What is the first condition that needs to be treated in an adult patient with a Carbapenem-Resistant Enterobacteriaceae (CRE) infection and no significant allergies to antibiotics?

Treatment of Carbapenem-Resistant Enterobacteriaceae (CRE) Infections

For adult patients with CRE infections, the first condition that must be treated is identifying the specific carbapenemase type (KPC, MBL, or OXA-48-like) through rapid molecular testing, as this determines which antibiotic will actually work—KPC-producers require ceftazidime-avibactam or meropenem-vaborbactam as first-line therapy, while MBL-producers require ceftazidime-avibactam plus aztreonam combination. 1, 2

Critical First Step: Rapid Carbapenemase Identification

Obtain rapid molecular testing immediately to identify the specific carbapenemase mechanism before selecting antibiotics, as each enzyme class confers completely different susceptibility profiles requiring distinct treatment strategies. 1, 2

• KPC (Class A) carbapenemases are the most common (47.4% of CRE), followed by metallo-β-lactamases/MBLs (20.6%), and OXA-48-like enzymes (19.0%). 1
• Time from blood culture collection to active antibiotic therapy directly influences mortality in critically ill patients with KPC-producing bloodstream infections. 1
• MBLs hydrolyze all β-lactams except aztreonam and are not inhibited by standard β-lactamase inhibitors, making them particularly dangerous. 1

Treatment Algorithm Based on Carbapenemase Type

For KPC-Producing CRE (Most Common)

Use ceftazidime-avibactam 2.5g IV every 8 hours (infused over 3 hours) OR meropenem-vaborbactam 4g IV every 8 hours as first-line monotherapy. 1, 2

• Both agents have strong recommendations with moderate certainty of evidence for KPC-producers. 1
• Ceftazidime-avibactam achieved 81.6% clinical success in complicated intra-abdominal infections and significantly lower 28-day mortality (18.3% vs 40.8%) compared to traditional regimens. 1, 2, 3
• Choose meropenem-vaborbactam specifically for pneumonia due to superior epithelial lining fluid penetration (63-65% plasma concentrations), maintaining levels several-fold higher than MIC90. 1, 2, 3
• Imipenem-relebactam and cefiderocol are conditional alternatives with lower certainty of evidence. 1

For MBL-Producing CRE (NDM, VIM, IMP)

Use ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam combination therapy as first-line treatment. 1, 2, 3

• This combination has strong recommendation with moderate certainty of evidence for MBL-producers. 1
• MBLs hydrolyze all β-lactams except aztreonam, but aztreonam alone is ineffective due to co-produced ESBLs—the ceftazidime-avibactam component inhibits these ESBLs. 1
• Cefiderocol is a conditional alternative with low certainty of evidence. 1
• Never use ceftazidime-avibactam or meropenem-vaborbactam as monotherapy for MBL-producers—they are completely ineffective. 1

For OXA-48-Like Producing CRE

Use ceftazidime-avibactam 2.5g IV every 8 hours as first-line therapy. 1, 3

• This has conditional recommendation with very low certainty of evidence due to limited clinical data. 1
• OXA-48 producers showed promising results in one comparative study where OXA-48 was the predominant carbapenemase. 1

Combination Therapy Indications

Do NOT routinely add combination therapy when using newer β-lactam/β-lactamase inhibitors (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) if the organism is susceptible—this provides no benefit and increases toxicity. 1, 2

Use combination therapy with two or more in vitro active drugs only in these specific situations: 1, 2

• Severe infections with septic shock or high mortality risk (adjusted HR 0.56,95% CI 0.34-0.91 for mortality reduction). 1, 3
• MBL-producing CRE (mandatory combination as described above). 1, 2
• Organisms resistant to all newer agents, leaving only polymyxins, aminoglycosides, tigecycline, or fosfomycin as active options. 1, 2

Critical Pitfalls to Avoid

Never use monotherapy with polymyxins, tigecycline, or aminoglycosides for severe CRE infections when these are the only active agents—always combine at least two in vitro active drugs. 2

• Traditional antibiotic regimens (including colistin-based therapy) resulted in approximately one in three patients dying and <70% achieving clinical/microbiological response. 1, 3
• Colistin monotherapy has poor efficacy and unfavorable nephrotoxicity profiles compared to newer agents. 1, 3

Avoid carbapenem monotherapy or standard-dose carbapenems for documented CRE infections unless using high-dose extended-infusion regimens (meropenem 6g/day as 3-hour infusions) with MIC ≤8 mg/L as part of combination therapy. 1, 2

Monitor for ceftazidime-avibactam resistance emergence (occurs in 0-12.8% of KPC-producing isolates during treatment), particularly with prior ceftazidime-avibactam exposure. 1, 3

• KPC variants (e.g., D179Y mutations in blaKPC-3 gene) confer ceftazidime-avibactam resistance but restore meropenem susceptibility—switch to meropenem-vaborbactam in this scenario. 1, 3

Site-Specific Considerations

For bloodstream infections: Use ceftazidime-avibactam 2.5g IV every 8 hours or meropenem-vaborbactam 4g IV every 8 hours for 7-14 days. 2, 3

For complicated urinary tract infections: Use ceftazidime-avibactam 2.5g IV every 8 hours for 5-7 days. 1, 3

For complicated intra-abdominal infections: Use ceftazidime-avibactam 2.5g IV every 8 hours plus metronidazole for 5-7 days. 2, 3

For hospital-acquired/ventilator-associated pneumonia: Prefer meropenem-vaborbactam 4g IV every 8 hours for 10-14 days due to superior lung penetration. 1, 2, 3