How to choose antibiotics for 4 types of “super-resistant bacteria”? The latest guidelines are here!

At present, the increasing incidence of antimicrobial resistance remains a deadly problem threatening global health. In clinical practice, how to choose effective antibiotics to treat infections caused by drug-resistant pathogens remains a challenging topic.

Recently, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) proposed new guidelines for the treatment of third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE) and carbapenem-resistant Gram-negative bacteria (CRE), focusing on the comparison of the effectiveness of combination antibiotic therapy with monotherapy.

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Third-generation cephalosporin-resistant Enterobacteriaceae

In recent years, with the widespread clinical application of third-generation cephalosporins, extended-spectrum β-lactamase-resistant Enterobacteriaceae (3GCephRE) have emerged. 3GCephRE often have multiple drug resistance and low sensitivity to commonly used antibiotics, making it difficult to select therapeutic drugs.

Which antibiotic should be chose for 3G CephRE infection?

ESCMID proposed the following 8 points for antibiotic selection for 3GCephRE infection:

1) For patients with bloodstream infections (BSIs) and severe infections: carbapenem antibiotics (imipenem or meropenem) are recommend (strong recommendation, moderate level of evidence).

2) Patients with bloodstream infection but without septic shock: Ertapenem is recommend. But imipenem or meropenem is not recommend (conditional recommendation, moderate level of evidence).

3) For patients with low-risk, non-severe infections: piperacillin/tazobactam, amoxicillin/clavulanic acid or quinolones are recommend (conditional recommendation, moderate level of evidence/good practice statement). For non-severe complicated urinary tract infection (cUTI), trimethoprim-sulfamethoxazole tablets are recommend. (Good practice statement).

4) For patients with cUTI who do not have septic shock: short-term treatment with aminoglycosides (with in vitro activity) (conditional recommendation, moderate-level evidence/good practice statement) or intravenous fosfomycin (strong recommendation, high-level evidence).

5) Tigecycline is not recommend (strong recommendation, very low level of evidence).

6) Among all 3GCephRE infections, new β-lactam/β-lactamase inhibitors (BLBLIs) are reserve antibiotics for extensively drug-resistant bacteria, so for antibiotic stewardship considerations, these drugs should be avoide as much as possible to treat infections cause by 3GCephRE (Good Practice Statement, Expert Opinion).

7) The use of cephalosporin antibiotics (such as cefoxitin, cefmetazole, and fluoxetine) and cefepime is not recommend for the treatment of 3G CephRE infection (conditional recommendation, very low level of evidence).

8) There is insufficient evidence to support the use of cefoperazone/sulbactam, ampicillin/sulbactam, ticarcillin/clavulanic acid, temocillin, and mecillinam for the treatment of patients with 3G CephRE infection (no recommendation).

No combination drug therapy is recommend!

Carbapenem-resistant Enterobacteriaceae

Carbapenem-resistant Enterobacteriaceae (CRE) is a type of bacterial infection disease that has appeared more and more frequently in clinical practice in recent years, and has even spread to become a global public health problem. The cause of this problem is largely the abuse of antibiotics.

Which antibiotic should be chose for CRE infection?

ESCMID proposed the following five points for antibiotic selection for CRE infection:

1) For patients with severe infection, meropenem-vaborbactam or ceftazidime-avibactam are recommend if they have in vitro activity (conditional recommendation, with moderate or low level of evidence, respectively).

2) For patients with severe infections cause by metallo-β-lactamase-producing CRE and/or resistance to all other antibiotics (including ceftazidime-avibactam and meropenem-vaborbactam), cefiderocol is recommend (conditional recommendation, low-quality evidence).

3) For patients with non-serious infections caused by CRE, an antibiotic with in vitro activity should be select based on the individual patient and the source of infection (good practice statement). For patients with cUTI, aminoglycosides, including prazomicin rather than tigecycline, are recommend (conditional recommendation, low-quality evidence).

4) Tigecycline is not recommended for the treatment of BSIs and hospital-acquire pneumonia/ventilator-associated pneumonia (HAP/VAP); if necessary, clinicians can use high-dose tigecycline for patients with pneumonia (conditionally not recommended, low-level evidence).

5) There is no evidence to support or refute the use of imipenem-relebactam and fosfomycin as monotherapy for CRE.

Are combination therapies use in CRE infections?

The ESCMI guidelines propose the following five points for combined treatment of CRE infection:

1) For patients infected with CRE who are sensitive to ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol and who are receiving the above drugs, combination therapy is not recommend (strongly not recommend, low-level evidence).

2) For patients with severe infections cause by metallo-β-lactamase-producing CRE and/or resistance to monotherapy with new antibiotics, treatment with aztreonam combine with ceftazidime-avibactam is recommend (conditional recommendation, moderate level of evidence).

3) For severe CRE infections that are in vitro sensitive only to polymyxins, aminoglycosides, tigecycline, or fosfomycin, or when no new BLBLs are available, the use of more than one in vitro sensitive drug is recommend (conditional recommendation, moderate-level evidence). No specific drug combination is recommend for or against.

4) For patients with CRE infection, clinicians are advise to avoid the use of carbapenem-based combination therapy (conditionally not recommend, low-level evidence) unless the meropenem MIC is ≤8 mg/L. In the absence of new BLBLIs, high-dose extended infusion of meropenem can be use as part of combination therapy (conditionally recommend, low-level evidence).

5) For patients with non-serious infections or low risk of CRE infection, monotherapy should be select among older antibiotics with in vitro activity on an individual patient basis and the source of infection, with consideration of antibiotic stewardship (Good Practice Statement).

Carbapenems Pseudomonas aeruginosa

Pseudomonas aeruginosa is a non-fermenting Gram-negative bacillus and the main pathogen of nosocomial infection, which can cause respiratory tract, urinary tract, bloodstream infection, etc. Carbapenems are potent β-lactam drugs for the treatment of Pseudomonas aeruginosa infection and are also one of the most effective drugs.

However, in recent years, with the widespread use of carbapenem antibiotics, carbapenem-resistant Pseudomonas aeruginosa (CRPA) has gradually increased, limiting the choice of drugs for anti-infection treatment.

Which antibiotic should be chose for CRPA infection?

Regarding the selection of antibiotics for CRPA infection, ESCMID proposed the following five points:

1) For patients with severe infections caused by DTR-CRPA (Pseudomonas aeruginosa resistant to β-lactams, enzyme inhibitor combinations, and quinolones), we recommend the use of ceftolozane-tazobactam (if effective in vitro) for treatment (conditional recommendation, very low level of evidence). There is currently insufficient evidence to recommend imipenem-lelibactam, cefdirox, and ceftazidime-avibactam.

2) In patients with non-severe or low-risk CRPA infection, it is good clinical practice to select older antibiotics with in vitro activity on an individual basis and base on the source of infection when antibiotic stewardship is consider (Good Practice Statement).

Can combination therapy be use for CRPA infection?

Regarding the combined treatment of CRPA infection, the ESCMI guidelines propose the following three points:

1) Due to lack of evidence, we cannot recommend for or against the use of the newer BLBLIs (ceftazidime-avibactam and ceftolozane-tazobactam). Or cefiderocol for the treatment of CRPA infections.

2) When using polymyxins, aminoglycosides, or fosfomycin to treat severe infections caused by CRPA. We recommend the use of two in vitro sensitive drugs (conditional recommendation, low-quality evidence). No recommendations can be make for or against specific combinations.

3) In patients with non-severe infections or low-risk CRPA infections, it is good clinical practice to select an antibiotic monotherapy with in vitro activity on an individual basis and base on the source of infection when antibiotic stewardship is being consider (Good Practice Statement).

Carbapenem-resistant Acinetobacter baumannii

Acinetobacter baumannii is a non-fermenting Gram-negative bacillus and an important pathogen of nosocomial infection. Which can cause pneumonia, bacteremia, urinary tract infection and other diseases. Carbapenem antibiotics are the main drugs for the treatment of Acinetobacter baumannii. But the application of antibiotics has gradually increased in recent years, resulting in carbapenem-resistant Acinetobacter baumannii (CRAB).

Which antibiotic should be chose for CRAB infection?

1) For HAP/VAP patients with sulbactam-sensitive CRAB, ampicillin-sulbactam is recommend (conditional recommendation, low level of evidence).

2) For patients with CRAB resistant to sulbactam, polymyxin or high-dose tigecycline can be use if effective in vitro. Due to lack of evidence, no first-choice antibiotic can be recommend.

3) Cefiderocol is not recommend for the treatment of infections cause by CRAB (conditionally not recommend, low level of evidence).

Is combination therapy use for CRAB infection?

1) For all patients with CRAB infection, we do not recommend colistin-meropenem. Combination therapy (strongly recommended not to use; high-certainty evidence) or colistin-rifampin combination therapy (strongly recommended not to use; intermediate-certainty evidence).

2) For patients with severe and high-risk CRAB infection. We recommend combination therapy with two in vitro active antibiotics included in the available antibiotics (polymyxin, aminoglycoside, tigecycline, sulbactam sodium combination) (conditional recommendation, very low-quality evidence).

3) For patients with CRAB infection and meropenem MIC < 8 mg/L, high-dose, extended infusion carbapenem regimens may be considered (good practice statement).

Finally, the following is the drug use regimen recommended by the Sanford Antimicrobial Treatment Guidelines for Fever

Recommended drug use regimen for fever (50th edition)

Imipenem/cilastatin: 1.0 g (0.5 g + 0.5 g) IV every 6 hours; for Pseudomonas aeruginosa, 2.0 g every 8 hours to every 6 hours

Meropenem: 0.5-1.0 g IV every 8 hours, increased to 2.0 g IV every 8 hours for meningitis

Ertapenem: 1.0 g IV or IM every 24 hours

Piperacillin/tazobactam: Recommended extended infusion regimen: 4.5 g injected over 30 minutes as a loading dose; 4 hours later. 3.375 g IV infusion over 4 hours every 8 hours. With IV access maintained for more than 12 hours per day

Co-trimoxazole: 960 mg orally twice a day;

Levofloxacin: 250-750 mg po/iv qd; 750 mg is the optimal dose for most indications.

Ciprofloxacin: 400 mg iv q12h; uncomplicated urethritis/cystitis, 250 mg po bid;

Amikacin: 15 mg/kg qd;

Fosfomycin: Osteomyelitis, complicated urinary tract infection. Hospital-acquired pneumonia, 12-24 g IV daily, divided into q8-12h; meningitis, 16-24 g daily, divided into q6-8h;

Meropenem-vaborbactam: 4 g (2 g + 2 g) IV every 8 hours infused over 3 hours;

Ceftazidime-avibactam: 2.5 g (2 g + 0.5 g) IV q8h infused over 2 hours;

Cefiderocol: 2 g iv q8h infused over 3 hours;

Amikacin: 15 mg/kg iv qd;

High-dose tigecycline: 200 mg first dose, 100 mg IV q12h;

Aztreonam: 1 g -2 g iv q6h-q8h;

High-dose extended infusion of meropenem: If CrCl ≥50 ml/min: 2 g q8h (infusion for more than 3 hours); If CrCl 30-49 ml/min: 1 g q8h (infusion for more than 3 hours); If CrCl 10-29 ml/min: 1 g q12h (infusion for more than 3 hours)

Cefuroxime-tazobactam: 1.5 g iv q8h infused over 1 hour;

Ampicillin/sulbactam: For the treatment of drug-resistant Acinetobacter, ampicillin 8g/sulbactam 4g iv q8h infusion over 4h;