Eduovisual
Multisystem Processes & Disorders
Carbapenem-resistant Enterobacterales: management
— Carbapenemase production (CP-CRE): KPC (most common in US), NDM, VIM, IMP, OXA-48-like
— Non-CP CRE: ESBL/AmpC + porin loss or efflux pump overexpression
— Mechanism dictates therapy — newer β-lactam/β-lactamase inhibitors work against some but not all carbapenemases
— Healthcare-associated UTI, pneumonia, bacteremia, or intra-abdominal infection failing carbapenem or extended-spectrum cephalosporin
— Patient with recent hospitalization, LTACH, SNF stay, dialysis, transplant, or chemotherapy
— International medical travel (especially Indian subcontinent → NDM; Mediterranean/Middle East → OXA-48)
— Prior CRE colonization on surveillance rectal swab
— Indwelling devices (Foley, central line, PEG, ventilator) + persistent fever despite broad-spectrum therapy
— Prolonged ICU stay, mechanical ventilation, prior carbapenem or fluoroquinolone exposure within 90 days
— Solid organ or stem cell transplant, neutropenia
— Structural lung disease, decubitus ulcers, recent abdominal surgery
Board pearl: A nursing-home resident readmitted with urosepsis whose urine cultures grew K. pneumoniae resistant to ertapenem and meropenem should trigger immediate isolation, infectious disease consult, and empiric coverage with a newer agent (ceftazidime-avibactam or meropenem-vaborbactam) rather than continuing standard carbapenem.
Step 3 management: Do not wait for susceptibilities if CRE risk is high and patient is septic — escalate empirically and send isolate for carbapenemase identification (Xpert Carba-R, mCIM/eCIM, or molecular panel) to guide definitive therapy.
— Complicated UTI / pyelonephritis — most frequent presentation; often catheter-associated
— Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) — particularly K. pneumoniae
— Bacteremia — central line-associated or secondary from urinary/intra-abdominal source; mortality up to 50%
— Intra-abdominal infections — post-surgical abscess, cholangitis, secondary peritonitis
— Surgical site and wound infections, including post-transplant
— Less commonly: meningitis (post-neurosurgical), endocarditis (rare)
— Antibiotic exposure within 90 days — carbapenems, fluoroquinolones, 3rd/4th-gen cephalosporins
— Healthcare exposure — hospitalization ≥3 days within 90 days, LTACH/SNF residence, hemodialysis
— Devices — duration of Foley, central line, ETT, biliary stent
— Travel — international travel with hospitalization abroad ("medical tourism")
— Colonization history — prior positive rectal/perirectal swab, prior CRE infection
— Immunosuppression: transplant regimen, chemotherapy, neutropenia, HIV
— Persistent fever >48–72 hours on appropriate-dose meropenem
— Repeat blood cultures positive despite "in-vitro susceptible" therapy (think mechanism mismatch)
— Recurrent UTI in catheterized patient after multiple courses
Key distinction: ESBL organisms are resistant to ceftriaxone but susceptible to carbapenems — treat with meropenem. CRE are resistant to carbapenems and require newer β-lactam/BLI combinations or cefiderocol. Misclassifying ESBL as CRE leads to unnecessary use of last-line agents and resistance pressure.
Board pearl: A returning traveler hospitalized in India or Pakistan within the past year with new Gram-negative bacteremia should raise concern for NDM-producing CRE — NDM is not covered by ceftazidime-avibactam alone; add aztreonam or use cefiderocol.
— qSOFA ≥2 (RR ≥22, SBP ≤100, altered mentation) → high mortality risk, expedite ICU evaluation
— MAP <65 despite 30 mL/kg crystalloid → septic shock, start vasopressors (norepinephrine first-line)
— Hypothermia in elderly/immunosuppressed is as ominous as fever
— Lactate ≥2 → tissue hypoperfusion; ≥4 → severe shock
— Urinary: CVA tenderness, suprapubic pain, cloudy/foul catheter drainage, perinephric fullness
— Pulmonary: crackles, consolidation, purulent ETT secretions, increased ventilator pressures, new infiltrate
— Intra-abdominal: focal tenderness, peritoneal signs, surgical wound erythema/discharge, drain output character
— Vascular access: central line site erythema, tenderness, exit-site purulence → suspect CLABSI
— Skin/wound: decubitus ulcers (especially sacral, heel), surgical site dehiscence, necrotic tissue
— Document every indwelling device: Foley, CVC, PICC, arterial line, ETT, NGT, PEG, biliary stent, drains
— Each device is a potential source AND a reason source control may fail
— Petechiae/purpura, acrocyanosis → DIC from severe sepsis
— Decreased urine output → AKI
— Altered mentation → sepsis-associated encephalopathy or meningitis (post-neurosurgical CRE)
CCS pearl: On a CCS case with suspected CRE sepsis, the first orders should be two sets of blood cultures, urine culture, lactate, CBC, BMP, lactate, IV access ×2, 30 mL/kg LR, and empiric anti-CRE therapy within 1 hour — then locate and address the source (remove/exchange catheter, drain abscess, debride wound).
Board pearl: Persistent bacteremia >72 hours mandates search for undrained focus, endovascular source, or biofilm-associated device that requires removal.
— Two sets of blood cultures from separate sites (peripheral + line if CLABSI suspected — differential time to positivity ≥2 hours suggests line source)
— Urine culture (catheterized: replace catheter and culture from new one per IDSA)
— Sputum/ETT aspirate or BAL for HAP/VAP — quantitative cultures preferred (BAL ≥10⁴ CFU/mL)
— Wound/drain/peritoneal fluid cultures with Gram stain
— Stool surveillance swab if rule-out colonization in high-risk admission
— CBC with differential — leukocytosis, bandemia, or leukopenia (poor prognosis)
— BMP — AKI from sepsis or nephrotoxic exposure; baseline for renal dosing of polymyxins/aminoglycosides
— LFTs — hepatic dosing considerations and source assessment (cholangitis)
— Lactate, procalcitonin — severity; PCT can help with antibiotic de-escalation
— Coagulation panel, fibrinogen, D-dimer if DIC suspected
— ABG if respiratory distress or shock
— MIC values for meropenem, imipenem, ertapenem (not just S/I/R)
— Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol susceptibilities
— Carbapenemase identification: Xpert Carba-R (PCR for KPC, NDM, VIM, IMP, OXA-48), mCIM/eCIM phenotypic tests
— Chest X-ray for all septic patients; CT chest if VAP unresolving
— Renal/bladder US or CT abdomen/pelvis with contrast for urinary source, obstruction, abscess
— CT abdomen for suspected intra-abdominal source — guides drainage
Step 3 management: Request carbapenemase mechanism testing on every CRE isolate — KPC and OXA-48 are covered by ceftazidime-avibactam; NDM/VIM/IMP (metallo-β-lactamases) are NOT, and require cefiderocol or ceftazidime-avibactam + aztreonam.
Board pearl: Ertapenem-resistant but meropenem-susceptible isolates often reflect porin loss + ESBL/AmpC, not carbapenemase — still treat as CRE for infection control purposes.
— mCIM (modified carbapenem inactivation method) — detects any carbapenemase production
— eCIM — distinguishes metallo-β-lactamases (MBLs: NDM, VIM, IMP) from serine carbapenemases (KPC, OXA-48)
— Carba NP test — rapid colorimetric
— Xpert Carba-R PCR — directly identifies KPC, NDM, VIM, IMP, OXA-48 genes (results in ~1 hour)
— Multiplex PCR panels (BioFire BCID2, Verigene) on positive blood cultures — speed time to targeted therapy by 24–48 hours
— Whole-genome sequencing for outbreak investigation and epidemiology
— CT abdomen/pelvis with IV contrast — abscess, perforation, obstruction; obtain early if intra-abdominal source possible
— MRCP or ERCP for biliary obstruction with cholangitis
— TTE → TEE for persistent bacteremia >72h or prosthetic valve/device — though Gram-negative endocarditis is rare, miss it and you lose the patient
— Tagged WBC scan or PET-CT for occult focus in recurrent bacteremia
— Every 48 hours until clearance for Gram-negative bacteremia
— Persistent positivity → endovascular source, undrained collection, or inadequate dosing/wrong drug
— Polymyxins (colistin, polymyxin B) — narrow therapeutic window, high nephrotoxicity
— Aminoglycosides — peak/trough levels
— Vancomycin/β-lactam TDM when extended infusions used (meropenem-vaborbactam)
Board pearl: A CRE isolate that is mCIM positive and eCIM positive = metallo-β-lactamase (NDM/VIM/IMP). First-line is cefiderocol or ceftazidime-avibactam PLUS aztreonam (aztreonam evades the MBL; avibactam protects aztreonam from co-produced ESBLs/AmpC).
Key distinction: Carbapenem-resistant Pseudomonas and Acinetobacter are NOT Enterobacterales — different organisms, different drug choices (Acinetobacter often needs sulbactam-durlobactam or minocycline + polymyxin).
— Uncomplicated cystitis with CRE: nitrofurantoin, fosfomycin (single dose), ciprofloxacin, TMP-SMX, or aminoglycoside if susceptible — reserve newer agents for systemic infection
— Pyelonephritis/cUTI: ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, or cefiderocol; aminoglycoside (plazomicin) acceptable alternative
— Infection outside urinary tract (bacteremia, HAP/VAP, intra-abdominal): preferred agent depends on carbapenemase
— KPC producers: ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam (all preferred)
— OXA-48-like: ceftazidime-avibactam (vaborbactam/relebactam do NOT cover OXA-48)
— NDM/VIM/IMP (MBLs): cefiderocol OR ceftazidime-avibactam + aztreonam
— Non-CP CRE (porin loss): often susceptible to ceftazidime-avibactam or meropenem-vaborbactam; cefepime/extended-infusion meropenem may suffice if MIC favorable
— Polymyxins (colistin), tigecycline (low serum levels), older aminoglycosides — reserve as salvage or combination, not first-line
— Generally NOT recommended when a new β-lactam/BLI is active — monotherapy with the preferred agent has equal or better outcomes with less toxicity
— Combination may be considered for MBLs, persistent bacteremia, or salvage
— Remove infected lines/catheters, drain abscesses, debride necrotic tissue, relieve obstruction
— Antibiotics fail without source control
Step 3 management: For a critically ill patient with suspected CRE bacteremia from unknown source: start ceftazidime-avibactam empirically (covers KPC and OXA-48, the most common US carbapenemases), obtain cultures and carbapenemase testing, consult ID, and address source control simultaneously.
Board pearl: Duration for uncomplicated Gram-negative bacteremia with source control is 7 days (Yahav trial, non-inferior to 14 days) — applies to CRE bacteremia too if source controlled and patient improving.
— Dose: 2.5 g IV q8h infused over 2 hours (normal renal function)
— Covers: KPC, OXA-48, ESBL, AmpC, P. aeruginosa; NOT MBLs
— Pairs with aztreonam 2 g IV q6h for MBL coverage (avibactam protects aztreonam from co-produced serine β-lactamases)
— Renal dose adjustment required (CrCl <50)
— Watch for emergent resistance during therapy — repeat susceptibility if clinical failure
— Dose: 4 g IV q8h over 3 hours
— Covers: KPC primarily; NOT OXA-48, NOT MBLs
— Best for confirmed KPC; AE: headache, infusion reactions
— Dose: 1.25 g IV q6h over 30 min
— Covers: KPC, P. aeruginosa; NOT OXA-48, NOT MBLs
— Lowers seizure threshold (imipenem) — caution in CNS disease, renal failure
— Dose: 2 g IV q8h over 3 hours
— Covers: all carbapenemases including MBLs, Stenotrophomonas, Acinetobacter
— Preferred for NDM/VIM/IMP producers or pan-resistant Gram-negatives
— CREDIBLE-CR trial showed higher mortality in Acinetobacter subgroup — use selectively; favor for CRE/Pseudomonas
— Iron-dependent uptake — works in iron-limited infection environments
— Tigecycline (high-dose 200 mg load, then 100 mg q12h) — intra-abdominal, skin/soft tissue; AVOID for bacteremia or UTI (poor serum/urine levels); black box: increased mortality
— Eravacycline — improved over tigecycline for intra-abdominal
— Plazomicin — aminoglycoside, useful for cUTI, monitor renal function and levels
— Polymyxin B preferred over colistin for systemic infection (better PK); both nephrotoxic and neurotoxic
— Fosfomycin IV — UTI; oral form for uncomplicated cystitis only
Key distinction: Vaborbactam and relebactam do NOT cover OXA-48; avibactam DOES cover OXA-48. If OXA-48 confirmed → ceftazidime-avibactam or cefiderocol.
Board pearl: Emergent ceftazidime-avibactam resistance during therapy is well-described (KPC mutations) — if bacteremia persists, repeat cultures and re-test susceptibility, then switch agent.
— Remove non-tunneled CVCs/PICCs in CRE bacteremia
— Tunneled catheters/ports: remove if bacteremia persists >72h, septic shock, endocarditis, suppurative thrombophlebitis, or metastatic infection
— Salvage with antibiotic lock therapy is rarely successful for CRE
— Replace the Foley catheter (don't just remove) before culturing if catheter remains needed
— Relieve obstruction (stent, nephrostomy) for obstructive pyelonephritis
— Drain perinephric or prostatic abscess
— Percutaneous or surgical drainage of abscess >3–5 cm
— Source control surgery for perforation, necrosis, anastomotic leak
— Remove/replace infected biliary stents
— Suction, bronchoscopy for retained secretions/mucus plugs
— Consider tracheostomy revision if device-related
— Inhaled colistin/aminoglycoside for VAP is adjunctive only, not monotherapy
— Contact precautions — gown + gloves; single room preferred
— Dedicated equipment; hand hygiene with soap and water or alcohol
— Surveillance rectal swabs for high-risk contacts
— Chlorhexidine bathing in ICUs
— Notify receiving facility on transfer ("interfacility transfer form")
— Active outbreak response — cohort patients, dedicated staff, environmental cleaning audits
— ID consult mandatory for confirmed CRE infection in most institutions
— Daily reassessment; de-escalate to oral or narrower agent when possible
— Avoid unnecessary carbapenem exposure to limit selection pressure
— Empiric carbapenem use only when high pretest probability of ESBL — narrow on susceptibilities
CCS pearl: On a CRE case, order "contact isolation" immediately on admission; failure to isolate is a common patient-safety question. Also order chlorhexidine bath daily and ID consult.
Board pearl: Patients colonized with CRE remain colonized for months to >1 year — flag the chart; precautions on every readmission until decolonization confirmed (typically 3 negative weekly swabs off antibiotics).
— Reduced GFR (use measured CrCl, not estimated) — most CRE drugs require renal dose adjustment
— Lower muscle mass → serum creatinine underestimates renal dysfunction
— Polypharmacy → drug interactions (e.g., aztreonam + vitamin K antagonists may increase INR)
— Higher risk of C. difficile from broad-spectrum therapy
— Increased delirium with cefepime, imipenem (neurotoxicity)
— Ceftazidime-avibactam: CrCl 31–50 → 1.25 g q8h; CrCl 16–30 → 0.94 g q12h; CrCl 6–15 → 0.94 g q24h; HD → 0.94 g q48h (give after HD)
— Meropenem-vaborbactam: CrCl <50 requires significant reduction
— Imipenem-relebactam: Renal adjustment; seizure risk rises in renal failure
— Cefiderocol: Adjust for CrCl <60 AND augmented renal clearance ≥120 mL/min (increase dose q6h)
— Polymyxins, aminoglycosides: Nephrotoxic — avoid if possible; TDM essential
— Most newer agents are dialyzable — dose AFTER HD sessions
— CRRT dosing tables differ from intermittent HD; consult pharmacy
— Cefiderocol dosing in CRRT: 1.5 g q12h typical
— Most agents are renally cleared — minor hepatic adjustment needed
— Tigecycline: reduce in Child-Pugh C (50 mg q12h after load)
— Watch LFTs with prolonged courses
— Young trauma/burn/sepsis patients with CrCl >130 — underdosing risk
— Use extended-infusion β-lactams; consider TDM
Step 3 management: In an elderly LTACH patient with CRE bacteremia and CrCl 25, prescribe ceftazidime-avibactam 0.94 g IV q12h with pharmacy verification; recheck SCr daily; reassess dose with renal function changes.
Board pearl: Cefiderocol underdosing in augmented renal clearance has been linked to clinical failure — always check for ARC in young septic patients.
— β-lactams (including CAZ-AVI, meropenem-vaborbactam) are generally safe (Category B equivalent — no convincing evidence of harm)
— Avoid: tigecycline, eravacycline (teeth/bone effects, Category D), aminoglycosides (ototoxicity to fetus — use only if life-threatening), fluoroquinolones (cartilage), polymyxins (limited data, nephrotoxicity)
— Cefiderocol: limited pregnancy data but no signal of harm in animal studies; use if no alternative
— Nitrofurantoin and TMP-SMX: avoid at term (kernicterus) and 1st trimester (TMP-SMX antifolate), respectively — but options for CRE cystitis if no alternative
— OB/ID multidisciplinary consult essential
— CRE in children is rising, especially NICU outbreaks and immunocompromised hosts
— Ceftazidime-avibactam approved ≥3 months for cUTI and cIAI
— Meropenem-vaborbactam approved ≥18 years; pediatric data emerging
— Cefiderocol approved ≥3 months (cUTI) in 2024
— Weight-based dosing; consult pediatric ID
— Avoid tetracyclines <8 years (tooth staining)
— High-risk populations; CRE is leading cause of mortality in liver transplant recipients
— Pre-transplant screening for CRE colonization in endemic regions
— Avoid agents with drug interactions: rifampin with tacrolimus/cyclosporine; aminoglycosides + calcineurin inhibitors → synergistic nephrotoxicity
— Lower threshold for combination therapy and longer durations
— Surveillance cultures more frequent
— Empiric coverage should include anti-CRE agent if prior colonization or local high prevalence
— Add G-CSF consideration; ID and oncology co-management
— Persistent fever → check for invasive fungal disease
— Not independently increased risk unless advanced (CD4 <200) with healthcare exposure
— Drug interactions: protease inhibitors metabolize via CYP — most new β-lactam/BLIs minimal interaction
Board pearl: A liver transplant recipient with rejection on high-dose immunosuppression and prior CRE rectal colonization who develops cholangitis should receive empiric ceftazidime-avibactam while awaiting cultures — don't wait for mechanism confirmation.
Key distinction: Tigecycline is contraindicated in pregnancy and pediatrics <8 — choose a β-lactam-based regimen.
— CRE bacteremia mortality: 40–50% historically with polymyxin-based therapy; 20–30% with newer β-lactam/BLI agents
— Independent risk factors: delay in active therapy, septic shock, neutropenia, inadequate source control
— Refractory hypotension despite vasopressors
— ARDS from VAP or sepsis-related capillary leak
— AKI requiring CRRT — both from sepsis and nephrotoxic drugs
— DIC, sepsis-induced cardiomyopathy, hepatic dysfunction
— Polymyxin nephrotoxicity — 30–60% incidence; often dose-limiting
— Polymyxin neurotoxicity — paresthesias, neuromuscular blockade
— Aminoglycoside ototoxicity (vestibular and cochlear), nephrotoxicity
— Tigecycline: nausea/vomiting, hepatotoxicity, increased all-cause mortality (black box)
— Imipenem-relebactam: seizures (especially renal failure, prior seizure history)
— Cefiderocol: infusion reactions, rare hypersensitivity
— C. difficile colitis from broad-spectrum exposure
— Ceftazidime-avibactam resistance in KPC has been reported within days of starting therapy (KPC-3 mutations); paradoxically may restore carbapenem susceptibility
— Always re-culture if clinical failure
— Heteroresistance complicates colistin therapy
— Persistent gut colonization → recurrent UTI, bacteremia
— Risk factors for recurrence: incomplete source control, immunosuppression, devices not removed
— Decolonization strategies (oral non-absorbable antibiotics, FMT) experimental, not routinely recommended
— Septic thrombophlebitis at line site
— Mycotic aneurysm (rare but devastating)
— Endocarditis (rare with Enterobacterales) — consider TEE for persistent bacteremia
— Post-sepsis syndrome: cognitive impairment, functional decline, depression, increased 1-year mortality
— Higher LTACH/SNF placement rates after CRE bacteremia
Board pearl: New ceftazidime-avibactam resistance during therapy may make the isolate re-susceptible to meropenem — re-test full panel before assuming the agent failed for mechanistic reasons.
Step 3 management: Persistent fever or positive cultures at 72h → repeat blood cultures, repeat susceptibility, image for occult source, evaluate all devices for removal, escalate ID involvement, consider TEE.
— Septic shock (vasopressor requirement after fluid resuscitation)
— Respiratory failure requiring mechanical ventilation or HFNC
— Lactate ≥4 or rising despite resuscitation
— Altered mentation with worsening trajectory
— Multi-organ dysfunction (SOFA increase ≥2)
— Need for invasive monitoring or CRRT
— Hemodynamically stable on single vasopressor weaning
— Improving lactate, stable mental status
— Frequent monitoring needs but no imminent organ failure
— Infectious Diseases — every confirmed CRE infection; many institutions require ID approval for new β-lactam/BLI agents (stewardship gate)
— Clinical Pharmacy — dosing, TDM, drug interactions
— Infection Prevention/Hospital Epidemiology — isolation, contact tracing, surveillance, outbreak investigation
— Source-control specialist based on site: Surgery (abdominal/wound), IR (drainage), Urology (obstruction/stones), Cardiology (endovascular)
— Notify receiving facility of CRE colonization/infection (federal requirement in many states via interfacility transfer form)
— Transport with PPE, single ambulance
— Continue contact precautions on arrival
— CRE bacteremia in frail elderly LTACH residents has high mortality — early goals-of-care discussion is part of best practice
— Palliative care consult appropriate when prognosis poor or treatment burden high
— Document advance directives, surrogate decision-maker
— Some patients complete therapy at home or SNF with PICC line + IV agent (e.g., ertapenem if susceptible, cefiderocol via portable pump)
— Requires reliable follow-up, weekly labs, ID oversight
— Many newer agents not OPAT-friendly (3-hour infusions, q6–8h dosing)
CCS pearl: On a CCS CRE sepsis case, transfer to ICU as soon as septic shock criteria are met — delays cost simulated mortality points. Order ID consult, infection prevention notification, and pharmacy consult in the first 24 hours.
Board pearl: Failure to notify the receiving facility of CRE status on transfer is a patient safety event and may violate state law.
— Resistant to 3rd-gen cephalosporins (ceftriaxone, ceftazidime)
— SUSCEPTIBLE to carbapenems — meropenem is first-line
— Often confused with CRE on stems — read susceptibilities carefully
— Mortality much lower than CRE if treated with active agent
— MERINO trial: piperacillin-tazobactam is inferior to meropenem for ESBL bacteremia → use carbapenem
— Inducible resistance — may appear susceptible to ceftriaxone initially, then "break through"
— Use cefepime or carbapenem; avoid ceftriaxone for serious infection
— NOT CRE unless carbapenem MIC elevated
— Not Enterobacterales but commonly co-occurs
— Preferred: ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, cefiderocol
— Mechanisms: AmpC overexpression, porin loss, efflux pumps
— Higher mortality than CRE
— Treatment: sulbactam-durlobactam (new), high-dose ampicillin-sulbactam, minocycline, polymyxin, cefiderocol (selective)
— OXA-23 most common mechanism; different agents needed
— Intrinsically resistant to carbapenems and most β-lactams
— Treat: TMP-SMX first-line, minocycline, levofloxacin, cefiderocol
— Common in immunocompromised, prior carbapenem exposure
— Not Enterobacterales — easy distractor
— Cystic fibrosis patients, immunocompromised
— TMP-SMX, meropenem, minocycline
Key distinction: Carbapenem-resistant Pseudomonas/Acinetobacter ≠ CRE — different organisms, different first-line drugs. The boards love this trap. Always identify the organism before choosing therapy.
Board pearl: Pip-tazo for ESBL bacteremia is inferior to meropenem (MERINO) — but don't reflexively call ESBL "CRE." ESBL = carbapenem-susceptible; CRE = carbapenem-resistant.
— β-lactams (including new agents) can cause drug-induced fever
— Eosinophilia, rash, relative bradycardia may accompany
— Resolves within 48–72 hours of discontinuation
— Re-challenge contraindicated if severe (SJS/TEN, DRESS)
— Hospitalized septic patients are hypercoagulable
— Suppurative thrombophlebitis at vascular access site → persistent bacteremia plus VTE
— D-dimer non-specific; image with CT or US
— The most common true "antibiotic failure" — antibiotics can't penetrate avascular collections
— Pursue aggressive imaging: CT abdomen/pelvis, MRI spine if back pain, TEE for endovascular
— Vertebral osteomyelitis/epidural abscess in IVDU or post-spinal procedure
— Often co-occurs after broad-spectrum exposure
— Fever, diarrhea, leukocytosis — easy to attribute to original infection
— Send stool toxin/PCR if loose stools ≥3 in 24h
— Late (2–8 weeks) onset rash, eosinophilia, hepatitis, fever
— Reported with vancomycin, sulfonamides, β-lactams
— Stop offending drug; supportive care; ID and dermatology consult
— Failure to remove infected device, drain abscess, or relieve obstruction is the #1 reason a "right antibiotic" fails
— Reassess source daily
— CRE may be one of several pathogens; missed anaerobes in intra-abdominal source, missed fungi in immunocompromised
— Repeat cultures, expand panel
— PE, MI, transfusion reaction, adrenal insufficiency, pancreatitis, acalculous cholecystitis
— Always reassess the whole picture
Step 3 management: If a CRE patient on appropriate ceftazidime-avibactam remains febrile at 72h, don't reflexively change the antibiotic — first repeat cultures, image for occult source, evaluate devices, check for C. diff and drug fever.
Board pearl: Persistent positive blood cultures on appropriate therapy = endovascular or undrained focus until proven otherwise — order TEE and cross-sectional imaging.
— Routine decolonization of CRE gut carriage is NOT recommended — selective digestive decontamination (SDD) showed mixed results; risk of further resistance
— Investigational: fecal microbiota transplantation (FMT) for recurrent CRE infections — promising but not standard
— Daily chlorhexidine bathing in healthcare settings reduces transmission
— Most CRE infections require IV therapy completion — coordinate OPAT with home infusion or SNF
— PICC line placement, weekly labs (CBC, BMP, LFTs), ID follow-up within 1–2 weeks
— Oral step-down options limited; fluoroquinolones, TMP-SMX, or fosfomycin for cystitis if susceptible
— Document mechanism and susceptibility on discharge summary so future providers can choose appropriate empiric therapy
— Uncomplicated cUTI: 7–10 days
— Bacteremia with source control: 7 days (Yahav)
— Bacteremia without source control or complicated: 14 days
— HAP/VAP: 7 days (IDSA recommends shorter courses)
— Intra-abdominal with source control: 4–7 days (STOP-IT trial principle)
— Endocarditis (rare): 6 weeks
— Osteomyelitis: 6 weeks IV ± oral step-down
— Replace any indwelling device that was potential source
— Avoid Foley catheters if at all possible (use bladder scanner, intermittent cath)
— Reassess all lines daily — remove ASAP
— Pneumococcal (PCV15/PCV20), influenza annually, COVID-19, RSV ≥60, shingles ≥50 — reduce future infectious complications
— Discuss with PCP within 30 days post-discharge
— Electronic health record flag for CRE colonization/infection — triggers isolation on every readmission
— Share with PCP, dialysis center, dental provider
— State health department reporting in many states (CRE is reportable)
— Hand hygiene at home
— Inform any future healthcare provider of CRE history
— Wound and device care if applicable
Board pearl: CRE is a reportable condition in most states — failure to report is a public health violation.
Step 3 management: At discharge, document mechanism (e.g., "KPC-producing K. pneumoniae"), susceptibility profile, total antibiotic duration, OPAT plan, ID follow-up date, and EHR flag for contact precautions.
— Daily: vital signs, exam for source, fluid balance, glucose, CBC, BMP, LFTs
— 48–72h: clinical response assessment — if not improving, broaden the workup, not just the antibiotic
— Q48h blood cultures until clearance for bacteremia
— Therapeutic drug monitoring for polymyxins (steady-state levels), aminoglycosides (peak/trough), vancomycin if co-administered
— Watch for drug-induced AKI, hepatitis, cytopenias, QTc prolongation
— Clinical improvement + negative cultures + source control → consider step-down or oral
— No improvement at 72h → re-image, re-culture, reassess source, ID re-consult
— Repeat susceptibility if persistent bacteremia (emergent resistance)
— ID clinic visit within 1–2 weeks of discharge
— Weekly CBC, BMP, LFTs while on IV antibiotics
— PICC line site assessment at each visit
— Recheck cultures based on syndrome (test of cure for UTI, repeat imaging for abscess/osteo)
— PCP follow-up within 2 weeks; coordinate care plan handoff
— Post-sepsis: PT/OT evaluation; up to 60% of sepsis survivors have new functional limitations
— Pulmonary rehab post-VAP
— Nutrition: malnutrition assessment; enteral nutrition support if needed
— Cognitive screening — sepsis-associated cognitive decline common, especially in elderly
— Post-ICU PTSD, depression, anxiety affect 20–40% of survivors
— Screen at follow-up visits; refer to mental health
— Family/caregiver support
— Some institutions repeat rectal CRE screening at intervals
— Many patients remain colonized for >12 months
— Counsel on recurrence risk and when to seek care
— Time to active therapy, source control success rate, 30-day mortality, recurrence rate, C. diff incidence, AKI incidence
CCS pearl: Schedule ID follow-up at 1 week and 4 weeks, PCP at 2 weeks, labs weekly during OPAT on the discharge orders — these scheduling steps earn points and prevent readmission.
Board pearl: Post-sepsis syndrome screening (functional, cognitive, mood) at follow-up is now part of guideline-concordant care.
— CRE is reportable to state health departments in most US jurisdictions and to CDC's NHSN
— Carbapenemase mechanism reporting (KPC, NDM, OXA-48, VIM, IMP) is increasingly required
— Failure to report = public health violation; provider and institution liable
— Federal and state requirements mandate written notification to receiving facility of CRE status
— Missing this is a sentinel patient safety event — has caused outbreaks in receiving LTACHs
— Use standardized interfacility transfer form (CDC template available)
— Use of off-label combinations (e.g., ceftazidime-avibactam + aztreonam for MBLs) — document rationale; many institutions require ID attending sign-off
— Cefiderocol carries FDA caution due to CREDIBLE-CR mortality signal in some subgroups — discuss risk/benefit when alternatives exist
— Compassionate-use access for novel agents requires informed consent
— Contact precautions associated with fewer provider visits, more delirium, more depression
— Maintain communication; minimize unnecessary isolation duration
— Patients and families need clear explanation — avoid stigmatizing language ("superbug")
— CRE bacteremia in advanced age/multimorbidity has 40–50% mortality — early palliative care consult and goals-of-care conversation are ethically required
— Discuss prognosis honestly; avoid futile escalation
— Surrogate decision-making per state law if patient lacks capacity
— Reserving newer agents preserves them for those who need them — but withholding effective therapy from an individual is also unethical
— Stewardship committees should approve, not block, indicated use
— Equity: ensure access regardless of insurance/payor (drug cost can exceed $5,000/day)
— Discharge to SNF without antibiotic plan or precautions → readmission and transmission
— Verbal handoff to outpatient providers
— Medication reconciliation at every transition
— Duty to investigate clusters; cooperate with infection prevention and public health
— Notify exposed patients per state requirements
Step 3 management: When transferring a CRE-colonized patient from hospital to SNF, complete the interfacility transfer form documenting CRE status, mechanism, and precautions — this is a patient safety best-practice and legal requirement that boards reward.
Board pearl: Failing to notify the receiving facility of CRE status is a reportable patient safety event and has been cited in outbreak litigation.
— KPC — most common in US, Israel, Italy, Greece, China
— NDM — Indian subcontinent, Middle East, Balkans
— OXA-48-like — Turkey, North Africa, Mediterranean
— VIM/IMP — Southern Europe, Asia-Pacific
— Ceftazidime-avibactam: KPC + OXA-48 (not MBLs)
— Meropenem-vaborbactam: KPC only
— Imipenem-relebactam: KPC only
— Cefiderocol: ALL (including MBLs)
— CAZ-AVI + aztreonam: ALL (including MBLs)
— Tigecycline for bacteremia or UTI (low serum/urine concentrations)
— Pip-tazo for ESBL bacteremia (MERINO inferior to meropenem)
— Ceftriaxone for AmpC inducers (Enterobacter, Serratia)
— Polymyxin monotherapy (high mortality, nephrotoxicity)
— Uncomplicated GNR bacteremia with source control: 7 days
— Intra-abdominal with source control: 4–7 days
— HAP/VAP: 7 days
— Pyelonephritis: 7–14 days depending on agent
— Resistant to any carbapenem (imipenem MIC ≥4, meropenem ≥4, doripenem ≥4, ertapenem ≥2) OR carbapenemase positive
— Rectal/perirectal swabs in high-risk admissions
— Chlorhexidine daily bathing in ICUs
— Hand hygiene with soap and water (alcohol works for CRE too, despite myths)
— Ceftazidime-avibactam resistance can emerge within 5–10 days during therapy
— KPC-3 D179Y mutation restores carbapenem susceptibility
— Always reculture if failing
— CRE bacteremia: 40–50% historically, 20–30% with new β-lactam/BLIs
— Delay in active therapy >48h doubles mortality
Board pearl: "India + bacteremia + carbapenem-resistant K. pneumoniae" = NDM → use cefiderocol or CAZ-AVI + aztreonam, NOT CAZ-AVI alone.
Key distinction: Vaborbactam = KPC only; Avibactam = KPC + OXA-48; Cefiderocol = everything.
— "78-year-old hospitalized in Delhi 2 months ago, now febrile with K. pneumoniae bacteremia resistant to meropenem, ertapenem, ceftriaxone, and ceftazidime-avibactam. Best next step?"
— Think: NDM (MBL) → answer is cefiderocol or CAZ-AVI + aztreonam
— Septic patient from LTACH with prior CRE colonization; appropriate empiric coverage?
— Answer: CAZ-AVI (covers most US KPC and OXA-48) + source control + ID consult
— E. coli bacteremia from UTI, resistant to ceftriaxone, susceptible to meropenem; ID confirmed ESBL.
— Answer: meropenem, NOT a new β-lactam/BLI — use the simplest active drug
— CRE bacteremia on CAZ-AVI, still febrile day 4, repeat blood cultures positive.
— Best next step: search for undrained source (CT), evaluate vascular access, repeat susceptibility for emergent resistance, ID re-consult — NOT empiric drug switch
— Catheter-associated cystitis with CRE susceptible to nitrofurantoin, fosfomycin, and CAZ-AVI. Best choice?
— Answer: fosfomycin or nitrofurantoin — reserve newer agents for systemic infection
— Plan to transfer CRE patient to SNF. Most important next step?
— Answer: Notify the receiving SNF in writing of CRE status and required precautions
— Lab calls with CRE isolate. What next-step test guides therapy?
— Answer: Carbapenemase identification (Xpert Carba-R or mCIM/eCIM)
— Pregnant patient with CRE pyelonephritis; safest active agent?
— Answer: β-lactam (CAZ-AVI or meropenem-vaborbactam) — avoid tigecycline, aminoglycosides, fluoroquinolones
— CRE bacteremia from urinary source, catheter replaced, afebrile by day 3. Duration?
— Answer: 7 days total (Yahav non-inferiority)
— Confirmed KPC-producing K. pneumoniae. Public health responsibility?
— Answer: Report to state health department and infection prevention
Step 3 management: Recognize the trigger words — "international hospitalization" → NDM; "LTACH" → KPC; "Turkey/Mediterranean" → OXA-48. Mechanism determines drug.
Board pearl: When the question lists a susceptibility report, read the resistant AND susceptible columns carefully — many questions hinge on noticing that meropenem is susceptible (just ESBL) or that CAZ-AVI is resistant (likely MBL).
Carbapenem-resistant Enterobacterales (CRE) require mechanism-directed therapy with newer β-lactam/β-lactamase inhibitor combinations (ceftazidime-avibactam for KPC/OXA-48, cefiderocol or CAZ-AVI plus aztreonam for metallo-β-lactamases like NDM/VIM/IMP), aggressive source control, contact precautions, ID consultation, and public health reporting — with empiric coverage triggered by healthcare exposure, prior colonization, or international hospitalization, especially in the Indian subcontinent or Mediterranean.
Board pearl: "India + carbapenem-resistant Klebsiella + CAZ-AVI resistance" = NDM (MBL) → cefiderocol OR ceftazidime-avibactam + aztreonam. "LTACH + KPC" = ceftazidime-avibactam first-line.
Step 3 management: ID consult + source control + carbapenemase identification + contact precautions + reporting + transfer notification — these orders define guideline-concordant CRE care.