How to treat efflux pump mediated colistin resistance in Klebsiella infections with Impaired renal function?

From the Guidelines

Treating efflux pump mediated colistin resistance in Klebsiella infections with impaired renal function requires a combination therapy approach, prioritizing carbapenem and tigecycline combinations over traditional polymyxins due to their nephrotoxicity. The recommended strategy involves combining a carbapenem, such as meropenem, with tigecycline, and considering the addition of an efflux pump inhibitor if available 1. For patients with severe renal impairment (CrCl <30 mL/min), dose adjustments are necessary, such as reducing meropenem to 250mg q12h and monitoring levels if possible.

Key Considerations

• Avoid traditional polymyxins like colistin due to their nephrotoxicity in already compromised renal function 1.
• Regular monitoring of renal function (daily creatinine and electrolytes), therapeutic drug monitoring where available, and assessment of clinical response at 48-72 hours are essential.
• Combination therapy using current and old antimicrobial agents targeting different resistance mechanisms are often used clinically based on the rationale of potential synergistic effect 1.
• If clinical improvement is not observed within 72 hours, consider consulting infectious disease specialists for alternative regimens potentially including newer agents like cefiderocol, plazomicin, or eravacycline, depending on susceptibility testing and availability.

Treatment Approach

• Combination therapy with meropenem and tigecycline is a recommended approach, with meropenem dosed at 500mg IV q12h (adjusted for renal function) and tigecycline dosed at 100mg IV loading dose followed by 50mg IV q12h 1.
• Consider adding an efflux pump inhibitor like Phenylalanine-Arginine Beta-Naphthylamide (PAβN) if available in your setting.
• Monitor for clinical response and adjust the treatment regimen as necessary, considering the potential need for newer agents or alternative combinations based on susceptibility testing and clinical guidelines 1.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION ... The daily dose and frequency should be reduced for the patients with renal impairment Suggested modifications of dosage schedule for patients with renal impairment are presented in Table 1. TABLE 1 Suggested Modification of Dosage Schedules of Colistimethate for Injection, USP for Adults with Impaired Renal Function Degree of Renal Impairment NormalMildModerateSevere Creatinine Clearance (mL/min)≥8050-7930-4910-29 Dosage Schedule2.5 to 5 mg/kg, divided into 2 to 4 doses per day2. 5 to 3.8 mg/kg, divided into 2 doses per day2.5 mg/kg, once daily or divided into 2 doses per day1. 5 mg/kg every 36 hours

The treatment for efflux pump mediated colistin resistance in Klebsiella infections with impaired renal function should follow the suggested modifications of dosage schedule for patients with renal impairment.

• The dosage schedule is as follows:
  • Mild renal impairment: 2.5 to 3.8 mg/kg, divided into 2 doses per day
  • Moderate renal impairment: 2.5 mg/kg, once daily or divided into 2 doses per day
  • Severe renal impairment: 1.5 mg/kg every 36 hours However, the FDA drug label does not provide information on how to treat efflux pump mediated colistin resistance specifically. The provided dosage schedule is for patients with impaired renal function, but it does not address the issue of efflux pump mediated resistance. Therefore, the treatment of efflux pump mediated colistin resistance in Klebsiella infections with impaired renal function cannot be determined based on the provided FDA drug label 2.

From the Research

Efflux Pump Mediated Colistin Resistance in Klebsiella

• Efflux pump mediated colistin resistance in Klebsiella pneumoniae is a significant concern, as it can lead to treatment failure and increased mortality 3, 4.
• Studies have shown that efflux pumps, such as H239_3064, can contribute to colistin resistance in Klebsiella pneumoniae 4.
• The CrrB protein has been identified as a key regulator of colistin resistance, and mutations in the crrB gene can lead to increased expression of efflux pumps and other resistance mechanisms 4, 5.

Treatment Options for Efflux Pump Mediated Colistin Resistance

• Combination therapy with aztreonam, ceftazidime/avibactam, and colistin has been shown to be effective in treating carbapenemase-producing Klebsiella pneumoniae infections 6.
• However, the effectiveness of this combination in treating efflux pump mediated colistin resistance is not well established.
• Other treatment options, such as tigecycline, may be effective against Klebsiella pneumoniae infections, but their use is often limited by resistance and toxicity concerns 6, 7.

Impaired Renal Function Considerations

• Patients with impaired renal function may require dose adjustments for colistin and other antibiotics to avoid toxicity 6.
• The use of combination therapy, such as aztreonam, ceftazidime/avibactam, and colistin, may be beneficial in patients with impaired renal function, as it can help to reduce the risk of toxicity and improve treatment outcomes 6.
• However, further studies are needed to determine the optimal treatment approach for patients with efflux pump mediated colistin resistance and impaired renal function.

Mechanisms of Resistance

• Efflux pumps, such as H239_3064, can contribute to colistin resistance by actively pumping the antibiotic out of the cell 4.
• The CrrB protein plays a key role in regulating colistin resistance, and mutations in the crrB gene can lead to increased expression of efflux pumps and other resistance mechanisms 4, 5.
• Other mechanisms of resistance, such as lipid A modification and porphyrin and chlorophyll metabolism, may also contribute to colistin resistance in Klebsiella pneumoniae 5.