Topic VII: Gram Negative Infections

What can 1 type of bacteria often cause?

Multiple disease

• Depends upon:

  • Location in host where infection occurs

  • Virulence factors (exotoxins)

• Pathogenic or opportunistic

What pathogenic Gm- bacteria can cause STIs?

• Chlamydia

• Neisseria

  • N. Gonorrhoeae

  • N. Meningitis

What pathogenic Gm- bacteria can cause respiratory infections?

• Haemophilus

• Bordetella

• Moraxella

• Legionella

What pathogenic Gm- bacteria can cause enteric infections?

• Enterobacterales

  • E. Coli

  • Klebsiella

  • Proteus

  • Salmonella & shigella

• Vibrio cholerae

• Helicobacter pylori

• Campylobacter jejuni

What is Chlamydia trachomatis?

• Atypical bacteria

  • Pleiomorphic, intracellular, Gm0

• Most commonly-reported bacterial STI in US

  • 1.8mil new cases annually

• Majority of cases are asymptomatic

  • “Silent” disease

• In women, initially infects cervix & urethra

  • Can spread to fallopian tubes, ovaries, or uterus → pelvic inflammatory disease (PID)

    • PID occurs in 10-15% of women w/ untreated chlamydia

    • Can lead to long-term pelvic pain & infertility

• Antibiotic resistance is uncommon

• No vaccine

What are the 2 pathogenic strains of Neisseria?

1. Neisseria gonorrhoeae (STI)

2. Neisseria meningitidis (not an STI)

What is Neisseria gonorrhoeae (STI)?

• Gm- diplococci

• Urogenital infection, rarely in blood

• Non-sexual transmission is rare

  • Can be passed to eyes of infants at birth → blindness

• 600,000 new cases/year in US

What is Neisseria meningitidis (not STI)?

• Gm- diplococci

• Meningitis: inflammation of membranes (meninges) surrounding brain & spinal cord

  • Starts by infecting bloodstream & then CNS

  • Fever, headache, stiff neck, seizures, increased cranial pressure

  • Mostly seen in infants & ages 18-20

What are the differences in the Neisseria?

• Both express similar surface proteins, like pili & LPS

• Key difference is in whether they have a capsule:

  • N. Gonorrhoeae

    • No capsule

    • Localized infection

  • N. Meningitidis

    • Capsule

    • Systemic infection

What is Neisseria gonorrhoeae?

• 2nd most commonly reported STI in US

• 95% of men are symptomatic, but only 50% of women

  • Risk of spread is high (up to 50%)

  • Increasing penicillin resistance

• Can lead to pelvic inflammatory disease (PID) in women & epididymitis in men

• No effective vaccine

What are the challenges for vaccination for N. Gonorrhoeae?

• “Antigenic variation” of pili

• We do not have a vaccine for N. Gonorrhoeae

  • Antigenic variation helps bacteria to evade antibodies

    • Antibodies serve as a tag for phagocytosis by our immune cells

• Screening is critical for both gonorrhea & chlamydia

  • Nucleic acid amplification test (NAAT)

    • Test for specific DNA of each bacteria

What is N. Meningitidis?

• Dm- diplococci w/ a capsule

• Person-to-person spread via respiratory route

  • 10-15% of adults are carriers in nasopharynx

• Can cause “endotoxic shock” in addition to meningitis

  • Shock is caused by release of LPS

• Immune evasion techniques:

  • Capsule

  • Steals host sugars

    • Incorporate host sugars into outer membrane

    • Acts as camouflage from host’s immune response

What are the vaccines for N. Meningitidis?

• First dose recommended at 11

  • Recommended as early as 2 months old for high-risk infants (HIV positive, complement deficiency)

• Booster at 16

  • Protects students entering college or military

What is Haemophilus?

• Gm- coccobacilli (short rods)

• Only found in humans

  • Part of normal flora in many people

• Haemophilus influenza

  • Can cause respiratory & sinus infections, otitis media, & conjunctivitis (pink eye)

  • Most viral strains have capsules

    • Pneumonia (lungs)

    • Can also invade CNS (meningitis) & joints (arthritis)

What are the serotypes of Haemophilus influenzae?

• 6 serotypes (A-F)

  • Different capsules & surface polysaccharides

• Serotype B (Hib)

  • Most virulent

    • Can cause meningitis & pneumonia, especially in kids under 5

    • Capsule includes a polysaccharide called polyribitol phosphate (PRP)

  • Vaccine is designed against PRP- recommended at 2 months old (conjugate vaccine→ generates strong antibody response in infants)

What is Bordetella pertussis?

• Gm- coccobacilli

• Cause of whooping cough

  • Produces “pertussis toxin”

    • A-B exotoxin

    • Antibodies against pertussis toxin prevent colonization of bacteria & disease

What is the effective vaccine against whooping cough?

DTaP

• Diphtheria, Tetanus, acellular Pertussis

• Schedule:

  • 2 months, 4 months, 6 months, 15-18 months, 4-6 years, & booster at 11-12 years

What are the complications of whooping cough?

• Nose bleeds & ear infections

• Pneumonia

• Brain damage

  • Mental impairments

  • Seizure disorders

  • Cerebral hemorrhage

  • Due to lack of oxygen to brain due to cough

  • Death

• Infants at highest risk

What is Moraxella?

• Gm- diplococci

• Moraxella catarrhalis is most common

• Mostly associated w/ localized infections in upper respiratory tract

  • Can cause lower respiratory tract infections in elderly patients w/ other pulmonary conditions

• Frequent beta-lactamase producer

  • Often found w/ other bacteria

  • Beta-lactamase release can protect other bacteria in area

What is Legionella pneumophilia?

• Intracellular Gm- bacilli

  • Ubiquitous in fresh water, plumbing

    • Lives w/in amoebas, Protozoa

• Causing necrotizing multifocal pneumonia

  • Infects alveolar macrophages in lung

  • Mortality is high (15-50%)

    • Respiratory failure, shock

    • Most often seen in immunocompromised patients & elderly

• Person to person transmission has not been shown

What Gm- bacteria are associated w/ GI infections?

• Straight Gm- rods (enterobacterales)

• Curved Gm- rods (vibrio cholerea, campylobacter, helicobacter)

What are enterobacterales?

• Large family of bacteria of enteric bacteria

  • Especially problematic if they escape digestive tract

  • Formerly known as enterobacteriaceae

• Straight Gm- bacteria

What are the main pathogens of the many family members of enterobacterales?

• Escherichia Coli

• Klebsiella

• Proteus

• Shigella

• Salmonella

• Last 2 very similar genetically; spread by contaminated food & fecal-oral route

What is the key lab finding for E. Coli & Klebsiella?

Lactose positive: can ferment lactose

What are the disease states of E. Coli?

• Gm- bacilli, lactose-positive

• Most E. Coli infections:

  • Food poisoning/diarrhea (gastroenteritis)

  • Urinary tract infections

• Also associated w/ more invasive infections:

  • Pyelonephritis

  • PID

  • Pneumonia

  • Meningitis

What are the E. Coli classifications?

• Over 700 different strains of E. Coli

• Classified by their surface antigen

  • H antigens: flagella

  • O antigens: LPS

  • K antigens: capsule

    • O157:H7- found in cow intestines; common source of outbreaks

  • Surface antigens are important for tracing origin of outbreaks

• Also classified according to virulence

1. Enteropathogenic (least pathogenic)

2. Enterotoxic

3. Enteroinvasive

4. Enterohemorrhagic (most pathogenic)

What is enteropathogenic?

• Adheres to gut, but doesn’t enter cells

• Destroys surface microvilli

• Causes diarrhea & vomiting

What is enterotoxic?

• Produces exotoxins

  • Cholera-like toxin- causes release of water & iron from cells

  • Heat-stable toxin- prevents uptake of water & iron by cells

• Overall effect: severe diarrhea & vomiting

What is enteroinvasive?

• Actually “invades” or enters inside our cells → ultimately kills our cells

• Causes dysentery

  • Damages cells of digestive tract, often killing them

  • Leads to bloody diarrhea & fever

• More likely to be fatal

• Mostly seen in kids under 5

What is enterohemorrhagic?

• Most common cause of acute kidney failure in children

  • O157:H7

• Acquired an exotoxin from Shigella

• Doesn’t stay in intestines!

• Invades bloodstream & causes systemic infection

  • Attacks kidneys (kidney failure)

  • Can cause descending UTIs (moves from kidneys → bladder)

  • Anemia (toxins kill RBCs)

  • Combination of symptoms referred to as “hemolytic uremic syndrome”

  • Hemorrhagic diarrhea

What is key for all E. Coli strains?

Prevention

• There are no vaccines

What is Klebsiella?

• Gm- bacilli, lactose-positive

• Klebsiella pneumoniae

  • Part of normal gut flora

    • Doesn’t usually cause disease in healthy people

  • Cause of healthcare-associated (nosocomial) infections

    • Pneumonia, bloodstream infections, surgical site infections, meningitis

• Klebsiella is becoming very resistant to antibiotics

  • Carbapenem-resistant Enterobacterales (CRE)

What is CRE?

• Bacteria that are resistant to carbapenems

• Caused by plasmids that carry genes for drug-resistant enzymes:

  • KPC (Klebsiella pneumoniae carbapenemase)

  • NDM1 Is another example

  • KPC is most widespread in US, but PA has both in circulation

What is Proteus?

• Gm- bacilli; lactose-negative

  • Normal part of gut flora

  • Becomes problem if enters urinary tract

    • Most common cause of hospital-acquired UTIs

    • Associated w/ urinary stones & complicated UTIs

• Proteus mirabilis is most common

  • Can “swarm”

    • Lots of flagella

    • Move over viscous & solid surfaces

    • Issue for urinary catheters, movement to kidneys

  • Strong fishy odor

    • Due to ammonia

What is Campylobacter jejuni?

• Leading cause of GI illness in developed countries

  • Contaminated food (raw chicken- 25-50%)

  • Causes diarrhea & dysentery

  • Usually self-limiting, but antibiotics are required if it escapes digestive tract

  • Can lead to Guillain-Barre syndrome

What is Guillain-Barre syndrome?

• Generally proceeded by an infection

• “Demyelinating neuropathy”

  • Weakness/numbness followed by paralysis

• Surface on C. Jejuni resembles gangliosideso of our peripheral myelin

  • RESULT: antibodies mistakenly recognize/attack myelin

    • “Cross reactive antibodies”

• Treatment does not involve antibiotics

  • Focus on diluting cross reactive antibody through high-dose immunoglobulin therapy

What is Helicobacter pylori?

• Gm- spiral or curved bacilli

  • Limited to stomach & stomach intestines

  • Produces urease

    • Allows bacteria to persist in low pH

• Associated w/ most gastric ulcers

  • Antibiotic treatment is common now

• May also associated w/ gastric cancers

  • Chronic inflammation in gut leads to rapid turnover of cells

  • Link b/w inflammation & cancer?

What are the opportunistic Gm- bacteria?

1. SPACE organisms

• Pseudomonas aeruginosa

• Acinetobacter baumannii

2. Bacteroides fragilis

What are the SPACE organisms?

• Serratia marcescens

• Pseudomonas aeruginosa

• Acinetobacter baumannii

• Citrobacter freundi

• Enterobacter cloacae

• Typically found in healthcare settings

  • Antibiotic resistance is an issue

What is Pseudomonas aeruginosa?

• Most common SPACE bug

• Gm- bacilli

• Produces Toxin A

  • An A-B exotoxin that is a “cytotoxic”

  • Prevents protein translation in many host cells

• Most often seen in patients w/ another illness/injury:

  • Burns/wounds

    • Destruction of blood vessels

    • Phagocyte access is limited

  • Cancer patietns

    • Chemotherapy → destroy immune system

  • Cystic fibrosis patients

    • Altered respiratory epithelium

    • Build up of thick mucus in lungs

What are aspects of Pseudomonas aeruginosa?

• Gm- bacilli, pyocyanin+

• Characterized by formation of blue pigment (pyocyanin)

• Forms biofilms in lung

  • Issues for cystic fibrosis patients

  • Biofilm leads to chronic infection, greater inflammation, & requires higher doses of antibiotics (100-1000x higher than MIC)

What is Acinetobacter baumannii?

• Pleiomorphic Gm-

• One of “SPACE” bugs

• Has many virulence genes

  • Induces apoptosis of infected cells, resists complement tagging, forms biofilms

• Causes multiple invasive disease states

  • Meningitis, wound infections, bloodstream infections, pneumonia

• Recent emergence of multi-drug resistant (MDR) & pan-drug resistant stains

What is bacteroides fragilis?

• Gm- bacillli

• Obligate anaerobe

  • Part of gut flora

  • Not invasive on its own

    • Causes abdominal abscesses during trauma

      • Usually follows damage to intestines

    • Most commonly isolated bacteria from anaerobic infections

What is the positive role of bacteroides fragilis?

May prevent colitis or inflammatory bowel disease

• Produce polysaccharide A

  • Inhibits inflammation

  • Support for hygiene hypothesis?

What is a major issue for Gm- bacteria?

Drug resistance

• Of CDC’s list of drug resistant threats:

  • 10 are Gm- bacteria

  • 6 are Gm+ bacteria

  • 2 are atypicals

  • 3 are fungi