Calohie CG

Clinical Evidence: Trials & Outcomes 

• Phase III cUTI vs Ceftriaxone: In a randomized trial (n≈204), CSE-1034 (2g/1g/74mg q24h) outperformed ceftriaxone alone in complicated UTI. Composite cure (clinical + microbiological) was 97% (68/70) for CSE-1034 vs 83% (58/71) for ceftriaxone (Δ = +12.6%; 95% CI 5.9–26.4%). Adverse events were fewer with CSE-1034 (21% vs 36%). 
• Phase III cUTI vs Meropenem (PLEA trial): In a double-blind trial (n=230), CSE-1034 was noninferior to meropenem for cUTI/AP. Symptomatic cure at test-of-cure was 95.9% vs 89.9%; eradication+symptom cure was 94.6% vs 87.0%. Microbiologic cure was 94.6% (CSE) vs 88.4% (meropenem). Authors conclude: “CSE…support[s] use…as a carbapenem-sparing treatment for patients with cUTI/AP caused by resistant Gram-negative pathogens.”. 
• Phase III Superiority (cUTI): The CSE-1034 vs ceftriaxone study also demonstrated superiority. At test-of-cure, CSE-1034’s 97% cure rate (vs 83%) showed statistically significant benefit, establishing efficacy and a favorable bacteriologic response. 
• Post-Marketing Surveillance: In 2,500+ real-world MDR infection cases, CSE-1034 achieved 79.4% cure and 20% improvement; only 0.2% failed. Common AEs (8.4% of patients) were mild (vomiting 3.0%, injection-site pain 2.5%, nausea 2.3%, rash/redness ~2%). No grade-4/5 toxicities were reported. 
• PK/PD Profile: Adults received 1.5 g CSE q12h (3 g/day). At this regimen, EDTA C_max ≈25 mg/L, sufficient for MBL inhibition. Ceftriaxone’s long half-life and high protein binding allow once- or twice-daily dosing. Pharmacodynamic targets (fT>MIC) are met for typical Gram-negative MICs, as supported by the high clinical cure rates. 

Clinical Highlight: In complex UTI, CALOHIE CG (2 g/1 g/74 mg) achieved 97% cure vs 83% with ceftriaxone alone (p=0.01). It also matched meropenem’s efficacy (94.6% vs 88.4% eradication), validating its role as a carbapenem-sparing agent. 

Unique Advantages of Disodium EDTA 

• MBL Enzyme Inhibitor: EDTA’s metal chelation is unique among β-lactam adjuncts. It directly inhibits NDM/VIM/IMP enzymes (IC₅₀ ≈55 µM for IMP-1). In animal pneumonia models, Ca-EDTA+imipenem dramatically reduced MBL-Pseudomonas lung counts versus antibiotic alone. 
• Membrane Permeabilizer: By stripping divalent cations from lipopolysaccharide, EDTA increases outer membrane permeability. This “opens the door” for ceftriaxone and sulbactam to reach periplasmic targets in highly resistant bacteria. 
• Anti-Biofilm: EDTA disrupts biofilm matrices. Studies show that combining EDTA with antibiotics can eradicate dense Gram-negative biofilms (preventing adherence and breaking existing biofilm). This enhances killing of persistent infections (e.g. catheter-related). 
• Efflux Inhibition: EDTA impairs energy-dependent efflux. In vitro, EDTA downregulated AcrAB-TolC pump genes 2–2.4-fold (at 10 mM). The net effect: synergistic MIC reductions (e.g. 32-fold for CSE vs 8-fold for meropenem in one study). 
• Plasmid/Curing Effect: Historical data show EDTA can eliminate resistance plasmids. In one classic study, EDTA-Tris alone “eliminated an antibiotic resistance marker” in an E. coli strain. This suggests EDTA may help block horizontal gene transfer of resistance. 
• Safety Profile & Drug Interactions 
• Adverse Events: CALOHIE CG’s safety mirrors its components. In trials, adverse events were mostly mild-to-moderate. Common AEs included GI upset (nausea, vomiting), injection-site reactions, rash and fever; all reported events were grade 1–2. No severe (grade ≥3) or unexpected toxicities occurred. Compared to ceftriaxone alone, CSE had a lower AE rate in one trial (21% vs 36%). 
• Organ Systems: Hematologic: Rare neutropenia or thrombocytopenia (cephalosporin-class effect) may occur with prolonged use. Monitor CBC in long courses. 
• Hepatobiliary: Ceftriaxone can cause biliary sludging or cholestasis; monitor LFTs if therapy exceeds 7–14 days. Avoid in neonates (risk of bilirubin displacement). 
• Renal: Sulbactam and EDTA are renally excreted. Adjust dose if creatinine clearance <30 mL/min. Ensure adequate hydration. 
• Electrolytes: EDTA chelates Ca²⁺/Mg²⁺. Avoid IV calcium during infusion (risk of chelate formation and hypocalcemia). No routine electrolyte binding is expected at the EDTA dose used (37 mg q12h), but prolonged use in critical patients warrants monitoring. 
• Drug Interactions: No major CYP drug-drug interactions. Interaction profile is as per β-lactams: 
• Calcium: Do not co-administer IV calcium products with CALOHIE CG (risk of ceftriaxone-calcium precipitates). Stagger infusions by ≥48 hours if necessary. 
• Anticoagulants: Cephalosporins (including ceftriaxone) may enhance warfarin/heparin effect (inhibit vitamin-K–dependent clotting). Monitor coagulation parameters. 
• Aminoglycosides: Concurrent use may increase nephrotoxicity risk. Monitor renal function if used together. 
• Contraceptives: Antibiotics can alter gut flora; advise additional contraception during therapy. 
• Others: No formal interactions reported for EDTA.