Table of Contents

ABOUT DATAMONITOR HEALTHCARE

2

About the Infectious Diseases and Respiratory (ID&R) pharmaceutical analysis team

2

CHAPTER 1 EXECUTIVE SUMMARY

3

Scope of the analysis

3

Datamonitor insight into the nosocomial infections market

4

CHAPTER 2 DISEASE BACKGROUND

8

Disease definition

8

Epidemiology

9

Modes of acquisition

13

Surgical site infections

16

Causative pathogens

18

General incidence

19

Pathogenesis

23

Bloodstream infections

24

Causative pathogens

25

General incidence

28

Intravascular catheter-related infections account for the majority of BSIs

30

Pathogenesis

31

Urinary tract infections

31

Causative pathogens

32

General Incidence

32

The majority of hospital acquired UTIs are associated with contaminated urinary catheters

33

Pathogenesis

34

Pneumonia

35

Causative pathogens

35

General incidence

36

Mechanical ventilation increases the risk of HAP

38

Pathogenesis

39

CHAPTER 3 ETIOLOGIC AGENTS

40

Bacterial pathogens

40

Bacterial resistance

45

Gram-positive bacteria

50

Staphylococcus aureus

50

Enterococci

56

Clostridium difficile

62

Gram-negative bacteria

66

Escherichia coli

66

Klebsiella pneumoniae

70

Pseudomonas aeruginosa

72

Acinetobacter baumannii

75

Viral pathogens

79

Fungal pathogens

80

CHAPTER 4 TREATMENT OPTIONS

82

Hospital antibacterial market

82

The overall value in terms of patient numbers

82

Size of the market in terms of sales

83

Classes of antibacterials

86

Cephalosporins

87

Penicillins

88

Fluoroquinolones

89

Carbapenems

89

Macrolides and ketolides

90

Glycopeptides

90

Empiric management of nosocomial infections

91

Cost of therapy by site of infection

91

Surgical site infections

94

Antibiotic prophylaxis prior to surgical operations

94

Post-operative treatment

95

Bloodstream infections

97

Urinary tract infections

99

Hospital acquired pneumonia

101

Pathogen specific therapy

107

Gram-positive pathogens

108

Staphylococcus aureus (including MRSA)

108

Enterococci

109

Clostridium difficile

111

Gram-negative pathogens

113

Klebsiella pneumoniae

113

Pseudomonas aeruginosa

114

Acinetobacter baumannii

115

Factors influencing physician decision-making

116

CHAPTER 5 FUTURE TRENDS AND IMPROVING TREATMENT OUTCOMES

122

New product development

122

Effective gram-negative drugs is the greatest unmet need

124

The financial burden of multidrug-resistant gram-negative organisms

125

Majority of newly introduced compounds and compounds in late-stage development target gram-positive pathogens

125

Tigecycline

128

Daptomycin

129

Dalbavancin

130

Telavancin

131

Doripenem

132

Ceftobiprole

132

Preventative strategies to help combat spread of infections in hospitals

133

Surveillance

137

Combating bacterial resistance

139

Financial burden of nosocomial infections

141

BIBLIOGRAPHY

144

Books

156

Press releases

156

Websites

156

Datamonitor reports

157

Contributing experts

158

Disclaimer

159

List of Tables

Table 1: Most common pathogens isolated from hospital acquired bloodstream infections, US

26

Table 2: Incidence rates and distribution of pathogens most commonly isolated from monomicrobial bloodstream infections and associated crude mortality rates for all patients, patients in intensive care units (ICUs) and patients in non-ICU wards

27

Table 3: Staphylococcus aureus-related discharge diagnoses in the US by patient age and infection site, 1999-2000

52

Table 4: The number of invasive S. aureus (SAU) isolates and the proportion resistant to methicillin in the five major EU markets, 2005

54

Table 5: Prolonged stay and mortality rate from Acinetobacter infections in the US

78

Table 6: Overall cost of therapy in the US by site of infection

93

Table 7: Overview of recently launched antibacterials and antibacterials in late stage development, 2007

126

List of Figures

Figure 1: The four major types of nosocomial infections

11

Figure 2: Percentage of four main types of nosocomial infections of all nosocomial infections

12

Figure 3: Endogenous and exogenous routes of acquisition

15

Figure 4: Infections associated with invasive devices and procedures

16

Figure 5: Types of Surgical Site Infections (SSI)

17

Figure 6: Diagrammatic representation of types of SSI

18

Figure 7: Incidence density (/1000 patient days) of registered SSI by surgical procedure (overall) and 95% confidence intervals

20

Figure 8: Incidence density (overall) mean of registered surgical site infection by NNIS risk index and by surgical procedure

21

Figure 9: Cumulative incidence of SSI in hospitals in England and Wales, 1997-2005

22

Figure 10: Adjusted SSI rates,1997-2005

23

Figure 11: Definition of Bloodstream infection (BSI)

25

Figure 12: Incidence rates and distribution of pathogens most commonly isolated from monomicrobial bloodstream infections and associated crude mortality rates for all patients, patients in intensive care units (ICUs) and patients in non-ICU wards

28

Figure 13: Estimated number of deaths caused by nosocomial BSIs each year in the US, 2001

29

Figure 14: Mean rates of BSI across ICUs in NNIS hospitals, 2004

30

Figure 15: The urinary tract

31

Figure 16: Mean rate of UTI per 1000 urinary catheter days in NNIS hospitals, 2004

33

Figure 17: Classification of Urinary Tract Infections (UTI)

34

Figure 18: Classification of Hospital-acquired pneumonia

35

Figure 19: Mean rate of VAP per 1000 ventilator-days in NNIS hospitals, 2004

37

Figure 20: Endotracheal intubation

38

Figure 21: Distribution of outbreaks of hospital infections by pathogen, 1997-2002

40

Figure 22: Gram-negative and gram-positive bacteria

42

Figure 23: Distribution of type of bacteria in hospital infections

44

Figure 24: Percentages of gram-negative and gram-positive organisms by site of infection from 1986-2003

45

Figure 25: Selected antimicrobial-resistant pathogens associated with nosocomial infections in ICU hospitals, comparison of resistance rates from January-December 2003 with rates for 1998-2002

48

Figure 26: Methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) among ICU patients, 1995-2004

53

Figure 27: Staphylococcus aureus: proportion of invasive isolates resistant to oxacillin (MRSA) in Europe, 2005

55

Figure 28: Staphylococcus aureus: trends of methicillin-resistance in the 5 major European markets, 1999-2005

56

Figure 29: Vancomycin-resistant Enterococci among ICU patients in the US, 1995-2004

59

Figure 30: Proportion of invasive Enterococcus faecalis isolates resistant to aminoglycosides in Europe, 2005

60

Figure 31: Proportion of invasive Enterococcus faecium isolates resistant to vancomycin in Europe, 2005

61

Figure 32: National estimates of US short-stay hospital discharges with Clostridium difficile listed as primary or as any diagnosis, 1996-2003

63

Figure 33: C. difficile reports from patients aged 65 years and over, received under the mandatory reporting scheme in England during 2004 and 2005

64

Figure 34: US states with the NAP1 strain C. difficile confirmed by the CDC as of September 2006

66

Figure 35: Escherichia coli: trends of amino-penicillin resistance in the five major Euripean markets 1999-2005

69

Figure 36: Escherichia coli: trends of fluoroquinolone resistance in the five major Euripean markets 1999-2005

69

Figure 37: Third generation cephalosporin-resistant Klebsiella pneumoniae among ICU patients in NNIS participating hospitals in the US,1995-2004

71

Figure 38: Proportion of invasive Klebsiella pneumoniae isolates resistant to 3rd generation cephalosporins, carbapenems, fluoroquinolones and aminoglycosides in Europe, 2005

72

Figure 39: Fluoroquinolone-resistant Pseudomonas aeruginosa among ICU patients in the US, 1995-2004

74

Figure 40: Proportion of invasive Pseudomonas aeruginosa isolates resistant to carbapenems, ceftazidime, fluoroquinolones and aminoglycosides in Europe, 2005

75

Figure 41: Total number of patients developing nosocomial infections in an average year in the US

83

Figure 42: Antibacterial sales across the seven major markets by sales and volume, 2001-05

84

Figure 43: Sales and volume use in the hospital versus the community market, excluding Japan, 2001-05

85

Figure 44: Sales of hospital antibacterials in the six major markets, excluding Japan, 2005

86

Figure 45: Percentage share of overall hospital antibacterial sales by class in the six major markets, excluding Japan, 2005

86

Figure 46: Cost of antibiotic therapy per patient by site of infection (US average wholesale prices)

92

Figure 47: Share of each type of infection of overall expenditure on antibacterials to treat nosocomial infections, US

93

Figure 48: Summary of management strategies for patients with suspected HAP, VAP and HCAP

102

Figure 49: Empiric management of HAP, HCAP, VAP

104

Figure 50: Initial antibiotic therapy for patients with no known risk factors for multidrug resistant pathogens, early onset and any disease severity

105

Figure 51: Initial therapy for hospital-acquired pneumonia in patients with late-onset disease or risk factors for multidrug resistant pathogens and all disease severity

105

Figure 52: Initial intravenous adult doses of antibiotics for empiric therapy of HAP, HCAP and VAP in patients with late-onset disease or risk factors for multidrug-resistant pathogens

106

Figure 53: Treatment options for CDAD

113

Figure 54: Summary of the factors influencing prescription choice from KOL research

117

Figure 55: Patient stratification by risk factors

135

Figure 56: Prevention strategies by risk factor

135

Figure 57: Antibiotic resistance: a vicious cycle

139

Figure 58: A schematic representation of the costs associated with HAI

142