Efficacy and Safety of Metronidazole Monotherapy versus Vancomycin Monotherapy or Combination Therapy in Patients with <i>Clostridium difficile</i> Infection: A Systematic Review and Meta-Analysis

<div><p>Background</p><p><i>Clostridium difficile</i> infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients.</p><p>Methods</p><p>A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported.</p><p>Results</p><p>Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p <i>=</i> 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p<0.0001).</p><p>Conclusions</p><p>Metronidazole and vancomycin are equally effective for the treatment of mild CDI, but vancomycin is superior for the treatment of severe CDI. Combination therapy is not superior to monotherapy because it appears to be associated with an increase in the rate of AEs.</p></div

Forest plot of the rate of clinical cure (a: metronidazole vs. vancomycin for mild CDI; b: metronidazole vs. vancomycin for severe CDI; c: monotherapy vs. combination therapy).

<p>The vertical line indicates no difference between the groups. ORs are represented by diamond shapes, and 95% CIs are depicted by horizontal lines. Squares indicate point estimates, and the size of each square indicates the weight of the given study in the meta-analysis. M-H, Mantel-Haenszel fixed-effects model.</p

Main characteristics of the studies included in the meta-analysis.

<p>Abbreviations: T: Treatment (Met or Mono); C: Control (Van or Combi); Met: Metronidazole; Van: Vancomycin; Rif: Rifampin; Mono: Monotherapy group; Combi: Combination therapy group; NA: Not available. Method 1: <i>C</i>. <i>difficile</i> toxin assay and/or a clinical diagnosis; Method 2: <i>C</i>. <i>difficile</i> toxin assay; (1): Rate of clinical cure; (2): Rate of CDI recurrence; (3): AEs.</p><p>Main characteristics of the studies included in the meta-analysis.</p

Forest plot of the rate of CDI recurrence (a: metronidazole vs. vancomycin for mild CDI; b: metronidazole vs. vancomycin for severe CDI; c: monotherapy vs. combination therapy).

<p>The vertical line indicates no difference between the groups. ORs are represented by diamond shapes, and 95% CIs are depicted by horizontal lines. Squares indicate point estimates, and the size of each square indicates the weight ofthe given study in the meta-analysis. M-H, Mantel-Haenszel fixed-effects model.</p

Flow chart depicting the selection process for the studies included in the meta-analysis.

<p>Flow chart depicting the selection process for the studies included in the meta-analysis.</p

Forest plot of the rate of AEs (a: metronidazole vs. vancomycin; b: monotherapy vs. combination therapy).

<p>The vertical line indicates no difference between the groups. ORs are represented by diamond shapes, and 95% CIs are depicted by horizontal lines. Squares indicate point estimates, and the size of each square indicates the weight of the given study in the meta-analysis. M-H, Mantel-Haenszel fixed-effects model.</p

Effect of Soil Fulvic and Humic Acids on Pb Binding to the Goethite/Solution Interface: Ligand Charge Distribution Modeling and Speciation Distribution of Pb

The effect of adsorbed soil fulvic (JGFA) and humic acid (JGHA) on Pb binding to goethite was studied with the ligand charge distribution (LCD) model and X-ray absorption fine structure (XAFS) spectroscopy analysis. In the LCD model, the adsorbed small JGFA particles were evenly located in the Stern layer, but the large JGHA particles were distributed over the Stern layer and the diffuse layer, which mainly depended on the JGHA diameter and concentrations. Specific interactions of humic substances (HS) with goethite were modeled by inner-sphere complexes between the −FeOH₂^0.5+ of goethite and the −COO^– of HS and by Pb bridges between surface sites and COO^– groups of HS. At low Pb levels, nearly 100% of Pb was bound as Pb bridges for both JGFA and JGHA. At high Pb levels and low HS loading, Pb–goethite almost dominated over the entire studied pH range, but at high HS loading, the primary species was goethite–HS–Pb at acidic pH and goethite–Pb at alkaline pH. Compared with JGFA, there was a constant contribution of Pb bridges of about 10% for JGHA. The linear combination fit of EXAFS, using Pb–HS and Pb–goethite as references, indicated that with increased HS loading more Pb was bound to adsorbed HS and less to goethite, which supported the LCD calculations

Depot-specific inflammation with decreased expression of ATM2 in white adipose tissues induced by high-margarine/lard intake

<div><p>A high-fat diet has been recognized as an important risk factor of obesity, with variable impacts of different fatty acid compositions on the physiological process. To understand the effects of a high-margarine/lard diet, which is a major source of trans fatty acids (TFAs)/ saturated fatty acids (SFAs), elaidic acid as a biomarker of margarine intake was used to screen affected adipokines on mature human adipocytes in vitro. Weaned male Wistar rats were fed a high-fat diet enriched with margarine/lard to generate obesity-prone (OP) and obesity-resistant (OR) models, which were then used to explore the inflammatory responses of depot-specific white adipose tissue. Adiposity, glucose and lipid metabolism parameters and macrophage cell markers were also compared in vivo. In the subcutaneous depot, a high-margarine diet induced elevated IL-6, MCP-1 and XCL1 expression levels in both M-OP and M-OR groups. High-lard diet-fed rats displayed higher protein expression levels of MCP-1 and XCL1 compared with the control group. In the epididymal depot, significantly elevated IL-6 production was observed in M-OP rats, and high-lard diet-fed rats displayed elevated IL-6 and decreased XCL1 expression. In the retroperitoneal depot, a high-margarine diet caused higher IL-6 and MCP-1 expression levels, a high-lard diet caused elevated IL-6 expression in L-OP/L-OR rats, and elevated XCL1 expression was observed only in L-OP rats. In general, CD206 mRNA levels were notably down-regulated by high-fat diet feeding in the above-mentioned depots. CD11c mRNA levels were slightly upregulated in the subcutaneous depot of OP rats fed a high-margarine/lard diet. In the epidydimal depot, higher expression levels of F4/80 and CD206 mRNA were observed only in high-margarine diet-fed OP rats. These results suggest that depot-specific inflammation with decreased expression of adipose tissue anti-inflammatory M2-type (ATM2) macrophages could be induced by high-margarine/lard intake.</p></div

Macronutrient profiles and energy content of the diets (g/kg).

<p>Macronutrient profiles and energy content of the diets (g/kg).</p

Comparison of serum lipid and glucose metabolism measurements of rats fed with high-lard/margarine diets.

<p>Comparison of serum lipid and glucose metabolism measurements of rats fed with high-lard/margarine diets.</p