How is chloramphenicol used with polymyxin B (Polymyxin B)?

Chloramphenicol with Polymyxin B Combination Therapy

Chloramphenicol combined with polymyxin B is used primarily for treating multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections, particularly New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae and other carbapenem-resistant Enterobacterales, where this combination demonstrates synergistic bacterial killing and suppresses polymyxin resistance emergence. 1

Primary Clinical Indications

Carbapenem-Resistant Gram-Negative Infections

• Polymyxin B combination therapy is recommended over monotherapy for carbapenem-resistant Gram-negative bacilli (CRGNB) infections, showing lower rates of treatment failure (119 fewer failures per 1000 patients, RR=0.82) and pathogen eradication failure (74 fewer failures per 1000 patients, RR=0.81). 2

• The combination specifically targets NDM-producing multidrug-resistant K. pneumoniae, where polymyxin B-chloramphenicol achieves synergistic killing in 25 out of 28 tested cases at 24 hours, with no viable bacteria detected in 15 out of 28 cases. 1

Respiratory Tract Infections

• For carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia and bloodstream infections, polymyxin-based combinations rank first in clinical cure (SUCRA 91.7%) and second in microbiological cure (SUCRA 68.7%). 2

• Intravenous polymyxin B is strongly recommended for hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) caused by Acinetobacter species sensitive only to polymyxins, with adjunctive inhaled colistin suggested as additional therapy. 2

Mechanism of Synergy

How the Combination Works

• Chloramphenicol significantly downregulates the arn operon responsible for lipid A modification, which is the primary mechanism bacteria use to develop polymyxin resistance. 3

• The combination produces persistent transcriptomic responses over 24 hours affecting cell envelope synthesis and metabolism of carbohydrates, nucleotides, and amino acids. 3

• Polymyxin B disrupts the bacterial outer membrane rapidly, while chloramphenicol inhibits protein synthesis and prevents the metabolic adaptations needed for resistance development. 4, 5

Administration Protocols

Dosing Considerations

• For critically ill patients, use a loading dose of 9 million units (5 mg/kg) polymyxin followed by maintenance dose of 4.5 million units twice daily (this applies to colistin; polymyxin B dosing should be adjusted accordingly: 1 mg polymyxin B = 10,000 units). 2, 6

• Chloramphenicol concentrations of 4-32 mg/L combined with polymyxin B at 0.5-2 mg/L achieve synergistic killing in time-kill studies. 1

Route of Administration

• For respiratory infections, add aerosolized polymyxin to intravenous therapy, which may reduce mortality (RR=0.86), clinical treatment failure (RR=0.82), and pathogen eradication failure (RR=0.84). 2, 6

• Colistin methanesulfonate (CMS) is preferred for inhalation therapy over polymyxin B sulfate, though both intravenous preparations can be used. 2

• Mean duration of polymyxin B combination therapy is approximately 19 days (range 2-57 days) for multidrug-resistant respiratory tract infections. 7

Critical Resistance Prevention

Suppression of Polymyxin Resistance

• Polymyxin B monotherapy at all concentrations produces rapid bacterial killing followed by rapid regrowth with emergence of polymyxin resistance within 24 hours. 1

• No polymyxin-resistant bacteria are detected when chloramphenicol is combined with polymyxin B, representing a major advantage over monotherapy. 1

• The combination significantly delays bacterial regrowth and prevents the selection of resistant subpopulations through chloramphenicol's inhibition of lipid A modification genes. 2, 3

Safety Profile

Nephrotoxicity Monitoring

• Nephrotoxicity occurs in approximately 10% of patients receiving polymyxin B combination therapy and does not typically require discontinuation. 7

• Regular monitoring of renal function is strongly recommended during treatment, though polymyxin B appears less nephrotoxic than colistin (adjusted HR 2.27 for colistin). 6, 8

Respiratory Adverse Events

• Monitor closely for bronchospasm when using aerosolized polymyxin, particularly in patients with underlying reactive airway disease. 2

Clinical Outcomes

Mortality and Treatment Success

• Combination therapy may reduce mortality by 14 fewer deaths per 1000 patients (RR=0.97,95% CI 0.84-1.13) compared to polymyxin monotherapy, though this effect has moderate-quality evidence. 2

• End-of-treatment mortality is approximately 21% with polymyxin B combination therapy for multidrug-resistant respiratory infections in critically ill patients. 7

Important Caveats

• Newer agents like ceftolozane-tazobactam should be used over polymyxin B when available and active in vitro due to lower nephrotoxicity profiles. 6, 8

• Optimal source control must always be prioritized to improve outcomes regardless of antibiotic selection. 8

• Therapeutic drug monitoring should be utilized when available to optimize polymyxin B dosing and minimize toxicity. 8

• The evidence for this specific combination (polymyxin B-chloramphenicol) comes primarily from in vitro studies and small case series 1, 4, 5, 3, while broader polymyxin combination therapy recommendations are based on moderate-quality clinical trial evidence. 2