Limits of treatment of health-care associated infections

Nicola PetrosilloNational Institute for Infectious Diseases

“L. Spallanzani” - Rome

Species BSI 86-97

BSI 06-07

VAP 86-97

VAP 06-07

UTI 86-97

UTI 06-07

S.aureus 13.4 14.5 17.4 24.4 Nd 2.2CoNS 33.5 34.1 - 1.3 Nd 2.5Enterococci 12.8 12.1 - - 14.1 9.6P.aeruginosa Nd 3.1 17.4 16.3 11.2 10.0Enterobacteria 5.2 3.9 20.7 18 19.2 11.8Acinetobacter - 2.2 - 8.4 - 1.2Candida spp 5.8 10.0 - 2.4 14.4 14.5Other

Idron AI et al. Inf Control Hospital Epidemiol 2008; 29:11 

Agents of Healthcare associated Infections

•Staphylococcus aureus the most flexible pathogen and its resistance prophile

•Acinetobacter spp: surprisingly MDR or PDR

•An old never forgotten opportunistic pathogen: P. aeruginosa

•Worrisome news in Enterobacteriaceae

Major emerging resistance issues in Gram‐negative pathogens

Pathogens Resistance issues Impact

Enterobacteriaceae

FQsExp.-spectrum cephems MDR (ESC/FQ/AG)Carbapenems

++++++++

+/ (++)*

P. aeruginosaAll anti-pseudomonas agents (ex. colistin) MDR/PDR/XDR

++

AcinetobacterAll anti-acinetobacter agents (MDR/PDR/XDR)Colistin R clone are emerging

++

* In some epidemiological settings 1) Giske CG et al AAC 2008; 52:813, 2) Pitout JDD et  alLancet Inf Dis 2008; 8:159, 3) Moellering RC et al AJIC 2007Nov., 4) Mendes RE et al CID 2008; 46:1324, 5) Li J et al CID 2007;45: 594, 6) Cornaglia G. et al IJAA 2007; 29: 380, 7) Endimiani et al 2007; 51:2211Courtesy by Prof. Stefani

Limits due to the lack of new

(and efficient) antimicrobials

Cooper MA, Shlaes D. Nature 2011;472:32.

Spellberg B et al, Clin Infect Dis 2008; 46:155-64

1999 Oxazolidinones1962 Quinolones

1962 Streptogramins

1958 Glycopeptides

1952 Macrolides

1950 Aminoglycosides

1949 Chloramphenicol

1949 Tetracyclines

1940 β-Lactams

1936 Sulfonamides

1930 1940 1950 1960 1970 1980 1990 2000

Development of New Antibiotics Over Time

2000 Glycylcyclines

2003 Lipopeptides

Emergence of serine carbapenemase KPC-3 among Klebsiella pneumoniae in hospitals of Rome, Italy

Carattoli A et al. ICAAC 2011, P-C2-660, Chicago

•101 patients with suspected CPKP were enrolled; KP-producing blaKPC-3 was identified in 95 cases (94%); 3 patients carried strains producing blaVIM (all from the same hospital) and 5 were infected with strains negative to the Hodge Test but positive to the blaCTX-M-15 ESBL gene associated to porin defects.

INTER-HOSPITAL SPRED OF KPC-PRODUCING STRAINS:

•We observed the inter-hospital spread of two major clones producing KPC-3: ST512 and ST258.

•KPC-3 was also identified in clones ST646 (new ST), ST650 (new ST) and ST14

•The blaVIM gene was identified in clones ST646, ST647 and ST648 (three new STs).

•4/5 strains negative for KPC but showing ESBL and porin defects belonged to ST37 the other was assigned to the new ST649.

Nordmann P et al. Emerg Infect Dis 2011; 17

Nordmann P et al. Emerg Infect Dis 2011; 17

Nordmann P et al. Emerg Infect Dis 2011; 17

Walsh TR et al. Lancet Infect Dis 2011; 11:355-62

Patel G et al. Expert Rev Anti Infect Ther 2011; 9: 555–570

Limits of the available agents:

is the combination therapy the solution?

Is combination antimicrobial treatment beneficial for serious bacterial infections?

• Most relevant analyses have not shown better results with combination antimicrobial treatment compared with broad-spectrum beta-lactam monotherapy– Paul M. et al. BMJ 2004;328:668 (beta-lactam

monotherapy versus beta-lactam –aminoglycoside combination therapy in immunocompetent patients)

– Cunha BA. Crit Care 2006;10:141 (ventilator associated pneumonia: monotherapy is optimal if chosen wisely)

• A specific population that deserves further study on this issue is patients with P. aeruginosa bacteremia

Bassetti M et al. Curr Med Chem 2008; 15:517-22

Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for

Pseudomonas aeruginosa bacteremia

Bliziotis IA, Petrosillo N, Michalopoulos A, Samonis G,Falagas ME

PLoS One 2011

Table 3. Multivariable analysis of factors possibly associated with treatment success

Factor OR 95% Conf. Interval p-value

Very long (>2 months) hospitalization

0.73 0.01-0.95 0.046

Hospitalization in ICU prior to bacteremia

0.67 0.09-4.78 0.69

Age-adjusted Charlson comorbidity index

1.02 0.76-1.38 0.88

HIV 0.59 0.08-4.23 0.60

Combination therapy 3.30 0.63-17.22 0.15

54 BSI

20 mono

34 combo

Petrosillo N et al. Expert Review Anti Infect Ther 2010;8:289-32

Int J Antimicrob Agents 2010;35:39-44.

• Rifampicin acts by inhibiting DNA dependent RNA polymerase in bacterial cells, thus preventing transcription to RNA and subsequent translation to proteins.

•Rifampicin is an antibiotic that does not effectively penetrate through the outer membrane of Gram-negative bacteria alone.

•However, if associated with antibiotics that permeabilise the outer membrane of Gram-negative bacteria (such as colistin), rifampicin may also be effective for Gram-negative bacteria.

•A literature review was performed of clinical studies reporting the use of rifampicin in the treatment of MDR Gram-negative bacterial infections.

•Nineteen studies were found, including only one randomised controlled study.

•Data in the literature on combined therapeutic regimens with rifampicin are limited and refer mostly to uncontrolled studies.

•Therefore, the real clinical benefit of using rifampicin-containing therapies for the treatment of Gram-negative multiresistant bacteria in terms of clinical outcome and survival rates still needs to be assessed.

Int J Antimicrob Agents 2010;35:39-44.

•Time-kill assays confirmed the synergistic interaction between tigecycline and levofloxacin, amikacin, imipenem and colistin for 5 of 7 selected isolates.

•No antagonism was confirmed by time-kill assays.

Table 2. Antibiotic resistance phenotype and checkerboard results obtained with DOR in

combination with five antibiotics in 24 A. baumannii isolates. Isolates are ranked in decreasing

order of resistance.

1Isolates showing an intermediate level of susceptibility were classified as resistant.

Abbreviations: R-, resistant to; S-, sensitive to; DOR, doripenem; TIG, tigecycline; COL, colistin;

AMK, amikacin; SAM, ampicillin/sulbactam; RIF, rifampicin; Sy, synergy; In, indifference. The

synergistic activities are shaded in grey.

DOR in combination with Study code (Hospital) Antibiotic-resistance phenotype1 DOR TIG COL AMK SAM RIF

5 (A) R-TIG-AMK-SAM-RIF (S-COL) R Sy In In In In 50 (C) R- COL-AMK-SAM-RIF (S-TIG) R In In In In In 80 (D) R-TIG-AMK-SAM-RIF (S-COL) R Sy In In In In 183 (D) R-TIG-AMK-SAM-RIF (S-COL) R Sy Sy In In In ACICU R-TIG-AMK-SAM-RIF (S-COL) R In Sy Sy Sy In 11 (B) R-TIG-AMK-RIF (S-SAM-COL) R Sy In In In In 71 (C) R-TIG-AMK-SAM (S-COL-RIF) R Sy In In In In 75 (C) R-TIG-AMK-RIF (S-COL-SAM-) S In In In In In 105 (C) R-AMK-SAM-RIF (S-TIG-COL) R In In In In In 108 (C) R-AMK-SAM-RIF (S-TIG-COL) R In Sy Sy In In 137 (L) R-AMK-SAM-RIF (S-TIG-COL) R In Sy In In In 138 (M) R-AMK-SAM-RIF (S-TIG-COL) R Sy Sy In Sy In 188 (D) R-AMK-SAM-RIF (S-TIG-COL) R In Sy Sy In In 198 (D) R-TIG-AMK-RIF (S-COL-SAM) R Sy Sy In In In 226 (P) R-TIG-SAM-RIF (S-COL-AMK) R Sy In In In In 82 (D) R-TIG-RIF (S-COL-AMK-SAM) S In In In In In 110 (I) R-SAM-RIF (S-TIG-COL-AMK) R In In In In In 133 (L) R-AMK-RIF (S-TIG-COL-SAM) S In In In In In 174 (P) R-SAM-RIF (S-TIG-COL-AMK) R In Sy Sy In Sy RUH 875 R-SAM-RIF (S-TIG-COL-AMK) S In In In In In 123 (L) R-SAM (S-TIG-COL-AMK-RIF) R In In In In In RUH 134 R-SAM (S-TIG-COL-AMK-RIF) S In In In In In 122 (L) (S-TIG-COL-AMK-SAM-RIF) S In In In In In 215 (P) (S-TIG-COL-AMK-SAM-RIF) S In In In In In

National Institute for infectious Disease “Lazzaro Spallanzani”,

Via Portuense 292, 00149, Rome, Italy.Phone: 39 0655170432

Fax: 39 0655170486

E-736 In Vitro Activity of Doripenem in Combination with Various Antimicrobials Against Multidrug Resistant Acinetobacter baumannii: Possible Options for the Treatment of Complicated Infections.

Principe L et al. ICAAC 2011

Daikos GL et al. Anticrob Agents Chemother 2009; 53: 1868-73

•Prospective observational studies of cases of VIM-producing K pneumoniae bacteremia

• 49 pts treated with appropriate empirical therapythose who were treated with 2 active drugs (carbapenem plus either colistin or aminoglicoside) had higher (but not significant) survival.

Lee J et al. J Clin Microbiol 2009; 47:1611-2

•None of those treated both with polymyxin and carbapenem showed changes in the MIC for either polymyxin B or carbapenem.

•Combination might be useful in the preventing the development of resistance during therapy

Kontopidou F et al. Clin Microbiol Infect 2011; 17: E9–E11

Carbapenemases

Courtesy by Prof. Stefani

Limits of treatment for MDR Gram negative agents:

How can we overcome it?

Ambrose PG et al. Diagn Microb Infect Dis 2009; 63:38-42

Ambrose PG et al. Diagn Microb Infect Dis 2009; 63:38-42

•Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L.

•For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.

Daikos GL et al. Clin Microbiol Infect 2011; 17: 1135–1141

Daikos GL et al. Clin Microbiol Infect 2011; 17: 1135–1141

Roberts JA et al. J Antimicrob Chemother 2009; 64:142-50

Keel RA et al. Int J Antimicrob Agents 2011; 37174-85

Pournaras S et al. Int J Antimicrob Agents 2011; 37:244-47

Pournaras S et al.Int J Antimicrob Agents 2011; 37:244-47

Nebulized and intravenous colistin in experimental pneumonia causedby P. aeruginosa Lu Q et al Intensive Care Med (2010) 36:1147–1155

Lung bacterial burden after 24 h of colistin administration

In the aerosol group, median peak lung tissue concen-tration of colistin was 2.8 mcg g-1 (25–75% IQR: 0.8- 13.7 )In the intravenous group, colistin could not be detected in any of the analyzed lung segments.