Combining antibiotics: when does it make sense and why? José Manuel Pereira

Combining antibiotics: when does it make sense and why? José Manuel Pereira Serviço de Medicina Intensiva do Centro Hospitalar S. João, EPE Faculdade de Medicina da Universidade do Porto Grupo de Infecção e Sepsis

Let s use antibiotics wisely! Adequate Antibiotic Treatment Avoid Unnecessary Antibiotics Correct antibiotic therapy Combination therapy? Proper dosing & interval Monitor cultures Susceptibilities? Colonization vs. infection Duration of therapy Monitor clinical endpoints Diagnostic evaluation A BALANCING ACT

Appropriateness of initial antimicrobial therapy Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Kumar A et al. Chest 2009; 136: 1237-1248

Mortality rates Rello et al Alvarez-Lerma Appropriate therapy Inappropriate therapy Ibrahim et al Luna et al Garnacho-Montero et al Vallés et al 0 20 40 60 80 100 Mortality (%) Rello J et al. Am J Respir Crit Care Med 1997;156:196 200; Alvarez-Lerma et al. Intensive Care Med 1996;22:387 394; Ibrahim et al. Chest 2000;118:146 155; Vallés et al. Chest 2003;123:1615 1624; Luna et al. Chest 1997;111:676 685 Garnacho-Montero et al. Crit Care Med 2003;31:2742 2751;

Surviving Sepsis Guidelines

Potential Advantages Achieve broader cover for the empiric therapy Treatment of mixed infections Prevention of the development of resistance Reduce toxicity Achieve antibacterial sinergysm

Synergism In vitro for many antibiotic combinations Calandra T et al. Am J Med 1986; 80: 45. Kumar A et al. ICAAC Proc 2004; 26: A-1296; Darras-Joly C et al. Antimicrob Agents Chemother 1996; 40: 2147; Giamarellou H. Am J Med 1986; 80: 126. Giamarellou H et al. Antimicrob Agents Chemother 1984; 25: 534. Clinical studies of infection (including endocarditis, Gram negative bacteremia and neutropenic infections) Anderson ET et al. Chemotherapy 1978;24(1):45 54. Bouza E et al. Med Clin North Am 2000;84(6):1357 89; De Jongh CA et al. Am J Med 1986;80(5C):96 100. Specific types of infection: HIV Tuberculosis Helicobacter pylori

Is clinical proof necessary? The Lab Real Life Use of measured antibiotic concentrations administered at precise time points and tested against a standard inoculum of bacteria Antibiotic concentrations in the host is determined by: dose, volume distribution and elimination rate of atb patient s age, volume status, weight, renal and hepatic function, hypoalbuminemia site of infection Bacterial load is highly variable

Potential Disadvantages Antagonism drug to drug interaction Adverse events Development of antimicrobial resistance Increased costs

When to use combination antibiotic therapy? Severe sepsis/ Septic shock Combination antibiotic therapy MRMo Source of infection

Severe Sepsis/Septic Shock Meta-analysis of 62 eligible datasets demonstrated an estimated pooled OR for death/clinical failure of 0.856 (95% CI, 0.713 1.027) for combination compared to monotherapy regimens (p= 0.094) Combination therapy demonstrates a significant advantage over monotherapy when the rate of death/clinical failure exceeds 25% (pooled OR, 0.54; 95% CI, 0.45 0.66; p = 0.0001) Kumar A et al. Crit Care Medicine 2010; 38 :1651-1654

Severe Sepsis/Septic Shock Kumar A et al. Crit Care Medicine 2010; 38 :1651-1654

Severe Sepsis/Septic Shock Hazard ratio 0.77; 95% CI 0.67 0.88; p =.0002 Kumar A et al. Crit Care Medicine 2010; 38: 1773-1785

Severe Sepsis/Septic Shock The beneficial impact of combination therapy applied to both Gram positive and Gram-negative infections Combination therapy was also associated: Reduction in ICU (35.7% vs. 28.8%; OR 0.75; 95% CI 0.63 0.92; p=.0006) and hospital mortality (47.8% vs. 37.4%; OR 0.69; 95% CI 0.59 0.81; p <.0001). Increased ventilator (10 [0 25] vs. 17 [0 26]; p =.008) and pressor/ inotrope-free days (23 [0 28] vs. 25 [0 28]; p=.007) up to 30 days. Kumar A et al. Crit Care Medicine 2010; 38: 1773-1785

Severe Sepsis/Septic Shock Restricted to patients treated with β- lactams in combination with aminoglycosides, fluoroquinolones or macrolides/clindamycin. The most potent β-lactams including carbapenems failed to exhibit evidence of combination therapy benefit. In this circumstance, the addition of a second drug may have little incremental benefit Kumar A et al. Crit Care Medicine 2010; 38 :1773-1785

Severe Sepsis/Septic Shock n= 1372 pts Mortality rate: DCCT 34% vs. non-dcct 40%; p= 0.042 Díaz-Martín et al. Critical Care 2012, 16:R223

When to use combination antibiotic therapy? Severe sepsis/ Septic shock Combination antibiotic therapy MRMo Source of infection

Bacterial Meningitis If risk factors for Listeria monocytogenes: Age > 50 years or < 2 months Diabetes Alchoolism Immunosupression Malignancy 3rd Gen Cephalosporin + Ampicillin Tunkel AR et al. CID 2004; 39 :1267-1284

Endocarditis Leibovici L International Journal of Antimicrobial Agents 2010; 36S: S46 S49

Endocarditis Mortality OR 0.44 95% CI 0.12-1.58 Clinical Failure OR 0.69 95% CI 0.40-1.19 Bacteriological Failure OR 0.89 95% CI 0.47-1.69 Leibovici L International Journal of Antimicrobial Agents 2010; 36S: S46 S49

Endocarditis and Staph aureus Renal impairment as an adverse event was more frequent with standard therapy (18.1 % vs. 6.7 %; p= 0.009)

Endocarditis and Staph aureus

Endocarditis and Staph aureus Vancomycin + gentamicin In humans more rapid clearance of MSSA (2.7 d vs 3.3 d) In vitro synergy > for CA-MRSA and > for gentamicin-sensitive MRSA Does not reduce morbidity or mortality Korzeniowski O et al. Ann Int Med. 1982;97:494-503. Shelburne SA et al. AAC. 2004;48:4016-4019. Vancomycin + rifampicin In vitro Most often indifference Synergistic against MRSA growing in biofilm MRSA NVE (RCT) Days bacteremic Vancomycin 7 (5-11) Vancomycin + rifampin 9 (6-13) Maybe only in prosthetic valve or other foreign bodies Raad I et al. AAC 2007; 51:1656 60. Bayer AS et al. J Infect Dis 1985; 151:157 65. Levine DP et al. Annals Intern Med. 1991;115:674-680.; Shelburne SA et al. AAC. 2004;48:4016-4019.

Enterococcus spp. The enterococci are inherently more resistant to β-lactam antibiotics and are typically more tolerant to the bactericidal activity of these and other antimicrobial agents that act at the level of cell wall synthesis. In vitro bactericidal synergism between penicillin G and streptomycin against enterococci (1950) Synergistic and bactericidal therapy can be reliably achieved with the addition of an aminoglycoside to the β-lactam (or other cell wall agent such as vancomycin), as long as the organism does not exhibit high-level resistance to the aminoglycoside, making this combination the standard of care for severe enterococcal infections (endocarditis and meningitis)

Abdominal Infections SIS and IDSA GUIDELINES Solomkin JS et al. Clinical Infectious Diseases 2010; 50:133 64

Abdominal Infections Bochud PY et al. Crit Care Med 2004; 32:S495-512

Combination therapy in ciai infections Colonized with MRSA or who are at risk of having an infection due to this organism because of prior treatment failure and significant antibiotic exposure (B-II). Postoperative infection, previous use of cephalosporins or other antimicrobial agents selecting for Enterococcus species, immunocompromised, and pts with valvular heart disease or prosthetic intravascular materials (B-II). If Candida is grown from intra-abdominal cultures (B- II) Solomkin JS et al. Clinical Infectious Diseases 2010; 50:133 64

Community-Acquired Pneumonia

Community-Acquired Pneumonia AUTHOR POPULATION TYPE Nº COMBO SUPERIOR Gleason CAP Retro 12945 Yes Mufson, 1999 Bact. Pneumo Retro 328 Yes Waterer, 2001 Bact. Pneumo Retro 225 Yes Martinez, 2003 Bact. Pneumo Retro 409 Yes Weiss, 2004 Bact. Pneumo Retro 95 Yes Harbarth Pneumococcal sepsis Retro 107 No Garcia-Vasquez CAP Retro 1391 Yes

261 patients received BLM and 254 received FQ For PSI class V patients, there were lower 14-day and 30-day mortality rates with BLM than with FQ (14-day rates, 8.2% vs. 26.8% [p= 0.02]; 30-day rates, 18.4% vs. 36.6% [p= 0.05]). No differences in mortality between treatment groups were noted for the lower PSI classes. Lodise TP et al. Antimicrobial Agents and Chemotherapy 2007; 51: 3977 3982

Prospective, multicenter, observational study to evaluate if combination antibiotic therapy for severe bacteremic pneumococcal pneumonia is associated with a lower mortality. 592 of 844 patients with bacteremia due to St. pneumoniae global critically ill patients 10,4 vs. 11,5%, p= NS 23,4 vs. 55,3%, p= 0,0015 Baddour LM et al. AJRCCM 2004; 170: 440-444

No Shock Shock Prospective observational cohort study of 529 adults with severe CAP OR = 1.69 95% CI 1.09 2.60 p= 0.01 p = 0.99 Even when monotherapy was appropriate, it achieved a lower 28-day survival than an adequate antibiotic combination OR 1,64 (1,01-2,64) Combination antibiotic therapy seems to increase ICU survival in patients with severe CAP and shock Rodriguez A (CAPUCI group) et al. Crit Care Med 2007; 35: 1493-1498

Dual Therapy in Severe CAP WHY Yes? Synergy? NO. Lin E et al. Antimicrob Agents Chemother 2003; 47: 1151-3 Better coverage of atypical microorganisms? Low incidence of atypical pathogens in the positive studies & Results adjusted for empirical innappropriate therapy

Retrospective study of 2209 Medicare patients with bacteremic pneumonia The initial use of any antibiotic active against atypical organisms was associated with a decreased risk of 30-day mortality (OR 0.76; p= 0.03) and hospital admission within 30 days of discharge (OR, 0.67; p= 0.02). Even when an alternative pathogen is identified, treatment including a macrolide results in improved outcome in patients with bacteremic CAP or HCAP Metersky ML et al. Chest 2007; 131: 466-473

Dual Therapy in Severe CAP Then WHY Yes? Action in two different bacteria sites - cell wall for beta-lactams - inhibition of protein synthesis for macrolides Combination of two mechanisms - huge lysis by beta-lactams - inhibition of virulence factors production by macrolides Macrolide immunomodulatory effects - Decrease of IL-6, IL-8, IL-1 and TNF and epithelial cell adherence

To investigate the effects of clarithromycin (0.01-0.5 mg/l) alone or in combination with ceftriaxone (0.1 and 0.25 mg/l) on pneumolysin production by both macrolide-susceptible and -resistant strains of Streptococcus pneumoniae. Exposure of not only macrolide-susceptible strains, but also the macrolide-resistant strains, of S. pneumoniae to sub-mics of clarithromycin resulted in dose-related inhibition of the pneumolysin production, whereas production of the toxin was unaffected by ceftriaxone. These observations demonstrate that even in the setting of macrolide resistance the production of pneumolysin, a key virulence factor of the pneumococcus, is attenuated by exposure of this microbial pathogen to clarithromycin. Anderson R et al. J Antimicrob Chemother 2007; 59: 224-229

Dual Therapy in Severe CAP Adrie et al. Critical Care 2013, 17:R265

Dual Therapy in Severe CAP Dual therapy was associated with a higher frequency of initial adequate antibiotic therapy. Initial adequate antibiotic therapy was significantly associated with better survival (shr), 0.63; 95% CI 0.42 to 0.94; p = 0.02); this effect was strongest in patients with: Streptococcus pneumoniae CAP (shr, 0.05; 95% CI, 0.005-0.46; p = 0.001) Septic shock (shr: 0.62; 95% CI 0.38 to 1.00; p = 0.05) No difference in 60-day mortality was found between monotherapy (β-lactam) and either of the two dual-therapy groups (β-lactam plus macrolide or fluoroquinolone). Adrie et al. Critical Care 2013, 17:R265

Dual Therapy in Severe CAP The rates of nosocomial pneumonia and multidrug-resistant bacteria were not significantly different across these three groups. Adrie et al. Critical Care 2013, 17:R265

Ventilator Associated Pneumonia

Inadequate Initial Antimicrobial Therapy for VAP

AJRCCM 2005; 171: 388-416 Ventilator Associated Pneumonia ATS GUIDELINES

Ventilator Associated Pneumonia n= 1459 patients MORTALITY RR 0.94; 95% CI 0.76 1.16 No significant difference in treatment failure in patients with clinically suspected pneumonia (RR 0.88, 0.72 1.07) or MD pneumonia (RR 0.86, 0.63 1.16) No significant differences in rates of superinfections (RR 0.77, 0.48 1.22) or serious adverse events (RR 0.84, 0.48 1.49) Aarts MA et al. Crit Care Med 2008;36:108 17

Heyland D et al. Crit Care Med 2008;36:737-744 For critically ill patients who have suspected late VAP and who are at low risk for difficult-to-treat gram-negative bacteria, monotherapy is associated with similar outcomes compared with combination therapy. For those patients at high risk of difficult-to-treat gram-negative bacteria, combination therapy is safe and may be associated with better microbiological and clinical outcomes.

IV + Aerosolized Antibiotics Treatment success All-cause mortality: OR = 0.84, 95% CI 0.43 1.64 Microbiological success: OR = 2.06, 95% CI 0.91 4.68 Drug-related adverse effects: OR = 0.34, 95% CI 0.04 2.53 Development of resistance: 6.5% (IV+aerosolized) Ioannidou E et al Journal of Antimicrobial Chemotherapy 2007; 60:1216 1226

Rattanaumpawan P et al. JAC 2010; 65: 2645-2649 100 pts with Gram-negative VAP Most of the cases were caused by MDR A. baumannii and/or Ps aeruginosa Duration of IV antibiotics: 9.5 vs. 11.8 days (p= 0.005) Nebulized CMS as adjunctive therapy for Gram-negative seems to be safe but a beneficial effect on clinical outcome was not ascertained Kofteridis DP et al. CID 2010; 51: 1238-1244 86 pts with Gram-negative VAP (mostly MDR-Ab) No significant differences were observed regarding eradication of pathogens (p=.679), clinical cure (p=.10), and mortality (p=289) No AS colistin related adverse events were recorded.

Colistin IV + Aerosolized Retrospective, 1:1 matched case-control study (n= 208) AS-IV colistin cohort: had a higher clinical cure rate (69.2% vs 54.8%, p=.03) required fewer days of MV after VAP onset (8 days vs 12 days, p=.001) higher eradication of the causative organism (63.4% vs 50%, p =.08). No differences were observed in all-cause ICU mortality, length of ICU stay after VAP onset, or rates of acute kidney injury (AKI) during colistin therapy. Tumbarello M et al. Chest 2013; 144: 1768-1775

When to use combination antibiotic therapy? Severe sepsis/ Septic shock Combination antibiotic therapy MRMo Source of infection

Pseudomonas aeruginosa

Combination Antibiotics Pseudomonas aeruginosa Broaden the antimicrobial spectrum Synergism Decrease emergence of antimicrobial resistance Minimize superinfection

In vitro synergism Wide ranges of results Dependent on several methodological factors: - method of synergy test used - susceptibility patterns of the isolates - concentrations of antibiotics used The greatest likelihood of synergy is an aminoglycoside with an antipseudomonal penicillin (~ 90%), and then, in decreasing order, with a cephalosporin (~ 80%) or a carbapenem (~ 50%). The interaction of fluoroquinolones combined with β-lactams or aminoglycosides was usually autonomous (additive) or indifferent. For quinolone combinations plus antipseudomonal β-lactams, the β-lactam drug accomplished most of the bacterial killing.

Ps aeruginosa Bacteremia Inadequate therapy and 28 day-mortality (AOR: 3,02; 95% CI: 1.15 7,93; p = 0.02) Park et al. BMC Infectious Diseases 2012, 12:308

Ps aeruginosa VAP Retrospective, observational, cohort study 183 episodes of monomicrobial P. aeruginosa VAP Initial use of combination therapy significantly reduces the likelihood of inappropriate therapy, which is associated with higher risk of death. However, administration of only one effective antimicrobial or combination therapy provides similar outcomes, suggesting that switching to monotherapy once the susceptibility is documented is feasible and safe. Garnacho-Montero J et al Crit Care Med 2007; 35: 1888-1895

Ps aeruginosa Bacteremia Meta-analysis of 17 studies to determine whether a combination of > 2 antibiotics reduces mortality in patients with Gram-negative bacteremia Most studies used beta-lactams or aminoglycosides alone and in combination. OR 0,96 (95% CI 0,7-1,32) indicating no mortality benefit with combination therapy Analysis of only Ps. aeruginosa bacteremias showed a significant mortality benefit (OR 0,5, 95% CI 0,3-0,79), but few patient and aminoglycosides in the monotherapy arm This meta-analysis does not support the routine use of combination antibiotherapy for Gram negative bacteremia beyond settings where Ps. aeruginosa bacteraemia is strongly suspected Safdar N et al. Lancet Inf Dis 2004; 4 :519-527

Ps aeruginosa Bacteremia The absence of septic shock at the time of bacteremia (AOR 0.07; 95% CI, 0.01-0.49; p = 0.008), and combination therapy (AOR 0.05; 95% CI 0.01-0.34; p = 0.002) as variables that were independently associated with decreased allcause 28-day mortality No significant difference in terms of the emergence of antimicrobial resistance between the monotherapy and combination therapy group (21.9% and 12.1% respectively; p = 0.29). However, the 2-week bacteria eradication rate (54.5% vs. 18.8%, p = 0.04) and the 4-week eradication rate (54.5% vs. 28.1%, p = 0.04) were significantly higher in the combination therapy group than the monotherapy group. Park et al. BMC Infectious Diseases 2012, 12:308

Ps aeruginosa Bacteremia OR=0.89 95%CI 0.57 1.40; p = 0.614 Hu Y et al International Journal Antimicrobial Agents 2013; 42: 492-496

Pseudomonas aeruginosa Definitive CT pts had nonsignificantly higher clinical cure (RR 1.36, 95% CI 0.99 1.86). RR= 0.97, 95% CI 0.77 1.22 Empirical CT pts had a significantly higher clinical cure rate (RR 1.23, 95% CI 1.05 1.43). RR= 1.02, 95% CI 0.78 1.34 Vardakas KZ et al International Journal Antimicrobial Agents 2013; 41: 301-310

Combination Antibiotics Pseudomonas aeruginosa Broaden the antimicrobial spectrum Synergism Drug Toxicity Decrease emergence of antimicrobial resistance Minimize superinfection Hu Y et al International Journal Antimicrobial Agents 2013; 42: 492-496

Acinetobacter baumannii > 50%

In vitro synergism Colistin Tigecycline Carbapenems Sulbactam Aminoglyc Rifampicin Others Colistin + + + Pipt/tazo Tigecycline + + + Carbapenems + + + Sulbactam + Cefepime Fosfomycin Colistin + Tigecycline: better with Tigecycline 200 mg q12h Colistin + Carbapenem: In vitro synergy rates of 77% (95% CI: 64 to 87%) Meropenem was more synergistic than imipenem Carbapenem + Aminoglycoside: probably no better than carbapenem (imipenem) monotherapy Carbapenem + Rifampicin: no clinical benefit Triple combination therapy of meropenem,sulbactam and colistin has consistently shown very high levels of synergy.

Carbapenem-based regimens Retrospective study of 55 pts with MDR-AB bacteremia Combination therapy: n= 46 pts (83.6%) In-hospital mortality rate: 58% 30-days mortality rate: 49% Mortality: Carbapenem alone (58.3%) / Carbapenem and amikacin (50.0%) Kuo LC et al Clin Microbiol Infection 2007; 13: 196-198

Colistin plus Sulbactam n= 89 patients Colistin (58.4 %) vs. Colistin/sulbactam (41.6 %) Median APACHE II score was higher and diabetes mellitus was more common in the colistin/sulbactam Kalin G et al. Infection 2014; 42: 37 42

Colistin plus Rifampicin Multicenter, parallel, randomized, open-label clinical trial 210 patients with life-threatening infections due to XDR A. baumannii Colistin alone (2 MU q8 h IV) or colistin (as above) plus rifampicin (600 mg q12 hours IV). Durante-Magoni E et al Clin Infect Dis 2013; 57: 349-358

Colistin plus Rifampicin Logistic Regression Analysis of Variables Related to Overall 30-Day Mortality At present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. Durante-Magoni E et al Clin Infect Dis 2013; 57: 349-358

Tigecycline-based regimens 386 patients with HAIs caused by MDRAB were retrospectively analyzed TG group (n=266): alone (n= 108) or in combination (n= 158) with ceftazidime, ceftriaxone, piperacillin/tazobactam, or a carbapenem. Non-TG group (n=120): treated with imipenem/cilastatin and sulbactam. Lee YT et al Eur J Clin Microbiol Infect Dis 2013; 32: 1211-1220

Tigecycline-based regimens Variable OR 95% CI p= Sepsis 1,737 1,078-2,798 0,023 TG alone 0,47 0,256-0,863 0,015 TG in combination 0,553 0,322-0,950 0,032 Switch to other antibiotics 0,468 0,294-0,746 0,001 Microbiological eradication 0,155 0,032-0,747 0,02 Multivariate analysis to identify risk factors influencing unfavorable clinical outcomes (stationary or deterioration) Although there were no significant differences in survival rates between the two groups, the rate of unfavorable outcome was significantly lower (p<0.05) among patients in the TG group than among patients in the non-tg group. The most significant predictors of favorable outcome were TG treatment and microbiological eradication. Lee YT et al Eur J Clin Microbiol Infect Dis 2013; 32: 1211-1220

Glycopeptide-colistin combination Retrospective study including episodes of VAP or bacteremia caused by carbapenem-resistant A. baumannii. 29 patients (group I) treated with colistin plus vancomycin (for at least 5 days) vs. 28 patients treated with colistin alone (group II). Baseline characteristics, clinical cure, microbiological eradication, and mortality were similar in both groups This combination significantly increases the risk of renal failure (55.2 vs. 28%; p = 0.04). Garnacho-Montero J et al Chemotherapy 2013; 59: 225-231

Glycopeptide-colistin combination Retrospective multicenter study of ICU patients 184 pts were treated with colistin and GNB infection was documented for 166 (MDR-Ab(59.6%), MDR Ps. aeruginosa (18.7%), and KPC-Kl. pneumoniae (14.5%)) 68 patients (40.9%) received CGC. Comparison of patients treated with and without CGC showed significant differences for respiratory failure (39.7% versus 58.2%), VAP (54.4% versus 71.4%), MDR-Ab infection (70.6% versus 52%), and GPB coinfection (41.2% versus 0%) No differences for nephrotoxicity (11.8% versus 13.3%) and 30-day mortality (33.8% versus 29.6%). Cox analysis for 30-day mortality performed on patients who survived for 5 days after treatment onset: Charlson index (HR 1.26; 95% CI: 1.01-1.44; p= 0.001) MDR A. baumannii infection (HR 2.51; 95% CI: 1.23-5.12; p= 0.01) Receiving CGC for 5 days was a protective factor (HR 0.42; 95% CI 0.19-0.93; p= 0.03). Petrosillo N et al AAC 2014; 58: 851-858

Carbapenemase-producing Kl. pneumoniae

Carbapenemase-producing Kl. pneumoniae KPC-Kl. pneumoniae has become a significant problem in terms of public health and clinical outcome. Not only able to hydrolyze carbapenems but they are often resistant to a variety of other antibiotics as well Small clinical studies have revealed high treatment failure rates and reported mortality rates range from 22% to 72% Treatment options are usually limited to colistin, gentamicin, and/or tigecycline, but the optimal regimen for infections caused by KPC-producing bacteria has yet to be defined. In vitro data demonstrated that combination therapies are often more effective than monotherapies Hirsch EB et al J Antimicrob Chemother 2010; 65:1119 25; Carmeli Y et al Clin Microbiol Infect 2010; 16:102 11. Borer A et al Infect Control Hosp Epidemiol 2009; 30:972 6; Pournaras S et al Int J Antimicrob Agents 2011; 37:244 7.

Carbapenemase-producing Kl. pneumoniae n= 67 cases % Daikos GL et al AAC 2009; 53: 1868-1873

Carbapenemase-producing Kl. pneumoniae Qureshi ZA et al. AAC 2012; 56: 2108-2113 The 28-day mortality was 13.3% in the CT vs. 57.8% in the M group (P = 0.01). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (OR 0.07 ;95% CI 0.009-0.71; p = 0.02). Despite in vitro susceptibility, patients who received monotherapy with colistinpolymyxin B or tigecycline had a higher mortality of 66.7%. Colistin/Tigecycline + carbapenem: most common (mortality - 12.5%). Zarkotou O et al. CMI 2011; 17: 1798-1803 Overall mortality was 52.8% and infection mortality was 34% Appropriate antimicrobial therapy was administered to 35 patients (66%) In the appropriate group: mortality in CT was significantly lower than in M group ( 0% vs. 46,7%; p= 0.001) In univariate analysis, combinations of active antimicrobials (p 0.001) were significantly associated with survival.

Carbapenemase-producing Kl. pneumoniae n= 125 KPC-KP bacteremia episodes 60% of empirical antibiotics were classified as inadequate. Postantibiogram regimens used: monotherapy in 36.8% and 63.2% received 2 drugs with in vitro activity against the KPC-Kp isolate 30 day-mortality: 41,6% (mono - 54,3% vs. combination- 34,1%; p= 0.02) Lowest mortality rate with tigecycline+colistin+meropenem (12,5%) Tumbarello M et al Clinical Infect Dis 2012; 55: 943-950

Carbapenemase-producing Kl. pneumoniae To improve survival, combined treatment with 2 or more drugs with in vitro activity against the isolate, especially those also including a carbapenem, may be more effective than active monotherapy. Tumbarello M et al Clinical Infect Dis 2012; 55: 943-950

Carbapenemase-producing pandrug-resistant Kl. pneumoniae Ertapenem + Doripenem In vitro and in vivo murine model enhanced efficacy of the combination regimens over that of the monotherapy regimens in both models Reduction in inoculum density by ertapenem acting as a suicide substrate Ertapenem and + thereby Doripenem/Meropenem permitting doripenem/meropenem to express 3 cases its (bacteremia, successful UTI) activity against an already reduced, manageable All responded inoculum. successfully without relapse at follow-up Ertapenem + Doripenem 5 cases (bacteremia) All had clinical and microbiologic cure Bulik CC et al AAC 2011; 55: 3002-3004; Giamarellou H et al AAC 2013; 57: 2388-90; Nogid B, Nicolau DP. ACC Submitted

Conclusions The most common indication of combination of antibiotics is empiric treatment, when the goal is to cover all potential pathogens and when such a wide spectrum is impossible to guarantee with a single drug Combination therapy is not without risks, such as increased toxicity and cost. The host The source Local epidemiology

Conclusions Combination therapy is recommended in: Severe CAP, especially in shocked patients and bacteremic pneumococcal pneumonia, for 3-5 days Bacterial meningitis (if predisposing factors for Listeria) Enterococci infections (mainly endocarditis and meningitis) Infectious endocarditis by Staph aureus? If so, only 3 to 5 days Empiric treatment of nosocomial pneumonia with high suspicion for MDR pathogens (chosen according to local patterns and surveillance cultures and only until susceptibility available) Infections caused by XDR/PDR pathogens