Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics

1. Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics �

3. So What Happened? Antibiotic overuse/misuse

5. So What Happened? Antibiotic overuse/misuse Fitness of organisms clonal spread

6. The spread of resistant bacteria. Present data on the spread of resistant bacteria: � Between countries - the 23f pneumococcus: clonal spread The spread of resistant bacteria. Present data on the spread of resistant bacteria: � Between countries - the 23f pneumococcus: clonal spread

7. Bad Bugs, No Drugs1 The Antimicrobial Availability Task Force of the IDSA1 identified as particularly problematic pathogens A. baumannii and P. aeruginosa ESBL-producing Enterobacteriaceae MRSA Vancomycin-resistant enterococcus Declining research investments in antimicrobial development2

8. Between 1962 and 2000, no major classes of antibiotics were introduced

9. A Changing Landscape forNumbers of Approved Antibacterial Agents

10. The Problems Gram negatives Resistant Enterobacteriaceae �-Lactamases Pseudomonas/Acinetobacter N. gonorrheae Gram positives MRSA Pneumococcus

11. The Gram Negatives

12. �Background.�����The prevalence of multidrug resistance (MDR) among gram-negative bacilli is rapidly increasing. Quantification of the prevalence and the common antimicrobial coresistance patterns of MDR gram-negative bacilli (MDR-GNB) isolates recovered from patients at hospital admission, as well as identification of patients with a high risk of harboring MDR-GNB, would have important implications for patient care.�����Methods.�����Over a 6-year period, patients who harbored MDR-GNB (i.e., patients who had MDR-GNB isolates recovered from clinical cultures within the first 48 h after hospital admission) were identified. "MDR-GNB isolates" were defined as Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, and Klebsiella species isolates with resistance to at least 3 antimicrobial groups. A case-control study was performed to determine the independent risk factors for harboring MDR-GNB at hospital admission. �����Results.�����Between 1998 and 2003, the prevalence of MDR-GNB isolates recovered from patients at hospital admission increased significantly for all isolate species (P < .001), with the exception of P. aeruginosa (P = .09). Of 464 MDR-GNB isolates, 12%, 35%, and 53% of isolates were coresistant to 5, 4, and 3 antimicrobial groups, respectively. Multivariable analysis identified age 65 years (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.1 7.4; P < .04), prior exposure to antibiotics for 14 days (OR, 8.7; 95% CI, 2.5 30; P < .001), and prior residence in a long-term care facility (OR, 3.5; 95% CI, 1.3 9.4; P < .01) as independent risk factors for harboring MDR-GNB at hospital admission. �����Conclusion.�����A substantial number of patients harbor MDR-GNB at hospital admission. Identification of common coresistance patterns among MDR-GNB isolates may assist in the selection of empirical antimicrobial therapy for patients with a high risk of harboring MDR-GNB �Background.�����The prevalence of multidrug resistance (MDR) among gram-negative bacilli is rapidly increasing. Quantification of the prevalence and the common antimicrobial coresistance patterns of MDR gram-negative bacilli (MDR-GNB) isolates recovered from patients at hospital admission, as well as identification of patients with a high risk of harboring MDR-GNB, would have important implications for patient care.�����Methods.�����Over a 6-year period, patients who harbored MDR-GNB (i.e., patients who had MDR-GNB isolates recovered from clinical cultures within the first 48 h after hospital admission) were identified. "MDR-GNB isolates" were defined as Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, and Klebsiella species isolates with resistance to at least 3 antimicrobial groups. A case-control study was performed to determine the independent risk factors for harboring MDR-GNB at hospital admission. �����Results.�����Between 1998 and 2003, the prevalence of MDR-GNB isolates recovered from patients at hospital admission increased significantly for all isolate species (P < .001), with the exception of P. aeruginosa (P = .09). Of 464 MDR-GNB isolates, 12%, 35%, and 53% of isolates were coresistant to 5, 4, and 3 antimicrobial groups, respectively. Multivariable analysis identified age 65 years (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.1 7.4; P < .04), prior exposure to antibiotics for 14 days (OR, 8.7; 95% CI, 2.5 30; P < .001), and prior residence in a long-term care facility (OR, 3.5; 95% CI, 1.3 9.4; P < .01) as independent risk factors for harboring MDR-GNB at hospital admission. �����Conclusion.�����A substantial number of patients harbor MDR-GNB at hospital admission. Identification of common coresistance patterns among MDR-GNB isolates may assist in the selection of empirical antimicrobial therapy for patients with a high risk of harboring MDR-GNB

13. Enterobacteriaceae The rapid and disturbing spread of: extended-spectrum �-lactamases AmpC enzymes carbapenem resistance metallo-�-lactamases KPC and OXA-48 �-lactamases quinolone resistance

14. Oxyimino cephs: cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and cefepimeOxyimino cephs: cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and cefepime

15. Increase in numbers of Group 1, 2 and 3 �-lactamases from 1970 to 2009 Group 2 (Class A and D) inhibitor-resistant and extended-spectrum �-lactamases, and serine carbapenemasesGroup 2 (Class A and D) inhibitor-resistant and extended-spectrum �-lactamases, and serine carbapenemases

16. Group 1 cephalosporinases. Group 1 enzymes are cephalosporinases belonging to molecular class C that are encoded on the chromosome of many Enterobacteriaceae and a few other organisms (27). They are more active on cephalosporins than benzylpenicillin and are usually resistant to inhibition by clavulanic acid and active on cephamycins, such as cefoxitin. When produced in large amounts, especially in a host with reduced ߖlactam accumulation, group 1 enzymes can provide resistance to carbapenems, especially ertapenem Group 2 serine �-lactamases. Functional Group 2, including molecular classes A and D, �-lactamases represent the largest group of �-lactamases, due primarily to the increasing identification of ESBLs during the past 20 years. TEM and SHV ESBLs have been joined by the functionally similar but more rapidly proliferating CTX-M enzymes that are related to chromosomally determined �-lactamases in species of Kluyvera (8). As the name implies, most (but not all) CTX-M enzymes hydrolyze cefotaxime more readily than ceftazidime. Many hydrolyze cefepime as well. Serine carbapenemases from molecular class A populate subgroup 2f. More worrisome, however, are the plasmid-encoded subgroup 2f �-lactamases including KPC and some GES (formerly IBC) enzymes. The KPC carbapenemases in particular have recently been associated with major outbreaks of multidrug-resistant gram-negative infections in hospitals including those in the New York City metropolitan area (10, 12, 70) and in Israel (32), with their spread now becoming worldwideGroup 1 cephalosporinases. Group 1 enzymes are cephalosporinases belonging to molecular class C that are encoded on the chromosome of many Enterobacteriaceae and a few other organisms (27). They are more active on cephalosporins than benzylpenicillin and are usually resistant to inhibition by clavulanic acid and active on cephamycins, such as cefoxitin. When produced in large amounts, especially in a host with reduced ߖlactam accumulation, group 1 enzymes can provide resistance to carbapenems, especially ertapenem Group 2 serine �-lactamases. Functional Group 2, including molecular classes A and D, �-lactamases represent the largest group of �-lactamases, due primarily to the increasing identification of ESBLs during the past 20 years. TEM and SHV ESBLs have been joined by the functionally similar but more rapidly proliferating CTX-M enzymes that are related to chromosomally determined �-lactamases in species of Kluyvera (8). As the name implies, most (but not all) CTX-M enzymes hydrolyze cefotaxime more readily than ceftazidime. Many hydrolyze cefepime as well. Serine carbapenemases from molecular class A populate subgroup 2f. More worrisome, however, are the plasmid-encoded subgroup 2f �-lactamases including KPC and some GES (formerly IBC) enzymes. The KPC carbapenemases in particular have recently been associated with major outbreaks of multidrug-resistant gram-negative infections in hospitals including those in the New York City metropolitan area (10, 12, 70) and in Israel (32), with their spread now becoming worldwide

17. Extended-Spectrum �-Lactamases �-lactamases capable of conferring bacterial resistance to the penicillins first-, second-, and third-generation cephalosporins aztreonam (but not the cephamycins or carbapenems) These enzymes are derived from group 2b �-lactamases (TEM-1, TEM-2, and SHV-1) differ from their progenitors by as few as one AA

19. CTX-M-type ESBLs Until 2000, most ESBL producers were hospital Klebsiella spp. with TEM and SHV mutant �-lactamases Now, the dominant ESBLs across most of Europe and Asia are CTX-M enzymes, which originated as genetic escapes from Kluyvera spp Currently recognized as the most widespread and threatening mechanism of antibiotic resistance, both in clinical and community settings 80% of ESBL-positive E. coli from bacteraemias in the UK and Ireland are resistant to fluoroquinolones 40% are resistant to gentamicin These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (eg, ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 40 CTX-M enzymes are currently known. Despite their name, a few are more active on ceftazidime than cefotaxime. They have mainly been found in strains of Salmonella enterica serovar Typhimurium and E. coli, but have also been described in other species of Enterobacteriaceae and are the predominant ESBL type in parts of South America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most widespread type in E. coli the UK and is widely prevalent in the community.[11]These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (eg, ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 40 CTX-M enzymes are currently known. Despite their name, a few are more active on ceftazidime than cefotaxime. They have mainly been found in strains of Salmonella enterica serovar Typhimurium and E. coli, but have also been described in other species of Enterobacteriaceae and are the predominant ESBL type in parts of South America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most widespread type in E. coli the UK and is widely prevalent in the community.[11]

20. Carbapenemases Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems Resilient against inhibition by all commercially viable �-lactamase inhibitors Subgroup 2df: OXA (23 and 48) carbapenemases Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae

21. KPC (K. pneumoniae carbapenemase) KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumoniae Substrate hydrolysis spectrum includes cephalosporins and carbapenems A few class A enzymes, notably the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Three variants are known, distinguished by one or two amino-acid substitutions. KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.A few class A enzymes, notably the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Three variants are known, distinguished by one or two amino-acid substitutions. KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.

22. K. pneumoniae carbapenemase-producing bacteria A few class A enzymes, notably the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Three variants are known, distinguished by one or two amino-acid substitutions. KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.A few class A enzymes, notably the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Three variants are known, distinguished by one or two amino-acid substitutions. KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.

23. Group 1 cephalosporinases. Group 1 enzymes are cephalosporinases belonging to molecular class C that are encoded on the chromosome of many Enterobacteriaceae and a few other organisms (27). They are more active on cephalosporins than benzylpenicillin and are usually resistant to inhibition by clavulanic acid and active on cephamycins, such as cefoxitin. When produced in large amounts, especially in a host with reduced ߖlactam accumulation, group 1 enzymes can provide resistance to carbapenems, especially ertapenem Group 2 serine �-lactamases. Functional Group 2, including molecular classes A and D, �-lactamases represent the largest group of �-lactamases, due primarily to the increasing identification of ESBLs during the past 20 years. TEM and SHV ESBLs have been joined by the functionally similar but more rapidly proliferating CTX-M enzymes that are related to chromosomally determined �-lactamases in species of Kluyvera (8). As the name implies, most (but not all) CTX-M enzymes hydrolyze cefotaxime more readily than ceftazidime. Many hydrolyze cefepime as well. Serine carbapenemases from molecular class A populate subgroup 2f. More worrisome, however, are the plasmid-encoded subgroup 2f �-lactamases including KPC and some GES (formerly IBC) enzymes. The KPC carbapenemases in particular have recently been associated with major outbreaks of multidrug-resistant gram-negative infections in hospitals including those in the New York City metropolitan area (10, 12, 70) and in Israel (32), with their spread now becoming worldwideGroup 1 cephalosporinases. Group 1 enzymes are cephalosporinases belonging to molecular class C that are encoded on the chromosome of many Enterobacteriaceae and a few other organisms (27). They are more active on cephalosporins than benzylpenicillin and are usually resistant to inhibition by clavulanic acid and active on cephamycins, such as cefoxitin. When produced in large amounts, especially in a host with reduced ߖlactam accumulation, group 1 enzymes can provide resistance to carbapenems, especially ertapenem Group 2 serine �-lactamases. Functional Group 2, including molecular classes A and D, �-lactamases represent the largest group of �-lactamases, due primarily to the increasing identification of ESBLs during the past 20 years. TEM and SHV ESBLs have been joined by the functionally similar but more rapidly proliferating CTX-M enzymes that are related to chromosomally determined �-lactamases in species of Kluyvera (8). As the name implies, most (but not all) CTX-M enzymes hydrolyze cefotaxime more readily than ceftazidime. Many hydrolyze cefepime as well. Serine carbapenemases from molecular class A populate subgroup 2f. More worrisome, however, are the plasmid-encoded subgroup 2f �-lactamases including KPC and some GES (formerly IBC) enzymes. The KPC carbapenemases in particular have recently been associated with major outbreaks of multidrug-resistant gram-negative infections in hospitals including those in the New York City metropolitan area (10, 12, 70) and in Israel (32), with their spread now becoming worldwide

24. AmpC �-lactamases Once expressed at high levels, confer resistance to many �-lactam antimicrobials (excluding cefepime and carbapenems) In E. coli, constitutive over expression of AmpC �-lactamases can occur because of mutations in the promoter and/or attenuator region (AmpC hyperproducers) the acquisition of a transferable ampC gene on a plasmid or other transferable elements (plasmid-mediated AmpC �-lactamases)

25. Emerging Metallo-�-Lactamaseswith Mobile Genetics(SENTRY Program 2001-2005)

27. Enterobacteriaceae: Breakpoints revised

28. Neisseria gonorrhoeae

29. Prevalence of and risk factors for quinolone-resistant Neisseria gonorrhoeae infection in Ontario

30. Treatment of N. gonorrhoeae Only current CDC-recommended options for treating N. gonorrhoeae infections are from a single class of antibiotics, the cephalosporins. Ceftriaxone, available only as an injection, is the recommended treatment for all types of gonorrhea infections (i.e., urogenital, rectal, and pharyngeal). Cefixime is the only oral agent recommended for treatment of uncomplicated urogenital or rectal gonorrhea

31. The Gram Positives Staphylococcus aureus MRSA Reduced-vancomycin susceptibility MRSA MDR Streptococcus pneumoniae

32. MRSA

35. Community -AssociatedMRSA Sports participants Inmates in correctional facilities Military recruits Children in daycare Native Americans, Alaskan Natives, Pacific Islanders Men who have sex with men Hurricane evacuees in shelters Foal watchers Rural crystal methamphetamine users

36. MRSA Infections Among Patients In The Emergency Department Adult patients with acute, purulent skin and soft-tissue infections presenting to 11 University-affiliated EDs during August 2004 S. aureus was isolated from 320/422 patients 59% overall were MRSA (15% to 74%) 97% of MRSA were USA300 74% were a single strain (USA300-0114) 98% of MRSA had SCCmec type IV and the PVL toxin gene Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly recognized in infections among persons in the community without established risk factors for MRSA. We enrolled adult patients with acute, purulent skin and soft-tissue infections presenting to 11 university-affiliated emergency departments during the month of August 2004. Cultures were obtained, and clinical information was collected. Available S. aureus isolates were characterized by antimicrobial-susceptibility testing, pulsed-field gel electrophoresis, and detection of toxin genes. On MRSA isolates, we performed typing of the staphylococcal cassette chromosome mec (SCCmec), the genetic element that carries the mecA gene encoding methicillin resistance. S. aureus was isolated from 320 of 422 patients with skin and soft-tissue infections (76 percent). The prevalence of MRSA was 59 percent overall and ranged from 15 to 74 percent. Pulsed-field type USA300 isolates accounted for 97 percent of MRSA isolates; 74 percent of these were a single strain (USA300-0114). SCCmec type IV and the Panton-Valentine leukocidin toxin gene were detected in 98 percent of MRSA isolates. Other toxin genes were detected rarely. Among the MRSA isolates, 95 percent were susceptible to clindamycin, 6 percent to erythromycin, 60 percent to fluoroquinolones, 100 percent to rifampin and trimethoprim-sulfamethoxazole, and 92 percent to tetracycline. Antibiotic therapy was not concordant with the results of susceptibility testing in 100 of 175 patients with MRSA infection who received antibiotics (57 percent). Among methicillin-susceptible S. aureus isolates, 31 percent were USA300 and 42 percent contained pvl genes. MRSA is the most common identifiable cause of skin and soft-tissue infections among patients presenting to emergency departments in 11 U.S. cities. When antimicrobial therapy is indicated for the treatment of skin and soft-tissue infections, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage. Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly recognized in infections among persons in the community without established risk factors for MRSA. We enrolled adult patients with acute, purulent skin and soft-tissue infections presenting to 11 university-affiliated emergency departments during the month of August 2004. Cultures were obtained, and clinical information was collected. Available S. aureus isolates were characterized by antimicrobial-susceptibility testing, pulsed-field gel electrophoresis, and detection of toxin genes. On MRSA isolates, we performed typing of the staphylococcal cassette chromosome mec (SCCmec), the genetic element that carries the mecA gene encoding methicillin resistance. S. aureus was isolated from 320 of 422 patients with skin and soft-tissue infections (76 percent). The prevalence of MRSA was 59 percent overall and ranged from 15 to 74 percent. Pulsed-field type USA300 isolates accounted for 97 percent of MRSA isolates; 74 percent of these were a single strain (USA300-0114). SCCmec type IV and the Panton-Valentine leukocidin toxin gene were detected in 98 percent of MRSA isolates. Other toxin genes were detected rarely. Among the MRSA isolates, 95 percent were susceptible to clindamycin, 6 percent to erythromycin, 60 percent to fluoroquinolones, 100 percent to rifampin and trimethoprim-sulfamethoxazole, and 92 percent to tetracycline. Antibiotic therapy was not concordant with the results of susceptibility testing in 100 of 175 patients with MRSA infection who received antibiotics (57 percent). Among methicillin-susceptible S. aureus isolates, 31 percent were USA300 and 42 percent contained pvl genes. MRSA is the most common identifiable cause of skin and soft-tissue infections among patients presenting to emergency departments in 11 U.S. cities. When antimicrobial therapy is indicated for the treatment of skin and soft-tissue infections, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage.

37. Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly recognized in infections among persons in the community without established risk factors for MRSA. We enrolled adult patients with acute, purulent skin and soft-tissue infections presenting to 11 university-affiliated emergency departments during the month of August 2004. Cultures were obtained, and clinical information was collected. Available S. aureus isolates were characterized by antimicrobial-susceptibility testing, pulsed-field gel electrophoresis, and detection of toxin genes. On MRSA isolates, we performed typing of the staphylococcal cassette chromosome mec (SCCmec), the genetic element that carries the mecA gene encoding methicillin resistance. S. aureus was isolated from 320 of 422 patients with skin and soft-tissue infections (76 percent). The prevalence of MRSA was 59 percent overall and ranged from 15 to 74 percent. Pulsed-field type USA300 isolates accounted for 97 percent of MRSA isolates; 74 percent of these were a single strain (USA300-0114). SCCmec type IV and the Panton-Valentine leukocidin toxin gene were detected in 98 percent of MRSA isolates. Other toxin genes were detected rarely. Among the MRSA isolates, 95 percent were susceptible to clindamycin, 6 percent to erythromycin, 60 percent to fluoroquinolones, 100 percent to rifampin and trimethoprim-sulfamethoxazole, and 92 percent to tetracycline. Antibiotic therapy was not concordant with the results of susceptibility testing in 100 of 175 patients with MRSA infection who received antibiotics (57 percent). Among methicillin-susceptible S. aureus isolates, 31 percent were USA300 and 42 percent contained pvl genes. MRSA is the most common identifiable cause of skin and soft-tissue infections among patients presenting to emergency departments in 11 U.S. cities. When antimicrobial therapy is indicated for the treatment of skin and soft-tissue infections, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage. Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly recognized in infections among persons in the community without established risk factors for MRSA. We enrolled adult patients with acute, purulent skin and soft-tissue infections presenting to 11 university-affiliated emergency departments during the month of August 2004. Cultures were obtained, and clinical information was collected. Available S. aureus isolates were characterized by antimicrobial-susceptibility testing, pulsed-field gel electrophoresis, and detection of toxin genes. On MRSA isolates, we performed typing of the staphylococcal cassette chromosome mec (SCCmec), the genetic element that carries the mecA gene encoding methicillin resistance. S. aureus was isolated from 320 of 422 patients with skin and soft-tissue infections (76 percent). The prevalence of MRSA was 59 percent overall and ranged from 15 to 74 percent. Pulsed-field type USA300 isolates accounted for 97 percent of MRSA isolates; 74 percent of these were a single strain (USA300-0114). SCCmec type IV and the Panton-Valentine leukocidin toxin gene were detected in 98 percent of MRSA isolates. Other toxin genes were detected rarely. Among the MRSA isolates, 95 percent were susceptible to clindamycin, 6 percent to erythromycin, 60 percent to fluoroquinolones, 100 percent to rifampin and trimethoprim-sulfamethoxazole, and 92 percent to tetracycline. Antibiotic therapy was not concordant with the results of susceptibility testing in 100 of 175 patients with MRSA infection who received antibiotics (57 percent). Among methicillin-susceptible S. aureus isolates, 31 percent were USA300 and 42 percent contained pvl genes. MRSA is the most common identifiable cause of skin and soft-tissue infections among patients presenting to emergency departments in 11 U.S. cities. When antimicrobial therapy is indicated for the treatment of skin and soft-tissue infections, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage.

39. S. aureus resistant or with reduced susceptibility to vancomycin VRSA, VISA and hVISA

40. Streptococcus pneumoniae Most important pathogen in mild-to-moderate RTIs Greatest morbidity Greatest mortality

41. Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction1998 - 2005 The overall incidence of IPD among children aged <5 years declined from 99 cases/100,000 during 1998 - 1999 to 23 cases/100,000 in 2005 The largest percentage decline (82%) and the largest absolute rate reduction in overall IPD (175.8 cases per 100,000) were observed among children aged 1 year, the age group with the highest baseline rate (Table). The incidence of PCV7-type IPD decreased significantly among all children aged <5 years from 1998--1999 to 2005. The largest absolute rate reduction in PCV7-type disease was observed among children aged 1 year (175.7 cases per 100,000). Non-PCV7--type IPD increased significantly among children aged <1 year and 4 years (Table). The largest percentage decline (82%) and the largest absolute rate reduction in overall IPD (175.8 cases per 100,000) were observed among children aged 1 year, the age group with the highest baseline rate (Table). The incidence of PCV7-type IPD decreased significantly among all children aged <5 years from 1998--1999 to 2005. The largest absolute rate reduction in PCV7-type disease was observed among children aged 1 year (175.7 cases per 100,000). Non-PCV7--type IPD increased significantly among children aged <1 year and 4 years (Table).

43. Serotype distribution of S. pneumoniae isolated from invasive disease in children and adults (France: 2007)

44. Multi-locus sequence typing of MDR serotype 19A isolates (n = 97)

45. Minimum spanning tree of MDR and non-MDDR serotype 19A

46. Emergence of a multidrug-resistant clone (ST320) among invasive serotype 19A pneumococci in Spain Objectives: Multidrug-resistant Streptococcus pneumoniae isolates of serotype 19A have emerged all over the world in recent years. The aim of this study was to characterize highly penicillin-resistant pneumococcal strains of the 19A serotype, collected in Spain from 1997 to 2007 from patients with invasive disease. Methods: Antibiotic susceptibility was studied by microdilution. All penicillin-resistant pneumococci were typed by PFGE and selected strains were studied by multilocus sequence typing (MLST). The presence of genes related to the Tn916 family of transposons was investigated by PCR. Results: From a total of 1197 invasive pneumococcal isolates of serotype 19A received at the Spanish Reference Laboratory between 1997 and 2007, 51 (4.3%) strains showed high-level resistance to penicillin (MICs of 2�4 mg/L). These 51 isolates belonged to three multiresistant clones related to sequence type (ST)81 (n521), ST320 (n519) and ST276 (n511). All 51 serotype 19A pneumococci were tetracycline-resistant and had the tet(M) gene, and 41 strains were macrolide-resistant, harbouring the erm(B) gene. The presence of int and xis genes was detected in all strains associated with other genes of the Tn916 family. Conclusions: The rise in penicillin-resistant serotype 19A invasive pneumococci in Spain was associated with the emergence and clonal spread of two worldwide-disseminated multiresistant clones (ST276 and ST320). The Spain23F-1-19A (ST81) clone remained stable throughout the study period. Multidrug resistance was associated with transposons of the Tn916 family.Objectives: Multidrug-resistant Streptococcus pneumoniae isolates of serotype 19A have emerged all over the world in recent years. The aim of this study was to characterize highly penicillin-resistant pneumococcal strains of the 19A serotype, collected in Spain from 1997 to 2007 from patients with invasive disease. Methods: Antibiotic susceptibility was studied by microdilution. All penicillin-resistant pneumococci were typed by PFGE and selected strains were studied by multilocus sequence typing (MLST). The presence of genes related to the Tn916 family of transposons was investigated by PCR. Results: From a total of 1197 invasive pneumococcal isolates of serotype 19A received at the Spanish Reference Laboratory between 1997 and 2007, 51 (4.3%) strains showed high-level resistance to penicillin (MICs of 2�4 mg/L). These 51 isolates belonged to three multiresistant clones related to sequence type (ST)81 (n521), ST320 (n519) and ST276 (n511). All 51 serotype 19A pneumococci were tetracycline-resistant and had the tet(M) gene, and 41 strains were macrolide-resistant, harbouring the erm(B) gene. The presence of int and xis genes was detected in all strains associated with other genes of the Tn916 family. Conclusions: The rise in penicillin-resistant serotype 19A invasive pneumococci in Spain was associated with the emergence and clonal spread of two worldwide-disseminated multiresistant clones (ST276 and ST320). The Spain23F-1-19A (ST81) clone remained stable throughout the study period. Multidrug resistance was associated with transposons of the Tn916 family.

47. S. pneumoniae Serotype 19A in Children, South Korea From 1991 through 2006, 538 strains of S. pneumoniae were obtained from various clinical specimens Figure 2. Distribution of serotypes with regard to 7-valent conjugate vaccine (PCV7) among 107 pneumococci isolated from children <5 years of age with an invasive pneumococcal infection (IPD) during fi ve 3- or 4- year periods from 1991 through 2006, South Korea. *The observed increase in the proportion of 19A (p = 0.005)and decrease in the proportion of 19F (p = 0.008) among invasive isolates were statistically signifi cant.Figure 2. Distribution of serotypes with regard to 7-valent conjugate vaccine (PCV7) among 107 pneumococci isolated from children <5 years of age with an invasive pneumococcal infection (IPD) during fi ve 3- or 4- year periods from 1991 through 2006, South Korea. *The observed increase in the proportion of 19A (p = 0.005)and decrease in the proportion of 19F (p = 0.008) among invasive isolates were statistically signifi cant.

48. S. pneumoniae Serotype 19A in Children, South Korea However, there is no evidence of capsular switching as a contributing factor to the increasen in serotype 19A in our study. According to eBURST analysis, 1 major CC (CC271) accounted for most of the isolates (n = 116, 92% of serotypes 19A and 19F). CC271 comprised 16 STs, where ST271 was predicted as the founder, and ST320 was the predominant allelic profi le. The 5 ST lineages that were unrelated to CC271 were nonlinked singlets (ST1203, ST1374, ST2394, ST2395, and ST2399) (Figure 3). ST320 was the only ST found among serotypes 19A and 19F; ST320 was the most common ST (n = 52, 90% of total 19A isolates) among serotype 19A. ST320 was observed in only 9% (n = 6) of serotype 19F isolates. The genetic structure of serotype 19A comprised primarily ST1374 during periods 1 and 2 (1991�1997), but ST1374 isolates were not recovered after 2001. In contrast, ST320 was the most common sequence type from 1998, and all 19A isolates from 2002�2006 were of ST320. The numbers of 19A isolates increased consistently from 1996 through 2003, which suggests that single clonal expansion of ST320 was responsible for the increase of serotype 19A isolates during this period (Figure 4). Unlike serotype 19A, serotype 19F comprises diverse STs grouped within CC271 (16 STs) and 5 different singlets. All STs, except ST1203, were associated with multidrugresistant mef/erm-containing isolates. The distributions of predominant STs among serotype 19F isolates varied during each study period (Figure 4). For example, ST2395 predominated in period 1 (1991�1994), but ST1464 (an SLV of ST271) predominated in periods 4 and 5 (2001�2006).However, there is no evidence of capsular switching as a contributing factor to the increasen in serotype 19A in our study. According to eBURST analysis, 1 major CC (CC271) accounted for most of the isolates (n = 116, 92% of serotypes 19A and 19F). CC271 comprised 16 STs, where ST271 was predicted as the founder, and ST320 was the predominant allelic profi le. The 5 ST lineages that were unrelated to CC271 were nonlinked singlets (ST1203, ST1374, ST2394, ST2395, and ST2399) (Figure 3). ST320 was the only ST found among serotypes 19A and 19F; ST320 was the most common ST (n = 52, 90% of total 19A isolates) among serotype 19A. ST320 was observed in only 9% (n = 6) of serotype 19F isolates. The genetic structure of serotype 19A comprised primarily ST1374 during periods 1 and 2 (1991�1997), but ST1374 isolates were not recovered after 2001. In contrast, ST320 was the most common sequence type from 1998, and all 19A isolates from 2002�2006 were of ST320. The numbers of 19A isolates increased consistently from 1996 through 2003, which suggests that single clonal expansion of ST320 was responsible for the increase of serotype 19A isolates during this period (Figure 4). Unlike serotype 19A, serotype 19F comprises diverse STs grouped within CC271 (16 STs) and 5 different singlets. All STs, except ST1203, were associated with multidrugresistant mef/erm-containing isolates. The distributions of predominant STs among serotype 19F isolates varied during each study period (Figure 4). For example, ST2395 predominated in period 1 (1991�1994), but ST1464 (an SLV of ST271) predominated in periods 4 and 5 (2001�2006).

49. Novel ?-lactams Ceftaroline Ceftobiprole Oral penem Faropenem

50. Spectrum of Activity

51. Clinical Utility

52. Novel Glycopeptides Dalbavancin Once weekly IV dosing Oritavancin Telavancin Versus vancomycin: Additional mechanisms of action Renal and hepatic excretion No known nephrotoxicity or dose adjustments

53. Spectrum of Activity

54. Clinical Utility

55. Novel Fluoroquinolone Garenoxacin (PO/IV) Bactericidal MIC90 = 0.06 ?g/mL for penicillin-, macrolide-, and ? 6 drug- resistant S. pneumoniae MIC90 = 1 ?g/mL for CIP- and LEV- resistant S. pneumoniae More potent than MOX

56. 56 Polymyxins a group of polypeptide antibiotics that consists of 5 chemically different compounds (polymyxins A-E), were discovered in 1947 Only polymyxin B and polymyxin E (colistin) have been used in clinical practice the primary route of excretion is renal

57. 57 Colistin The target of antimicrobial activity of colistin is the bacterial cell membrane Colistin has also potent anti-endotoxin activity The endotoxin of G-N bacteria is the lipid A portion of LPS molecules, and colistin binds and neutralizes LPS

58. 58 Colistin Active: Acinetobacter species, Pseudomonas aeruginosa, Enterobacteriaciae

59. 59 Colistin 160 mg (2 million IU) ever 8 h 240 mg (3 million IU) every 8 h for life-threatening infections

60. 60 Colistin Dose adjustment for renal failure Adverse effects: nephrotoxicity (acute tubular necrosis) neurotoxicity (dizziness, weakness, facial paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, which can lead to respiratory failure or apnea)

61. 61 MIC distribution MIC break point to identify bacteria susceptible to colistimethate sodium is =4 mg/L. MIC is >8 mg/L should be considered resistant

62. 62 Use of Parenteral Colistin for the Treatment of Serious Infection Due to Antimicrobial-Resistant P. aeruginosa Colistin was used as salvage therapy for 23 critically ill patients with multidrug-resistant P. aeruginosa infection Peumonia (n = 18) Intra-abdominal infection (n = 5). Colistin was administered for a median of 17 days (range, 7-36 days). A favorable clinical response was observed in 14 patients (61%); only 3 patients experienced relapse

63. Safety and effectiveness of colistin compared with tobramycin for MDR A. baumannii infections A retrospective cohort study of patients treated with colistin or tobramycin for A. baumannii infections in ICUs 240 mg (3 MUs) 8 hourly and adjusted for renal failure 32 patients, with similar admission APACHE scores and serum creatinine, were treated with each antimicrobial 63

64. Safety and effectiveness of colistin compared with tobramycin for MDR A. baumannii infections There were no significant differences between the colistin and tobramycin groups in ICU mortality (p = 0.54) Nephrotoxicity (p = 0.67) Change in creatinine from baseline to highest subsequent value (p = 0.11) Time to microbiological clearance (p = 0.75) 64

65. Ceftobiprole (Zeftera�) June 30, 2008 -- Health Canada has authorised the marketing of ceftobiprole medocaril for injection (Zeftera and marketed by Janssen Ortho) for the treatment of complicated skin and soft tissue infections including diabetic foot infections

66. Ceftobiprole in vitro Activity vs Staphylococci PCMC-approved 8/7/07 *US isolates from 2005-2006 *Tested by broth microdilution *Poster includes comparative data for imipenem, linezolid and vancomycin *Methicillin susceptible isolates generally have lower MIC. Reference Sahm DF et al . Poster presented at the 46th Annual International Conference on Antimicrobial Agents and Chemotherapy; Sept. 27-30, 2006; San Francisco, CA. Poster E-0113. PCMC-approved 8/7/07 *US isolates from 2005-2006 *Tested by broth microdilution *Poster includes comparative data for imipenem, linezolid and vancomycin *Methicillin susceptible isolates generally have lower MIC. Reference Sahm DF et al . Poster presented at the 46th Annual International Conference on Antimicrobial Agents and Chemotherapy; Sept. 27-30, 2006; San Francisco, CA. Poster E-0113.

67. Ceftobiprole in vitro Activity vsStreptococci and Enterococci Organism Total MIC Range (�g/ml) MIC90 (�g/ml) E. faecalis1,2 76 0.12 - >32 4 Vanco-R E. faecalis3 17 <0.015 � 4 1 E. faecium Amp-S1 16 1 - 8 8 Amp-R 1,2 71 0.25 - >32 >32 S. pneumoniae4 299 0.008- 4 Pen-S 0.008 - 0.03 0.016 Pen-I 0.008 � 1 0.5 Pen-R 0.016 - 4 1 PCMC approved 8/20/07 The antibacterial spectrum of ceftobiprole was evaluated against significant Gram-positive and Gram-negative pathogens in a study by Hebeisen et al. Ceftobiprole showed high antibacterial activity in vitro against Gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium.1 Ceftobiprole was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC(90) = 2 �g/ml). The in vivo findings in Hebeisen�s study were in accordance with the in vitro susceptibilities of the pathogens. In another study, ceftobiprole was tested against a large number (n = 2263) of recent isolates, including 1097 Gram-positive strains, from various international surveillance programs.2 Susceptibility to (S) and activity of ceftobiprole (mg/L) against some pathogens, based on proposed breakpoints (MIC[50]/MIC[90]/% S), were as follows: MSSA (0.5/0.5/100%), MRSA (1/2/100%), Streptococcus pneumoniae ( = 0.015/0.25/100%), viridans group streptococci (0.03/0.5/99%), beta-haemolytic streptococci = 0.015/ = 0.015/100%), Enterococcus faecalis (0.5/16/90%), and Enterococcus faecium (>32/>32/22%). All S. pneumoniae were inhibited by ceftobiprole at = 1 mg/L. Ceftobiprole demonstrates excellent activity against many tested pathogens displaying various resistance phenotypes, and should be particularly valuable in the treatment of MRSA and drug-resistant streptococci. References Hebeisen P et al. Antimicrob Agents Chemother 2001;45:825-836. Jones RN et al. J Antimicrob Chemother. 2002;50:915-932. Kosowska et al. Antimicrob Agents Chemother 2005;49:1932-42.PCMC approved 8/20/07 The antibacterial spectrum of ceftobiprole was evaluated against significant Gram-positive and Gram-negative pathogens in a study by Hebeisen et al. Ceftobiprole showed high antibacterial activity in vitro against Gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium.1 Ceftobiprole was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC(90) = 2 �g/ml). The in vivo findings in Hebeisen�s study were in accordance with the in vitro susceptibilities of the pathogens. In another study, ceftobiprole was tested against a large number (n = 2263) of recent isolates, including 1097 Gram-positive strains, from various international surveillance programs.2 Susceptibility to (S) and activity of ceftobiprole (mg/L) against some pathogens, based on proposed breakpoints (MIC[50]/MIC[90]/% S), were as follows: MSSA (0.5/0.5/100%), MRSA (1/2/100%), Streptococcus pneumoniae ( = 0.015/0.25/100%), viridans group streptococci (0.03/0.5/99%), beta-haemolytic streptococci = 0.015/ = 0.015/100%), Enterococcus faecalis (0.5/16/90%), and Enterococcus faecium (>32/>32/22%). All S. pneumoniae were inhibited by ceftobiprole at = 1 mg/L. Ceftobiprole demonstrates excellent activity against many tested pathogens displaying various resistance phenotypes, and should be particularly valuable in the treatment of MRSA and drug-resistant streptococci. References Hebeisen P et al. Antimicrob Agents Chemother 2001;45:825-836. Jones RN et al. J Antimicrob Chemother. 2002;50:915-932. Kosowska et al. Antimicrob Agents Chemother 2005;49:1932-42.

68. Ceftobiprole in vitro Activity vs Gram-Negatives PCMC Approved 7/2/07 -Most data from the ICAAC 2006 abstract -E. Coli MIC90 has remained the same -High MICs seen in ESBL+ and derepressed ampC -Vs. P. aeruginosa, similar to cefepime, a little less than ceftaz References: 1. Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA. Hebeisen P et al. Antimicrob Agents Chemother 2001;45:825-836. 3. Issa NC et al. Diagn Micro Infect Dis 2004. 4. Jones R et al. J Antimicrob Chemother 2002; 50:915-932. PCMC Approved 7/2/07 -Most data from the ICAAC 2006 abstract -E. Coli MIC90 has remained the same -High MICs seen in ESBL+ and derepressed ampC -Vs. P. aeruginosa, similar to cefepime, a little less than ceftaz References: 1. Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA. Hebeisen P et al. Antimicrob Agents Chemother 2001;45:825-836. 3. Issa NC et al. Diagn Micro Infect Dis 2004. 4. Jones R et al. J Antimicrob Chemother 2002; 50:915-932.

69. Comparative in vitro activity vs P. aeruginosa (n=403) PCMC Approved 7/2/07 North American isolates. Note that against P. aeruginosa, ceftobiprole�s MIC90 was equal to cefepime and lower than ceftazadime and piperacillin/tazobactam. Reference: Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA. PCMC Approved 7/2/07 North American isolates. Note that against P. aeruginosa, ceftobiprole�s MIC90 was equal to cefepime and lower than ceftazadime and piperacillin/tazobactam. Reference: Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA.

71. Daptomycin (Cubicin�) On September 24, 2007, Health Canada approved daptomycin intravenous infusion (Cubicin, Cubist Pharmaceuticals, Inc, and marketed by Oryx Pharmaceuticals, Inc) for the treatment of complicated skin and skin structure infections caused by certain gram-positive infections and for bloodstream infections, including right-sided infective endocarditis, caused by S. aureus.

72. Daptomycin (Cubicin�) New drug class (lipopeptide) Rapidly bactericidal New mechanism of action: acts by binding to cell membrane and disrupting the cell membrane potential No cross resistance Dose: 4-6 mg/kg once daily

73. Daptomycin�s Mechanism of Action Irreversibly binds to cell membrane of Gram-positive bacteria Calcium-dependent membrane insertion of molecule Rapidly depolarizes the cell membrane Efflux of potassium Destroys ion-concentrationgradient Purpose of slide: To discuss the unique mechanism of action of daptomycin. In viable bacteria, the polarized state of the cytoplasmic membrane results from the maintenance of ion and proton gradients across the bilayer of the plasma membrane. One of the most prominent gradients involves potassium (K+), with high intracellular and low extracellular concentrations. Mechanism of action (MOA) of daptomycin: Step 1: Daptomycin inserts into the cytoplasmic membrane of bacteria. This step is calcium-dependent, as indicated by whole cell and in vitro studies. Step 2: An ion-conduction structure (eg, a channel, pore, or a less structured aggregate) is formed by the oligomerization of inserted drug. This step is hypothetical. Step 3: The ion-conduction structure disrupts the functional integrity of the membrane, resulting in the efflux of intracellular potassium ions. No lag time between membrane depolarization and bacterial killing was found, which strongly suggests that depolarization is the primary MOA. Results of in vitro studies using fluorometry and flow cytometry have shown that the rapid depolarization of the bacterial cell membrane by daptomycin correlates with bactericidal activity. Purpose of slide: To discuss the unique mechanism of action of daptomycin. In viable bacteria, the polarized state of the cytoplasmic membrane results from the maintenance of ion and proton gradients across the bilayer of the plasma membrane. One of the most prominent gradients involves potassium (K+), with high intracellular and low extracellular concentrations. Mechanism of action (MOA) of daptomycin: Step 1: Daptomycin inserts into the cytoplasmic membrane of bacteria. This step is calcium-dependent, as indicated by whole cell and in vitro studies. Step 2: An ion-conduction structure (eg, a channel, pore, or a less structured aggregate) is formed by the oligomerization of inserted drug. This step is hypothetical. Step 3: The ion-conduction structure disrupts the functional integrity of the membrane, resulting in the efflux of intracellular potassium ions. No lag time between membrane depolarization and bacterial killing was found, which strongly suggests that depolarization is the primary MOA. Results of in vitro studies using fluorometry and flow cytometry have shown that the rapid depolarization of the bacterial cell membrane by daptomycin correlates with bactericidal activity.

74. Daptomycin In Vitro* Antimicrobial Activity Against Other Gram-positive Organisms Purpose of slide: To present in vitro activity of daptomycin against additional Gram-positive bacteria in which clinical efficacy has not been established. The CUBICIN product monograph states that daptomycin has activity in vitro against these microorganisms. However, because treatment of clinical infections due to these pathogens has not been established in adequate and well-controlled clinical trials, the monograph states that the �in vitro data are available, but their clinical significance is unknown.� Daptomycin is also active in vitro against other clinically relevant Gram-positive bacteria�only organisms relevant to complicated skin and skin-structure infections are listed in the product monograph. Greater than 90% of the microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. Clinical significance of these data is unknown. Purpose of slide: To present in vitro activity of daptomycin against additional Gram-positive bacteria in which clinical efficacy has not been established. The CUBICIN product monograph states that daptomycin has activity in vitro against these microorganisms. However, because treatment of clinical infections due to these pathogens has not been established in adequate and well-controlled clinical trials, the monograph states that the �in vitro data are available, but their clinical significance is unknown.� Daptomycin is also active in vitro against other clinically relevant Gram-positive bacteria�only organisms relevant to complicated skin and skin-structure infections are listed in the product monograph. Greater than 90% of the microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. Clinical significance of these data is unknown.

75. Daptomycin Favorable initial trials in skin and soft tissue infections with qd dosing; significantly less need for step-down oral therapy (4 mg/kg) Less effective than ceftriaxone in community-acquired pneumonia (CAP) Bacteremia and endocarditis studies with larger single daily dose (6 mg/kg)