautions apply to every patient: hand hygiene, safe injection practice, appropriate use of gloves, gowns and masks for any anticipated blood or body-fluid exposure, respiratory hygiene, and correct handling of soiled equipment.^[6]
• Transmission-based precautions are added for suspected or confirmed spread by contact, droplet or airborne routes and use gowns, gloves, masks or respirators and patient placement or cohorting.^[6]
• MRSA and CRE are commonly managed with contact precautions during active infection or wound colonisation; the exact list is set by local policy and by the CDC 2007 isolation guideline, last updated in 2024.^[6]
• Hand hygiene before and after patient contact, after body-fluid exposure, after touching the patient's surroundings, and before aseptic tasks; equipment and high-touch surfaces need regular cleaning. It is low-cost and high-yield.
• Decolonisation (nasal mupirocin plus/minus chlorhexidine baths) reduces MRSA infection in selected high-risk settings, but optimal regimen and duration are still debated; follow the local protocol.

• Septic shock, metastatic infection (endocarditis, osteomyelitis), and death; resistant bacteraemia has worse outcomes than susceptible disease.
• Toxicity from last-resort drugs: nephrotoxicity with aminoglycosides and polymyxins, myelosuppression with linezolid, C. difficile infection after broad-spectrum therapy.
• Outbreaks on wards, prolonged stay, resistance spread beyond the index patient, and enormous cost; healthcare-associated resistant organisms can force temporary unit closure.
• C. difficile and other collateral damage from broad empiric therapy.

Resistant infections are harder to treat and are often inadequately covered in the first days; bloodstream infection with resistant organisms carries higher 30-day mortality than with susceptible ones (in the IDSA-cited ESBL trial, 30-day mortality was 12% versus 4% with piperacillin-tazobactam versus meropenem).^[2] Outcomes depend on the speed of appropriate therapy, source control, host factors, and whether the organism carries a carbapenemase. For MRSA, effective agents exist but prolonged bacteraemia and endocarditis are serious, prolonged disease.

• Stewardship and infection control run together in national strategy.^[1][5]
• Judicious antibiotic use in hospitals, clinics, farming and veterinary practice under a "one health" view; improvement in any sector helps all of them.
• Vaccination indirectly reduces antimicrobial use by preventing bacterial infection; routine immunisation programmes matter here.
• Screening of high-risk admissions (for example for CRE carriage in high-prevalence settings) and prompt isolation to prevent transmission, where locally adopted, are increasingly used.

• Children. IDSA 2022 guidance applies to paediatric populations, but paediatric dosing is not in the agent table; use a paediatric reference and pharmacist review.
• Pregnancy and breastfeeding. Avoid fluoroquinolones and trimethoprim-sulfamethoxazole near term; choose pregnancy-compatible agents and involve obstetrics. MRSA in a pregnant or postpartum patient can present as severe skin infection or mastitis with abscess and needs prompt drainage plus a pregnancy-compatible drug.
• Older adults. Renal clearance falls with age, so aminoglycosides, vancomycin and many renally cleared drugs need dose adjustment; toxicity risk rises.
• Immunocompromised patients. More likely to be colonised with resistant organisms and to develop invasive disease; therapy often needs longer courses, specialist input and careful toxicity balance.

• Many newer agents (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol and others) are costly or unavailable. Older options still work with optimised pharmacokinetics: high-dose meropenem 2 g every 8 hours infused over 3 to 4 hours, possibly with a second in vitro-active agent such as an aminoglycoside, colistin, fosfomycin or tigecycline.^[3]
• Where laboratories cannot genotype carbapenemases, ceftriaxone non-susceptibility (MIC at or above 2 mcg/mL) remains a workable ESBL proxy, and "susceptible to a carbapenem or not" is a fair therapeutic divide.^[2]
• Infection control can be done cheaply: locally prepared alcohol hand rub, gloves, cohorting, environmental cleaning and device-care bundles.
• Nitrofurantoin, co-trimoxazole, gentamicin and other older drugs cover a large share of ESBL cystitis and low-risk infection in the IDSA scheme.^[2][3]
• Build a local antibiogram from your own isolates; treating from a borrowed one is a common cause of failure.

• AMR is selected by antibiotic use and spreads on hands, equipment and the environment, so stewardship and infection control must run together.
• MRSA resists all beta-lactams through PBP2a; disease ranges from a drainable abscess to bacteraemia and endocarditis.
• ESBLs break penicillins, cephalosporins and aztreonam but not carbapenems; heavy carbapenem use then selects CRE.
• CRE is a carbapenem above the susceptible breakpoint, by an enzyme (KPC, OXA-48-like, NDM, VIM, IMP) or porin loss plus another beta-lactamase.
• Laboratory proxies (ceftriaxone MIC at or above 2 mcg/mL) and a local antibiogram guide empiric therapy better than any single national table.
• ESBL cystitis: nitrofurantoin or co-trimoxazole preferred; reserve carbapenems for pyelonephritis, complicated UTI and any infection outside the urinary tract.
• Avoid piperacillin-tazobactam and cefepime for invasive ESBL-E infection.
• CRE targeted therapy depends on the enzyme: KPC with ceftazidime-avibactam, meropenem-vaborbactam or imipenem-cilastatin-relebactam; OXA-48-like with ceftazidime-avibactam; metallo-beta-lactamases with ceftazidime-avibactam plus aztreonam or cefiderocol. ^[3]
• De-escalation, shortest effective duration, IV-to-oral conversion and a documented stop date are the highest-value stewardship acts.
• CDC Core Elements structure a hospital stewardship programme around leadership, accountability, pharmacy expertise, action, tracking, reporting and education.
• Standard precautions plus transmission-based precautions, hand hygiene and equipment cleaning remain the backbone of infection control.
• New agents are unavailable in many settings; optimised older regimens (extended-infusion carbapenems, aminoglycosides) remain effective.
• Refer suspected or proven CRE, bacteraemic MRSA and deep-seated infection to microbiology early.