Combination Therapy For Infections Research Articles

Monotherapy versus combination for the treatment of Stenotrophomonas maltophilia: a multicenter cohort study

ABSTRACT Background The aim of this study was to compare the safety and effectiveness of monotherapy versus combination therapy for the treatment of infections caused by S. maltophilia. Methods This retrospective, multicenter, cohort study included patients treated with either monotherapy or combination therapy for infections caused by S. maltophilia. Primary outcomes included overall in-hospital mortality, 30-day mortality, and clinical cure. Safety outcomes were also evaluated. Multivariable logistic regression was used as a control for confounding variables. Results A total of 407 patients were included, 330 patients received monotherapy and 77 patients received combination therapy. A total of 21% presented with concomitant bacteremia. After adjusting the differences between the two groups, there were no statistically significant differences between patients who received monotherapy versus combination therapy in clinical cure (55% vs 65%; OR, 0.72; 95% CI, 0.40–1.31) and overall in-hospital mortality (52% vs 49%; OR, 0.84; 95% CI, 0.45–1.57). However, patients who received monotherapy had a lower rate of 30-day mortality (28% vs 32%; OR, 0.45; 95% CI, 0.22–0.90) and acute kidney injury (9% vs 18%; OR, 0.35; 95% CI, 0.16–0.78). Conclusion Clinical outcomes did not significantly differ in patients who received combination therapy versus monotherapy. More data are needed to validate these findings.

Determination of In Vitro Synergy of Ampicilin and Chloramphenicol against Multidrug Resistant Bacillus cereus Species

Nowadays, combination therapy has become one of the most effective clinical practices in treating infections due to the emergence of multi-resistant microorganisms. In this study, minimum inhibitory concentrations (MICs) of six selected antibiotics; ampicillin, gentamicin, tetracycline, rifampicin, chloramphenicol, and ciprofloxacin were screened towards five Bacillus cereus isolates; KS2, E2, F2, F6, and K2W2 isolated from aquaculture sources and river in Kukup, Johor, Malaysia. Determination of MICs on tested antibiotics showed that all B. cereus isolates were resistant towards ampicillin and rifampicin but most sensitive to chloramphenicol, ciprofloxacin, and gentamicin. Apart from that, this investigation also provides the synergistic effect of ampicillin and chloramphenicol against the B. cereus isolates. On contrary, K2W2 resulted as an antagonism while F6 resulted as indifference. In particular, synergy or double therapy of antibiotics may be required to treat multi-resistant organisms. Furthermore, the observed synergy between ampicillin and chloramphenicol opens a new window of using bacteriocins and antibiotics in combination therapy of infections.

Pharmacodynamics of the Novel Metallo-β-Lactamase Inhibitor ANT2681 in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

Enterobacteriaceae that produce metallo-β-lactamases (MBLs) are an emerging threat to public health. The metallo-β-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner β-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

Molecular Epidemiology of Plasmid-Mediated Fosfomycin Resistance Gene Determinants in Klebsiella pneumoniae Carbapenemase-Producing Klebsiella pneumoniae Isolates in China.

The Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae has become a serious problem because the species is wide ranging and there are few treatment options. Fosfomycin has attracted renewed interest in combination therapy for infections caused by KPC-producing K. pneumoniae isolates. Because of the increasing use of fosfomycin, resistant isolates have been continually reported in carbapenem-resistant K. pneumoniae (CRKP). At present, multiple mechanisms can result in fosfomycin resistance. However, there is limited knowledge with respect to plasmid-mediated fosfomycin resistance gene (fosA3) determinants in KPC-producing K. pneumoniae isolates. In this study, a total of 101 CRKP strains were collected from four hospitals in Zhejiang province from January 2013 to August 2014; 28.7% (29/101) of CRKP isolates were resistant to fosfomycin. Gene fosA3 was detected in 29 fosfomycin-resistant KPC-producing K. pneumoniae isolates, whereas genes fosA, fosB, fosB2, fosC, fosC2, and fosX were all negative among the resistant isolates. In addition, among 29 fosfomycin-resistant KPC-producing K. pneumoniae isolates, pulsed-field gel electrophoresis (PFGE) analysis revealed five pulsotypes. S1-PFGE and Southern blot showed that the fosA3 gene was located on an approximately 140-kb plasmid in all isolates. Eight of the 29 isolates (27.6%) tested could successfully transfer their fosfomycin-resistant phenotype to Escherichia coli strain J53. All fosA3-positive isolates were determined to have an identical genetic background, IS26-tetR-cadC-orf1-fosA3-IS26, which is the same as that of the fosA3-positive plasmid pFOS18 in China. The primary resistance mechanism to fosfomycin was caused by a plasmid-mediated fosA3. Furthermore, it is noteworthy that the plasmid genetically carrying a combination of the fosA3 and blaKPC-2 genes could accelerate the spread of antibiotic resistance. Effective and persistent monitoring and surveillance will be vital to prevent further dissemination of these resistance genes.

β-Lactam Combinations with Vancomycin Show Synergistic Activity against Vancomycin-Susceptible Staphylococcus aureus, Vancomycin-Intermediate S. aureus (VISA), and Heterogeneous VISA.

Increasing utilization of vancomycin due to the high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections has led to the emergence of vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA) strains. In vitro data suggest the potential for potent synergy between several beta-lactams and vancomycin. The objective of this study is to evaluate the synergy between beta-lactams and vancomycin against MRSA that is vancomycin susceptible, vancomycin-susceptible Staphylococcus aureus (VSSA), hVISA, and VISA. Fifty randomly selected clinical MRSA strains with various susceptibility levels to vancomycin were evaluated for vancomycin alone and vancomycin in combination with various concentrations of cefazolin (CFZ), cefepime (FEP), ceftaroline (CPT), and nafcillin (NAF). The potential for synergy was assessed by 24-h time-kill studies. Beta-lactams reduced vancomycin MIC values against all strains (4- to 16-fold reduction). In time-kill studies against MRSA, CFZ, FEP, CPT, and NAF all demonstrated similar degrees of killing at 24 h, and all showed synergistic activity with vancomycin against VSSA, hVISA, and VISA. Each of these combinations was also superior to any single agent against isolates of all three phenotypes, and each was bactericidal (P < 0.001 for all comparisons). All single-agent exposures demonstrated no activity at 24 h. The combination of vancomycin and beta-lactams significantly improved antibacterial activity against VSSA, hVISA, and VISA strains compared to the activity of any agent alone, supporting the potential use of vancomycin-beta-lactam combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergy of vancomycin against these Staphylococcus strains.

Vancomycin (VAN) Combinations with Β-Lactams (BLs) against Methicillin-Resistant Staphylococcus aureus (MRSA), Heterogeneous Intermediate-Level Resistance to Vancomycin (hVISA) and Vancomycin-Intermediate Staphylococcus aureus (VISA)

Background Staphylococcus aureus (S. aureus), especially Methicillin-resistant S. aureus (MRSA) remains a major cause of serious infection and is associated with increased morbidity and mortality. Vancomycin (VAN) has been the mainstay of therapy for MRSA infections. However, decades of selective pressure have led to increasing concerns regarding the efficacy of VAN against MRSA. In vitro data suggest the potential for potent synergy between several Β-lactams (BLs) and VAN. The objective of this study is to further explore the synergistic effect between BLs and VAN against MRSA strains with varying susceptibility to VAN.MethodsFifty randomly selected clinical MRSA strains from the Anti-Infective Research Laboratory library with varying susceptibility to VAN were evaluated for VAN alone and VAN in combination with Cefazolin (CFZ), Cefepime (FEP), Ceftaroline (CPT), and Nafcillin (NAF) minimum inhibitory concentration (MIC) by microdilution in duplicate. The potential for synergy was assessed by 24 hours time-kills (TK). Synergy was defined as >2 log10 CFU/mL difference between combination and the most active single agent at 24 hours.ResultsBLs reduced VAN MIC values against all strains (4–16 fold reduction). In TK studies against MRSA, all BLs demonstrated a similar extent of killing at 24 hours and showed synergy with VAN against all strains. Each combination was superior to any single agent alone, and each was bactericidal (3.42 ± 0.26 log10 CFU/cm2 reduction, P < 0.001 for all comparisons). All single agent exposures demonstrated no activity at 24 hours.Phenotype (Number of Strains)VAN MIC Range (µg/mL)VAN MIC Range with CFZVAN MIC Range with FEPVAN MIC Range with CPTVAN MIC Range with NAFMRSA (15)0.5 – 20.0625 – 0.250.0625 – 10.0625 – 0.250.125 – 0.5hVISA (20)0.5 – 20.125 – 0.50.0625 – 0.50.0625 – 0.50.125 – 1VISA (15)4 (all)0.0625 – 0.50.5 – 20.0625 – 0.250.125 – 1ConclusionThe combination of VAN and BLs significantly improved antibacterial activity against MRSA, hVISA, and VISA compared with any agent alone, supporting the potential use of Vancomycin/BL combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergistic activity of vancomycin against these Staphylococcus strains.Disclosures M. J. Rybak, Allergen: Scientific Advisor, Consulting fee

Synergistic effect of haloduracin and chloramphenicol against clinically important Gram-positive bacteria

The emergence of drug-resistant pathogens has triggered the search for more efficient antimicrobial agents and formulations for treatment of infections. In recent years, combination therapy has become one of the effective clinical practices in treating infections. The present study deals with the effect of haloduracin, a lantibiotic bateriocin and chloramphenicol against clinically important bacteria. The combined use of haloduracin and chloramphenicol resulted in remarkable synergy against a spectrum of microorganisms including strains of Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis and different groups of Streptococcus. The synergy allowed using these antimicrobial agents at substantially reduced concentrations without compromising their efficiency. Use of lower doses of chloramphenicol can avoid the severity of its side effects. In addition to minimizing undesirable side effects of some drugs, this approach brings the possibility of using antibiotics that are no longer effective due to drug resistance. Furthermore, the observed synergy between haloduracin and chloramphenicol opens a new window of using bacteriocins and antibiotics in combination therapy of infections.

β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium.

Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci. Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5 × MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments. Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001). The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted.

Time-kill effect of levofloxacin on multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii: synergism with imipenem and colistin.

In the present study, we challenged the concept that levofloxacin should not be used for the management of ventilator-associated pneumonia (VAP) when minimum inhibitory concentrations (MICs) exceed 2 μg/ml. Multidrug-resistant (MDR) and genetically distinct isolates of Pseudomonas aeruginosa (n = 49) and Acinetobacter baumannii (n = 29) from patients with VAP were exposed over time to levofloxacin, imipenem, colistin and their combinations. Synergy between levofloxacin and imipenem was found in 55.3 % and between levofloxacin and colistin in 90.9 % of isolates of P. aeruginosa within the first 4 h of growth. Synergy with imipenem but not with colistin was dependent of the MIC. Synergy between levofloxacin and imipenem was found in 58.6 % of isolates of A. baumannii after 24 h of growth. Considerable synergy was found between levofloxacin and colistin, reaching 84.8 % of isolates of A.baumannii after 6 h of growth. Synergy was independent from the MIC. These results create hopes that levofloxacin can be used as combination therapy for infections by MDR bacteria.

SP16-4 When is combination therapy indicated in the treatment of Gram-negative bacteria?

Combination therapy for infections with Gram-negative bacteria (GNB) has been the subject of debate over years, with studies leading to different and at times conflicting outcomes. Proponents of combination therapy propose several arguments: efficacy with expanded broad-spectrum coverage provided by two antimicrobial agents with different spectra of activity; prevention of the emergence of resistance; in vitro synergy between two antibiotics, and improved mortality.Most of the reviewed published data included retrospective studies, and no randomized controlled trials were found. There seems to be a consensus that in sensitive GNB, combination therapy has no added benefit in improving mortality. Hence, the widely used practice is to de-escalate the coverage as soon as the cultures grow a sensitive organism. However, in the era of multidrug resistant (MDR) bacteria and the absence of new antimicrobials in the pipeline, combination therapy should be readdressed.Most of the available data derive from studies involving Pseudomonas aeruginosa , carbapenem-resistant Enterobacteriaceae (CRE), and Acinetobacter baumannii . The results of clinical studies on combination therapy in the treatment of P. aeruginosa are conflicting and non-conclusive. One of the largest recent retrospective cohort studies found no difference in 30-day mortality between combination and monotherapy. However, the isolation of an MDR organismwas not specifically examined. In another study, in vitro activity against MDR P. aeruginosa demonstrated the effectiveness of antimicrobial agents when used in combination, and that despite documented resistance, bacterial killing may still be achieved with some combinations. As for CRE, several retrospective and prospective observational studies showed improvement inmortality with combination therapy. In vitro studies showed that the combination of colistin/tigecycline, rifampin/polymyxin, tigecycline/meropenem, and imipenem/colistin had synergistic activity and fosfomycin/carbapenems prevented the emergence of resistance. Recent studies suggested that combination therapy of 2 or more agents was associated with less mortality. Extended infusion of meropenem in combination with other drugs seemed to have the best outcome when the MIC is <4 ug/ml and a combination of colistin, meropenem and tigecycline had the best outcome regardless of the MIC to meropenem. In addition, a recent study suggested that a combination of 2 carbapenems – ertapenem and doripenem – was effective in treating infections with CRE. Finally, for MDR A. baumannii , the clinical information regarding the use of combination therapy is scarce and is limited for themost part to in vitro studies. In view of the extremely limited armamentarium, few antimicrobials remain active against MDR A. baumannii . Polymyxins and tigecycline are such drugs, and both are recommended for use in combination with other drugs. In summary, the available active agents againstMDRGNB aremainly the same: polymyxin, tigecycline, systemic fosfomycin, carbapenems and rifampin. However, their limited PD/PK makes them less potent for the treatment of serious infections. Hence their use should be avoided as monotherapy in the treatment of severe infections. Symposium 17. How to use PK–PD for our best practice

Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response

The aim of the study was to evaluate the effects of epoetin-beta on anemia and sustained viral response in patients with chronic hepatitis C receiving treatment with pegylated interferon and ribavirin. Forty-two Caucasian patients with chronic hepatitis C infection, treated with pegylated interferon alpha-2a or alpha-2b plus ribavirin, who experienced at least a 2 log decline in HCV-RNA in the first month of therapy and a > or =2.5 g/dl hemoglobin drop from baseline, were recruited. They were divided into two groups: 22 patients received epoetin-beta 30,000 U administered s.c. q.w. (group A) and 20 patients received a reduced ribavirin dose of 600 mg daily (group B). The end-of-treatment response was 95.4% (21/22) in group A and 80% (16/20) (P = 0.2) in group B. Sustained viral response in group A was 81.8% (18/22), statistically higher than in group B (45%, 9/20) (P = 0.03). Mean corpuscular volume of erythrocytes was statistically lower in group A than in group B 4 weeks after starting epoetin-beta or reduced ribavirin dose (P < 0.001), end-of-treatment (P < 0.001) and after 6 months follow-up (P < 0.001). A negative correlation between the levels of ferritin serum was found in group A at the baseline and mean corpuscular volume value after 1 month of combination antiviral therapy (r = -0.45; P = 0.35), 4 weeks after starting epoetin-beta (r = -0.43; P = 0.04) and after 6 months follow-up (r = -0.45; P = 0.03). Administration of epoetin-beta increases sustained viral response rates among patients developing anemia, because the standard dose of ribavirin is maintained, thereby reducing the side-effects of antiviral treatment.

Piperacillin and netilmicin combination therapy for febrile episodes in neutropenic patients

We assessed the efficacy of a piperacillin (3 x 4 g/d) and netilmicin (5 mg/kg/d) combination therapy for infections in febrile neutropenic patients. The study was conducted over a 30-month period and 203 patients were included. Bone marrow transplant recipients were not included in this study. Origin of infection was documented in 101 (50%) episodes: 33 fungal, viral or parasitic infections and 68 bacterial infections mainly composed of septicemia. Of the 169 evaluable patients with proved bacterial infections or non-documented infections, 129 (76%) recovered with the piperacillin and netilmicin combination treatment. All gram-positive bacterial infections failing first line therapy were cured after the addition of vancomycin. Piperacillin and netilmicin appeared very effective in this large monocentric prospective study. It does not seem necessary to include vancomycin in first line therapy of infections of the neutropenic patients in our institution; however, vancomycin must be added early in the case of suspected or documented staphylococcal infection failing empiric treatment.

Emergence of resistance to beta-lactams, aminoglycosides, and quinolones during combination therapy for infection due to Serratia marcescens.

Emergence of resistance to beta-lactams, aminoglycosides, and quinolones during combination therapy for infection due to Serratia marcescens.