G7 Lecture, Berlin, 300415

Infectious Diseases and Antimicrobial Resistance

Professor Dr Seyed E Hasnain(www.seyedehasnain.org)

Indian Institute of Technology, Delhi;and

Dr Reddy’s Institute of Life Sciences, Hyderabad  

Human Infectious Diseases

DiseasesViral FungalBacterial

Antimicrobial Resistance

Way to go

Common viral diseases SOME NEWLY EMERGING/EMERGED VIRUSES

Chickenpox 2009 H1N1 influenza virus

Flu (influenza) Ebola virus

Human immunodeficiency virus (HIV/AIDS)

H5N1 avian influenza virus

Human papilloma virus (HPV) Marburg virus

Herpes Nipah virus

Infectious mononucleosis SARS virus

Mumps, measles and rubella West Nile virus

Shingles MERS

Chickenpox Chickungunya

Viral gastroenteritis (stomach flu) JEV

Viral hepatitis Dengue

Viral meningitis

Viral pneumonia

Viral diseases in human

Global Summary of HIV‐AIDS epidemic: 2013

AIDS death in 2013

Total = 1.5 million Adults = 1.3 million Children (>15) = 190 000 

No. of People newly infected with HIV  in 2013 

Total = 2.1 million Adults = 1.9 million Children (>15) = 240000 

No. of people living with HIV in 2013 

Total = 35 million Adults = 31.8 million Women = 16.0 million 

• AIDS Therapy : Highly Active Anti‐Retroviral Therapy (HAART)

Global Burden of Dengue

Dengue Infection Annualy

• 390 million dengue infection

• 96 million manifested clinically

Global region affected

• Endemic in more than 100 countries

• Mostly affected Asia, America, Western Pacific and South East Asia.

Cases Reported

• 1.2 million in2008 and over 3million in 2013

• AcrossAmerica, SouthEast Asia andWesternPacific.

Four distinct, but closely related, serotypes of Dengue virus (DEN‐1,‐2, ‐3 and ‐4)

Global Burden of Japanese EncephalitisFlavivirus related to dengue, yellow fever and West Nile 

viruses and spread by mosquitoes

68,000 clinical cases of JE in many countries of Asia

Endemic JE transmission in 24 countries in WHO South East Asia and Western Pacific region

Case fatality rate is 30% among infected with JE

No cure for JE, vaccination is available

Avian influenza A(H7N9) virus

•A subtype of influenza viruses; Initially detected only in birds •First human infection detected in March 2013 in China.•Cause‐ Recent exposure to live poultry or especially markets where live birds have been sold.•Symptoms‐ severe pneumonia, fever, cough and shortness of breath. •Treatment‐Influenza antiviral medicines called neuraminidase inhibitors (e.g. oseltamivir, zanamivir) are effective against H7N9 

The 2009 H1N1 virus is a hybrid of swine, avian and human strains 

Caused world wide pandemic in 2009

Now a human seasonal flu that also circulates in pig

Best way to prevent H1N1 is to get seasonal flu vaccine

H1N1 resurgence in IndiaConfirmed cases: 33,761Deaths: 2,035 (as of March 30, 2015)

Viral Re-assortment

Reassortment in pigs

Reassortment in humans

Pandemic Influenza Virus

H1N1 (originally referred to as Swine Flu)

Ebola Virus Disease in Africa 1976 ‐ 2014

http://www.cdc.gov/vhf/ebola/outbreaks

Treatment of EVD

Rehydration with oral or intravenous fluid, treatment of specific symptoms improves survivalYet no proven treatment for EVDNo licensed vaccine  is available

Ebola Virus family

Prevent Catching or Passing on GermsHand Washing•Simplest, easiest, and most effective ways to prevent germs•Amazingly,  one of the most overlooked•Scrub your hands vigorously for at least 15 seconds with soap and water•Wash away cold and flu viruses and staph and strep bacteria as well as many other disease‐causing microbes

It is especially important to wash handsBefore preparing or eating foodAfter coughing or sneezingAfter using the bathroomAfter changing a diaper

Cough etiquette

• Respiratory etiquette– Cover nose / mouth when coughing or sneezing

Voluntary Isolation, Voluntary Quarantine

• Separation and restricted movement of ill persons with contagious disease (often in a hospital setting and Primarily individual level)– Isolate severe and mild cases – Location of isolation (home, hospital) depends on several factors 

(severity of illness, the number of affected persons, the domestic setting) 

– Do not wait for lab confirmation– Plan for large number of severe cases– Provide medical and social care

Vaccine Benefits

Disease Baseline 20th century pre-vaccine annual cases

2009cases

% decrease

Measles 503,282 71 99.9%

Diphtheria 175,885 0 100%

Mumps 152,209 1,991 98.7%

Pertusis 147,271 13,214 91%

Rubella 47,745 3 99.9%

Polio 16,316 0 100%

Tetanus 1,314 18 98.6%

Anti‐Viral drugs

• Purine or Pyrimidine analogs.• Many are Prodrugs: phosphorylated by viral or cellular enzymes 

for activation.• Anti‐virals inhibit active replication so the viral growth resumes 

after drug removal.• Current anti‐viral agents do not eliminate non‐replicating or latent 

virus• Some examples of antiviral drugs: 

Acyclovir/Valacyclovir; Famciclovir/Penciclovir; Ganciclovir/ Cidofovir; Foscarnet; Trifluridine/Idoxuridine/Vidarabine; guanine nucleoside analogsInterferons; Lamivudine – HBV; Entecavir – HBV – lamivudineresistance strains

Virus Diseases Drug(s) of choice

Alternative drugs

FLU A Influenza Amantadine Rimantadine

RSV Pneumonia,bronchiolitis

Ribavirin(aerosol)

HSV Genital herpes Acyclovir Foscarnet

KeratitisConjunctivitis Trifluridine Idoxuridine

Vidarabine

Encephalitis Acyclovir

Neonatal HSV infection Acyclovir Vidarabine

Herpes infections in immuno-compromised host

Acyclovir Foscarnet

Fungal InfectionsTypes of Fungal Infections

Superficial infections  Systemic infections 

Subcutaneous infections (Skin or mucosa)

e.g.• Ring worm• Athelet’s foots• Joke itch• Yeast infections 

True pathogens Opportunists

(Healthy and immunocompromise) (Immunocompromise)

•Each year, around 1.5 million deaths•Cost $12 billion to treat fungal disease worldwide

Candidiasis

• Infection by Candida species. 

• Fourth most common cause of hospital‐derived bloodstream    infections in the developed world.

• The estimated annual global incidence of candidiasis, caused by Candida albicans, is 400,000 cases per year

• Mortality rates are very high ranging between 46 and 75%.

Candida albicans

• Caused by Pneumocystis jiroveci pneumonia.

• Pneumonia‐like symptoms in immunocompromised individuals.

• Number one most serious infection in people with advanced HIV.

• 400,000 cases occur every year worldwide. 

• Mortality rates varying between 20 and 80%.

Pneumocystis

Pneumocystis jiroveci

Cryptococcosis

• Caused by Cryptococcus neoformans.

• One million cases of Cryptococcus infections per year worldwide.

• The majority of cases present with meningoencephalitis (meningitis).

Cryptococcus neoformans

• Caused by Aspergillus spp.

• Mainly arise in the lungs, e.g. chronic obstructiveaspergillosis ( COPD ).

• Can be life‐threatening to individuals with underlyingconditions like tuberculosis, COPD and cystic fibrosis.

• Greater than 200,000 cases per year worldwide

• Overall 50% mortality rate.

Aspergillosis

Aspergillus fumigatus

Azole resistance frequency in A. fumigatus by patient 1997–2009.

Ahmed Bueid et al. J. Antimicrob. Chemother. 2010;65:2116-2118

Fungal Threats: Increasing Antifungal Drug Resistance

Bacterial Diseases

• Staphylococcal Infections– These bacteria are normally on our skin at all times and usually do not cause problems

– When a cut or break in the skin occurs, the bacteria may enter and cause an infection

– Acne, boils, styes (eyelid infections), wounds are common staph infections

http://improvisedhomeremedies.com/abscess‐treatment‐learn‐symptomscauses‐

Bacterial Diseases

• Streptococcal Infections– Causes strep throat and scarlet fever

• Pneumonia– One form is caused by a bacterial infection with the following symptoms: chronic cough, chest pain, chills, high fever, fluid accumulation and eventual respiratory failure

http://www.breathingmatters.co.uk/2013/11/world‐i d 12 11 13/

In sub‐Saharan Africa, TB remains the number one cause of death in HIV/Aids patients, and those infected with HIV show a much greater incidence of TB than those who are HIV‐negative. WHO statistics do show, however, that HIV‐positive adults receiving ARV treatment have substantially lower rates of TB infection than those who are not receiving treatment. This may not be the case following development of anti‐retroviral drug resistance!

http://myfundi.co.za/e/Global_distribution_of_diseases:_TB,_HIV/Aids,_cholera_and

Global distribution of tuberculosis (TB)

TB Completely Curable, but Long Drug Regime: No new TB drug  since 1963

• Compared to other antibiotic treatments, TB drug regime is very long

• Standard TB treatment with 4 drugs takes 6‐9 months!

• MDR treatment: 4‐6 drugs, duration 2 years!

NON‐COMPLIANCE BY PATIENTS AS THE SYMPTOMS IMPROVE OR DISAPPEAR

Treatment success 86% globally

Global WHO Regions

8584

86 86

83

80

75

80

85

90

2003 2004 2005 2006 2007 2008

Trea

tmen

t suc

cess

rat

e (%

)…but Europe lagging behind

65

70

75

80

85

90

95

2003 2004 2005 2006 2007 2008

W. Pacific

SE Asia

EMR

Africa

93

88

80

Americas77

66Europe

Epidemiology I

EPTB prevalence in HIV uninfected individuals

Ref: Sharma, Indian J Med Res 2004

EPTBprevalence15 20%

Epidemiology II

EPTB prevalence in HIV infected individuals

Ref: Sharma, Indian J Med Res 2004

EPTBprevalence70%

Extrapulmonary TB (EPTB)Occurrence of TB at body sites other than lungs

•No rapid Diagnosis•Prolonged and extended treatment•TB‐IRIS complications

Synergism with other infections or immuno‐suppressed conditions: The Impending ‘Triple’

trouble: TB‐HIV‐Diabetes

HIV impacts TB in the following ways

• Reactivates latent TB infection• Increases rate of TB recurrence• Development of TB related IRIS 

(Immune Reconstitution Inflammatory Syndrome) in HIV patients

Diabetes and TB: Chicken or egg problem

Mycobacterium tuberculosis: an extra‐ordinarily intelligent bacterium

MSCs: A perfect niche for M.tb invasionand proliferation

MSCs: A new ‘tool’ for M.tb?

Niche

Dissemination Pre‐dominant Th2 response

Sensor for host immune system competence

Vertical Transmission?EPTB?Drug resistance?

Sakshi et al 2015

Gene Cooption in M.tb• Sequence variation was observed between virulence factors of M.tb

and their homologs in MIP.• These changes were reflected in altered globularity and

hydrophobicity.• Increased hydrophobicity of MCE family proteins.• Lateral acquisition of few Virulence Factors proteins of H37Rv.• Gene duplication with increased antigenicity in PE_PGRS family.

Tundup and Hasnain,(2015)

B cells

T cells

Is the PE25/PPE41 complex involved in quorum sensing of the immune system? A schematic representation of the likely role of the secreted PE25/PPE41 complex on the host immune system. The secretion of the PPE41 or PE25/PPE41 complex is mediated by esx5 locus. The PPE41 or the PE25/PPE41 protein complex is secreted outside by the bacterium, which could be recognized by host immune system. But the proteins may help the bacterium by sensing the strength of the host immune system. Weak immune system may induce these proteins to regulate their own expression or signal for multiplication of the bacteria to spread outside the cells by inducing direct lysis of macrophages via necrosis, which in turn helps the pathogen to multiply and spread infection in the surrounding cells resulting into disease progression. 

PE‐PPE  Proteins: Role in ‘Immune Quorum sensing’

Cytokine secretion, expression of co-

stimulatory molecules and receptors

Infected macrophage

High bacterial load, low iron (nutrients depletion)

Expression, membrane localization and proteolysis of PPE37

Progress of infection

NFB/ p38‐MAPK/ caspase‐3 activation

NFB/ Akt/IKK

IL‐10 Recruitment of T-reg cells anddevelopment of tolerence againstM.tb antigensIL‐10

TNF‐

An environment ofIL-10high, TNF-low and IL-10low maintains the semi immature state of dendritic cellsFe3+

M.tb apoptosis

Circulating monocytes

Release of M.tb cellsin apoptotic vesicles

Semi-immature dendritic cell

differentiation

Antibiotic Resistance

http://blogs.cdc.gov/safehealthcare/2015/02/20/antibiotic‐resistance‐health‐threat‐jeopardizing‐modern‐medicine/

In 2013, CDC outlined the top 18 drug‐resistant threats to the United States. These threats were categorized based on level of concern: urgent, serious, and concerning.

1. Urgent Threats: Clostridium difficile; carbapenem‐resistant Enterobacteriaceae; Neisseria gonorrhea

2. Serious Threats: MDR AcinetobacterDrug‐Resistant CampylobacterExtended Spectrum Enterobacteriaceae (ESBL)Vancomycin‐Resistance Enterococcus (VRE)MDR Non‐typhoidal Salmonella Drug‐Resistant Salmonella serotype TyphiDrug‐ Resistant ShigellaDrug‐ Resistant streptococcus PneumoniaeDrug Resistance Tuberculosis

3. Concerning Threats: Vancomycin‐Resistant staphylococcus aureusErythromycin‐Resistant group A streptococcusClindamycin‐Resistant Group B streptococcus

•NDM‐1: Carbapenem‐resistant Enterobacteriaceae (CRE) producing the New Delhi metallo‐β‐lactamase (NDM)

•Resistance conferred through genes present on Plasmids: E.coli and K.pneumoniae

•NDM‐4: co‐resistant to cephalosporins and monobactams

NDM: New Delhi Metallo‐beta‐lactamaseFirst reported (2007) in a patient who had been hospitalized in New Delhi, India

TB treatment involves two lines of drugs

First‐line Drugs

1. Isoniazid

2. Rifampicin

3. Pyrazinamide

4. Ethambutol

5. Aminoglycosides6. Capreomycin7. Quinolones8. Thioamides9. Cycloserine10. PAS

• Standard TB treatment with 4 drugs for 6-9 months•Safe, effective, comparatively inexpensive with 95% cure

……no effective drug for TB after ‘rifampin’introduced way back in1963!

Emergence of MDR/XDR/TDR TB

Second‐line Drugs1. Isoniazid2. Rifampicin

3. Pyrazinamide4. Ethambutol

5. Aminoglycosides6. Capreomycin7. Quinolones8. Ethionamide9. Cycloserine10. Para-amino salicylic acid (PAS)

• Treatment based on laboratory drug‐resistance testing and epidemiology information• 4‐6 drugs, duration 2 years • Less effective, • high toxicity and expense• <80% cure

MDR TB: TB isolate that is resistant to both isoniazid and rifampin (surrogate marker for MDR) 

In 2012,  0.4 Mn new cases of MDR‐TB , 6% of new TB cases and 20% of previously treated TB cases

XDR TB: MDR with further resistance to fluoroquinoloneand 1 of the 3 injectable drugs (second line drugs like amikacin, kanamycin, capreomycin)

TDR TB: Resistant to all drugs

The Way Forward: The TB Management and Control 

Some desperate needs• Therapeutics: new drugs and shorter regimens

• Develop public‐private partnerships for drug development• Speed up drug evaluation and approval processes

Exploit bioinformatics for more flexible designs for studiesDevelop markers for clinical outcomes

• Support basic research in drug development

• HIV, TB and Diabetes related issues• Access to ART to decrease the susceptible population• Access to TB therapy at the right time to reduce chances of IRIS

• Interrupt transmission• Develop, implement  and monitor site appropriate infection control strategies in health care facilities

• Vaccine• Alleviation of social and economic conditions and health disparities that breed both TB and HIV 

What is the Way Forward ?

Programmatic Decisions

Strengthen the basic TB control program further so as to reach out to the  as yet un‐notified and missed cases poor and highly  vulnerable populations address the social determinants of TB

Strengthen the health surveillance systems

Strengthen and rapidly expand  the laboratory network

Human resource and financial management

Drug supply chain management

Credit: PHFI, 2011

What is the Way Forward ?

Policy Decisions

Strengthen mechanisms to ensure that tuberculosis medicines are sold on prescription only are prescribed/ dispensed by accredited public and private providers (Developing Countries problem)

Develop policy for airborne infection‐control  Increase investment to promote research

Credit: PHFI, 2011

1. 2015 targets: reduction in global TB incidence (per capita prevalence and death rates) by 50% relative to 1990 levels (fairly un‐ambitious target: 35% decline since 1990)

2. 2050 target: eliminate TB (incidence of active TB <1 case per million population per year) with new discoveries, POC diagnostics, shorter therapeutic and preventive regimens, and potent vaccines

To achieve this:

Harmonize research efforts globally, build a "continuum" across fields and among all investigators maximising knowledge sharing and promoting consensus on strategic directions

Political Commitment

The Grand Challenge for TB Control and Elimination

Thank you