FINAL Micro topics + Pract Flashcards
Prokaryotic cell structure, essential and non-essential organelles
Prokaryotic cell structure
* Based on morphology, we can classify prokaryotes as cocci (chain–> Streptococcus, cluster
–> Staphylococcus), rods (chain –> Streptobacillus), coccobacilli, vibrios (curved rods),
spirilla (rigid coils), and spirochetes (flexible coils)
- No separate nucleus
- Transcription and translation occurs simultaneously
- The cell is surrounded by a membrane
- There are no internal membranes
Prokaryotes versus Eukaryotes
Essential organelles
1) Nucleoid
- DNA is circular, haploid (allows for more rapid growth and quicker adaptation to the
environment than diploid)
- Plasmids are extra-circular DNA that can confer antibiotic resistance and encode for
virulence factors
2) Cytoplasm
- 80% water, 20% salts and proteins
- No organelles (mitochondria, Golgi, etc.)
3) Cytoplasmic membrane
- Bilayer of phospholipid
- Flexible and impermeable to water
- Site of biosynthesis of DNA, cell wall polymers, and membrane lipids
- Selective permeability and transport of solutes into cell
4) Cell wall
- Determines the shape of bacteria
- Strength prevents osmotic rupture
- Plays an essential role in cell division and is unique to bacteria
- Gram(+) cell walls are composed of peptidoglycans, lipoteichoic acids, and wall
teichoic acids
- Gram(–) cell walls are composed of an outer bilayered phospholipid membrane
(containing lipopolysaccharides/lipooligosaccharide and proteins) and peptidoglycan
5) Polyribosomes
- Numerous and distributed throughout the cytoplasm, 15-20 nm in diameter
- Composed of a small 30S subunit and a large 50S subunit that together make up the
70S structure
Non-essential organelles
1) Flagellae
- Provide motility and movement to bacteria (e.g. P. mirabilis, V. cholerae)
- Arrangement is the basis for classification (monotrichous – 1 flagellum;
lophotrichous – tuft at one end; amphitrichous – both ends; peritrichous; all around
bacteria)
2) Pili
- Short protein appendages that are smaller than flagellae
- Adhere bacteria (e.g. E. coli) to surfaces
- F-pilus is used in conjugation for the exchange of genetic information
3) Capsule
- Adheres the bacteria (e.g. S. mutans) to a surface and prevents phagocytosis
4) Inclusions
- Discrete structures that are generally intracytoplasmic
- Function as metabolic reserves, cell positioners, or as metabolic organelles
5) Spores
- Resistant structures that protects the bacteria (e.g. B. anthracis, C. difficile) from heat,
irradiation, and cold
- Location of the spore is the basis for classification (central, subterminal, terminal)
Antibiotics inhibiting bacterial cell wall synthesis. Mechanism of action, spectrum of effect,
resistance mechanisms
β-lactams
- Basic structure consists of a thiazolidine ring connected to a β-lactam ring
- Penicillin binding proteins (PBPs) are the target for all β-lactams
- Interfere with the last step of bacterial cell wall synthesis, causing cell lysis (bactericidal)
- Only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall
(inactive against Chlamydia spp., Mycoplasma spp., mycobacteria, fungi, and viruses) - Can cause allergic reactions such as urticaria, pruritus, angioedema, bronchoconstriction,
and shock
1) Natural penicillins
- Penicillin G has a narrow spectrum and is susceptible to inactivation by β-lactamase
- Penicillin V is more acid stable
- Mainly used for the treatment of meningitis caused by susceptible organism
2) β-lactamase resistant β-lactams
- Methicillin, nafcillin, and oxacillin
- Have a narrow spectrum and are mainly used against β-lactamase producing
Staphylococci
3) Aminopenicillins
- Ampicillin and amoxicillin
- Broader spectrum against Gram(–), but are susceptible to β-lactamase producing
bacteria (e.g. Klebsiella)
- Reach therapeutic concentration in the CSF
4) Ureidopenicillins
- Piperacillin is the main one
- Effective against P. aeruginosa
- Reach therapeutic concentration in the CSF
5) Carbapenems
- Meropenem, imipenem, doripenem, and ertapenem
- Can resist many β-lactamases
- Good efficacy against facultative anaerobe Gram(–) (such as P. aeruginosa) and ESBL
(extended spectrum β-lactamase) producing Gram(–)
- Ineffective against MRSA, E. faecium and others
- Carbapenemases belong to 2 major groups:
a) Metallo-β-lactamases (MBLs) – e.g. P. aeruginosa
b) Serine-β-lactamases – e.g. K. pneumoniae
6) Cephalosporins
- Related to penicillins structurally and functionally, but are more resistant to
β-lactamases
- Five generations:
- Cefazolin and others; effective for treating Staphylococcal and Streptococcal
infections but do not penetrate into the CSF - Cefaclor, cefurozime axetil, and cefoxitin; broader spectrum and includes some
Gram(–) (H. influenzae, Neisseria); more resistant to β-lactamases; useful for
treating upper and lower resp. tract infections; do not penetrate into the CSF - Cefotaxime, ceftriaxone, ceftazidime and others; extended spectrum of action
against Gram(–); resistant to most β-lactamases; reach therapeutic
concentration in the CSF (cefotaxime and ceftriaxone are used for the blind
treatment of meningitis) - Cefepime and cefpirome; greater resistance to β-lactamases, many can cross
the blood brain barrier; active against P. aeruginosa; only used for severe
infections - Ceftaroline, ceftobiprole, and ceftolozane; can enter into the CSF and look
effective against MRSA as well as S. pneumoniae; ceftolozane is often combined
with tazobactam
7) Monobactams
- Narrow spectrum, only effective against Enterobacteriaceae and Pseudomonas spp.
- Resistant to β-lactamases
β-lactamase inhibitors (large molecules, do not penetrate into the CSF)
Glycopeptides
* Vancomycin, teicoplanine, dalbavancin, and telavancin
* Bind firmly to and inhibit transglycosylase, inhibiting cell wall synthesis
* Have no effect against Gram(–)
* Narrow spectrum against MRSA, penicillin-resistant S. pneumoniae, C. jekeium, and
C. difficile
* Some species of S. aureus, Enterococci, and C. difficile show acquired resistance
Other agents
1) Daptomycin
- Novel cyclic lipopeptide that is similar to vancomycin
- Active against vancomycin resistant strains of Enterococci, and S. aureus
2) Fosfomycin
- Analog of phosphoenolpyruvate
- Active against both Gram(+) and Gram(–)
3) Cycloserine
- Used against M. tuberculosis
4) Bacitracin
- Effective against Gram(+)
- Topical application due to nephrotoxicity, often used for traumatic abrasions
Antibiotics inhibiting bacterial protein synthesis. Mechanism of action, spectrum of effect,
resistance mechanisms
30S subunit inhibitors
1) Aminoglycosides
- Amikacin, gentamycin, tobramycin, etc.
- Inhibit initiation and promote misreading of translation (bactericidal)
- Have no effect against anaerobes, Enterococci, and causative agents of atypical
pneumonia (e.g. C. pneumoniae, M. pneumoniae, L. pneumophila) - Oto- and/or nephrotoxic
- Often combined with β-lactams or glycopeptides in endocarditis and other severe infections
- Do not penetrate into the CSF
- Resistance is most commonly due to phosphorylation, adenylation, or acetylation of
the antibiotic by the bacterium
2) Tetracyclines
- Tetracyclin, minocyclin, eravacycline
- Inhibit binding of the aminoacyl-tRNA to the 30S subunit (bacteriostatic)
- Broad spectrum (except for Pseudomonas and Proteus spp.), but many pathogens are
resistant - Effective against causative agents of atypical pneumonia
- Contraindicated in pregnancy and in children with developing teeth (<8 yrs)
3) Glycylcyclines
- Tigecyclin
- Same mode of action as tetracyclines (bacteriostatic)
- Broad spectrum (except for Pseudomonas and Proteus spp.)
- Can be used against Acinetobacter and C. difficile
50S subunit inhibitors
1) Chloramphenicol
- Old and toxic agent that is now used for the treatment of meningitis in case of
penicillin-allergic patients
- Side effects include dose-dependent bone marrow suppression and doseindependent aplastic anemia
2) Macrolides
- Erythromycin, clarithromycin, spiramycine, azithromycin (preferred), and
fidaxomicin (inhibits C. difficile sporulation)
- Inhibit translocation of polypeptides to the 50S subunit (bacteriostatic)
- Narrow spectrum, mainly Gram (+) but also Campylobacter spp. and causative agents
of atypical pneumonia
- Alternative agents for the treatment of tonsillitis caused by S. pyogenes
3) Lincosamides
- Lincomycin and clindamycin
- Same mechanism of action as macrolides (bacteriostatic)
- Narrow spectrum, mainly Gram(+) facultative anaerobes (Staphylococci,
Streptococci) but also Gram(+) and Gram(-) obligate anaerobes
- Used in the treatment of osteomyelitis
- Can easily cause pseudomembranous colitis
4) Ketolides
- Telitromycin
- Similar to macrolides
5) Streptogramins
- Quinopristin+dalfopristin=Synercid
- Same mechanism of action as macrolides
- Effective against vancomycin-resistant E. faecium, MSSA, and MRSA
6) Oxazolidinons
- Linezolid and tedizolid
- Effective against MRSA, VISA, VRSA, and VRE
- Not effective for the treatment of bacteremia
Antibiotics inhibiting bacterial folate, DNA, or RNA synthesis. Mechanism of action,
spectrum of effect, resistance mechanisms
Fluoroquinolones
- Inhibit DNA gyrase or topoisomerase IV (bactericidal)
- Good tissue penetration, widely used
- Four generations:
- Nalidixic acid, oxalinic acid; effective against Gram(–) but not Pseudomonas spp.; only
used for UTIs - Norfloxacin (UTI), ciprofloxacin, ofloxacin; effective against Gram(–), some Gram(+)
and some atypicals; used in case of anthrax exposure and prophylaxis - Levofloxacin; extended Gram(+) and atypical spectrum; used in atypical pneumonia
- Moxifloxacin; broader anaerobic coverage
- It has been recommended that use of fluoroquinolones be restricted or suspended entirely
due to the risk of disabling and potentially permanent adverse effects such as tendonitis,
gait disturbance, and depression
Sulfonamides and trimethoprim
- Sulfonamides (sulfadiazine, sulfamethoxazole (SMX)) inhibit synthesis of folic acid by
competing with PABA (substrate for folic acid synthesis) - Trimethoprim (TMP) inhibits synthesis of folic acid by inhibiting dihydrofolate reductase
- SMX:TMP (Bactrim) are typically given together in a 5:1 ratio
- Good activity against Gram(+) and Gram(–)
- May be effective against MRSA
- Very effective against Pneumocystis spp. (fungus) but not against P. aeruginosa and
Enterococci - Used in the treatment and prophylaxis of UTIs
Rifamycines
* Rifampicin, rifapentin, rifabutin
* Inhibit RNA synthesis by inhibiting RNA polymerase (bactericidal)
* Good penetration into tissues, peritoneal and pleural cavity, bile, bones, and abscesses
* Reach therapeutic concentration in the CSF
* Prophylactic use against N. meningitidis and H. influenzae
* Active against mycobacteria
* Cause the urine, saliva, and sweat to become orange
Antituberculotic agents. Mechanism of action
Tuberculosis infection is treated with a multiple-drug therapy for 6-9 months consisting of
isoniazid (INH), rifampin, pyrazinamide, and ethambutol.
It is important to treat tuberculosis
with several drugs due to the long treatment period, which can yield strains of M. tuberculosis
that are resistant against one of the drugs but not the others.
Treatment of strains of M. tuberculosis resistant to multiple drugs (MDR strains) involves the use
of four or five drugs, including ciprofloxacin, amikacin, ethionamide, and cycloserine
Isoniazid (INH)
- Able to penetrate human cells well is therefore effective against M. tuberculosis, which
resides within macrophages. - Inhibits mycolic acid synthesis (bactericidal), making it specific for mycobacteria and
relatively nontoxic for humans - The active drug is probably a metabolite of INH formed by the action of catalase peroxidase
- Its main side effect is liver toxicity.
Rifampin
* Inhibits RNA synthesis by inhibiting RNA polymerase (bactericidal)
* Good penetration into tissues, peritoneal and pleural cavity, bile, bones, and abscesses
* Reaches therapeutic concentration in the CSF
* Cause the urine, saliva, and sweat to become orange
Pyrazinamide
* Bactericidal
* Mechanism of action is uncertain, but it is thought to involve inhibition of a fatty acid
synthase that prevents the synthesis of mycolic acid
* Particularly effective against semidormant organisms in the lesion, which are not affected
by INH or rifampin
Ethambutol
* Bacteriostatic
* Acts by inhibiting the synthesis of arabinogalactan, which functions as a link between the
mycolic acids and the peptidoglycan of the organism
Sterilization
Sterilisation is the killing of all microorganisms in a material or on the surface of an object.
Typically the last thing to die when one attempts sterilization is the highly heat- (and chemical-,
etc.) resistant endospores.
Heat sterilization and decontamination
- Red-heat flame, dry heat (hot air oven, dry heat sterilizator), or most heat (pasteurization,
tyndallization, boiling, autoclaving) can be used for sterilization
1) Hot air oven, dry heat sterilizator - 160°C for at least 60 min, or 180 °C for at least 20 min
2) Autoclave
- 121°C for 20-30 min at 1 bar overpressure
3) Pasteurization
- Consists of heating milk to 62°C for 30 minutes followed by rapid cooling
- Sufficient to kill the vegetative cells of the milk-borne pathogens (e.g. M. bovis,
Salmonella, Streptococcus, Listeria, and Brucella), but not to sterilize the milk
Electromagnetic irradiation
* At 254 nm wavelength (ultraviolet) electromagnetic irradiation damages DNA but can exert
its effect only on surfaces and in the air, which makes it unsuitable for sterilization
* “Hard X-rays“ (less than ~0.01 nm wavelength) and gamma rays are reliable methods of
sterilization
Filtration
* The preferred method of sterilizing certain solutions (e.g. those with heat-sensitive
components)
* The most commonly used filter is composed of nitrocellulose and has a pore size of 0.22 μm
Gas sterilization
* Ethylene oxide gas is used extensively in hospitals for the sterilization of heat-sensitive
materials such as surgical instruments and plastics
* It is classified as a mutagen and a carcinogen
*Incomplete method of sterilization
Disinfectants
Disinfection means reducing the number of viable microorganisms present in a sample.
A disinfectant is a chemical or physical agent that is applied to inanimate objects to kill microbes.
Not all disinfectants are capable of sterilizing, and therefore spores and some bacteria, viruses,
and fungi may survive. Typically, an antiseptic is a chemical disinfectant agent that is applied on
skin or mucous membranes to kill microbes.
Disruption of cell membranes
1) Alcohol
- Ethanol is widely used to clean the skin before immunization or venipuncture
- Requires the presence of water for maximal activity (i.e. it is far more effective at 70%
than 100%)
2) Detergents
- Composed of a long-chain, lipid-soluble, hydrophobic portion and a polar hydrophilic
group
- Quaternary ammonium compounds are cationic detergents widely used for skin
antisepsis
3) Phenols
- Chlorhexidine is a chlorinated phenol that is widely used as a hand disinfectant prior
to surgery and in the cleaning of wounds
- Hexaclorophene is used in germicidal soaps, but may be neurotoxic
Modification of proteins
1) Chlorine
- Used as a disinfectant to purify the water supply and to treat swimming pools, as well
as being the active component of bleach
2) Iodine
- The most effective skin antiseptic used in medical practice and should be used prior
to obtaining a blood culture and installing intravenous catheters because
contamination with skin flora such as S. epidermidis can be a problem
3) Heavy metals
- Mercury and silver have the greatest antibacterial activity of the heavy metals and
are the most widely used in medicine
4) Hydrogen peroxide
- Used as an antiseptic to clean wounds and to disinfect contact lenses
- Its effectiveness is limited by the organism‘s ability to produce catalase, an enzyme
that degrades H2O
5) Formaldehyde and glutaraldehyde
- Formaldehyde is an alkylating agent available as a 37% solution in water (formalin)
- Glutaraldehyde has two reactive aldehyde groups and is 10 times more effective than
formaldehyde and is less toxic
6) Ethylene oxide
- Gas that is used extensively in hospitals for the sterilization of heat-sensitive
materials such as surgical instruments and plastics
- It is classified as a mutagen and a carcinogen
7) Acids and alkalis
- Although most bacteria are susceptible, it is important to note that M. tuberculosis
and other mycobacteria are relatively resistant
- Weak acids, such as benzoic, propionic, and citric acids, are frequently used as food
preservatives because they are bacteriostatic
Modification of nucleic acids
* A variety of stains not only stain microorganisms, but also inhibit their growth
- Crystal violet is used as a skin antiseptic
- Malachite green is used for the culturing of M. tuberculosis on Löwenstein-Jensen‘s
medium, because it inhibits the growth of unwanted organisms in the sputum during
the 6-week incubation period
Bacterial virulence factors
Bacterial virulence factors can be toxic (exotoxins, endotoxins) or non-toxic (adherence factors,
invasive factors, other factors)
Exotoxins
* Excreted by living cells
* Produced by both Gram(+) and Gram(–)
* Heat labile, highly antigenic, and highly toxic polypeptides that have specific effects and can
generally be converted to toxoids with formalin
* Unique exotoxins include erythrogen toxin of S. pyogenes(cannot be converted to toxoid by
formalin), heat stable enterotoxin of E. coli, botulinus toxin of C. botulinum (resistant to
digestive enzymes), and heat-resistant enterotoxin of S. aureus
* We can differentiate between two types of exotoxins:
) Toxic enzymes (cytolysins)
- Phospholipase: destroy membranes, e.g. lecithinase (alpha toxin)
(C. perfringens)
- Pore forming cytolysins: destroy membranes, e.g. streptolysin O (S. pyogenes)
and alpha toxin (S. aureus)
- Detergents: destroy membranes, e.g. delta toxin (S. aureus)
2) Exotoxins with 2 subunits (A and B)
- Inhibition of protein synthesis: inhibit EF-2 by ADP-ribosylation, e.g.
diphtheria toxin (C. diphtheriae) and “A“ toxin (P. aeruginosa)
- Increasing of cAMP: increase adenylate cyclase activity, e.g. cholera toxin
(V. cholerae), heat-labile enterotoxin (E. coli), and pertussis toxin (B. pertussis) - Neurotoxins: e.g. tetanus toxin (C. tetani) which block release of inhibitory
mediators at spinal synapses, or botulinus toxin (C. botulinum) which blocks
release of acetylcholine at synapses and NMJs - Pyrogenic toxins: increase production of IL-1 and TNF-α, e.g. TSST
(S. aureus), exfoliatin toxin (S. aureus), enterotoxin (S. aureus), and
erythrogenic toxin (S. pyogenes) - Other toxins: e.g. complex toxin (B. anthracis), A and/or B toxin (C. difficile),
and Panton-Valentine leukocidin (PVL) toxin (S. aureus)
Endotoxins
- LPS, which is found only in Gram(–) bacteria, is responsible for toxicity (more specifically,
the lipid A portion) - Relatively heat stable, weakly immunogenic, moderately toxic, cannot be converted to
toxoids, and has a universal mode of action - Cause fever, hypotension, DIC, activation of the complement cascade (alternative pathway),
leukopenia, and hypoglycemia - B. fragilis has a lipid A endotoxin that is slightly different from other bacteria, leading to
abscess formation
Extracellular enzymes
* Coagulase (S. aureus), fibrinolysin (streptokinase) (S. pyogenes), urease (K. pneumoniae,
Proteus spp., H. pylori), lipase (S. aureus), protease (P. aeruginosa, Proteus spp.), IgA
protease (H. influenzae, S. pneumoniae, N. meningitidis, N. gonorrhoeae)
Surface components
1) Antiphagocytic factors
* Capsule (S. pneumoniae, K. pneumoniae, H. influenzae, N. meningitidis, B. anthracis),
LPS (O specific chain), cord factor (mycolic acid) (M. tuberculosis), M protein
(S. pyogenes), protein A (S. aureus), soluble chemotaxis inhibiting factor (B. pertussis)
2) Adhesion factors
* Pili (N. gonorrhoeae), adhesive fimbriae (E. coli, V. cholerae, S. dysenteriae,
B. pertussis), afimbrial adhesins (chlamydia, mycoplasma, S. pyogenes)
Invasion factors
* Invasins (shigella, E. coli, yersinia, L. monocytogenes), flagellae, enzymes (lecithinase,
hyaluronidase etc.), S fimbriae (bind to sialic acid receptors –> sepsis, meningitis caused by
E. coli)
Siderophores
* Aerobactin (E. coli) and enterobactin (Enterobacteriaceae)
* Pick up iron from transferrin, lactoferrin
Transmission of infections, the portals of entry of pathogenic microbes
An understanding of the mode of transmission of bacteria and other infectious agents is
extremely important from a public health perspective, because interrupting the chain of
transmission is an excellent way to prevent infectious diseases.
Fomites are inanimate objects, such as towels, that serve as a source of microorganisms that can
cause infectious diseases.
Human to human transmission
A. Direct contact
- e.g. gonorrhea (N. gonorrheae)
- Intimate contact (e.g. sexual or passage through birth canal)
B. No direct contact
- e.g. dysentery (S. dysenteriae, EIEC, etc.)
- Fecal-oral (e.g. excreted in human feces and then ingested in food or water)
C. Transplacental
- e.g. congenital syphilis (T. pallidum)
- Bacteria cross the placenta and infect the fetus
D. Bloodborne
- e.g. syphilis (T. pallidum)
- Transfused blood or intravenous drug use can transmit bacteria and viruses;
screening of blood for transfusions has greatly reduced this risk
Nonhuman to human transmission
A. Soil source
- e.g. tetanus (C. tetani)
- Spores in soil enter wound in skin
B. Water source
- e.g. Legionnaire‘s disease (L. pneumophila)
- Bacteria in water aerosol are inhaled into lungs
C. Animal source
a) Directly:
- e.g. cat-scratch fever (B. henselae)
- Bacteria enter into the blood stream through a cat scratch
b) Via insect vector:
- e.g. Lyme disease (B. burgdorferi)
- Bacteria enter into the blood stream through a tick bite
c) Via animal excreta:
- e.g. hemolytic-uremic syndrome (EHEC O157:H7)
- Bacteria in cattle feces are ingested in undercooked hamburger
D. Fomite source
- e.g. staphylococcal skin infection
- Bacteria on an object (e.g. a towel) are transferred onto the skin
Portals of entry of some common pathogens
* There are four important portals of entry: respiratory tract, gastrointestinal tract, genital
tract, and skin
1) Respiratory tract
- S. pneumoniae –> pneumonia
- N. meningitidis, H. influenzae –> meningitis
- Influenza virus –> influenza
2) Gastrointestinal tract
- S. dysenteriae –> dysentery
- Norovirus –> gastroenteritis
- Trichinella spiralis –> trichinosis
3) Genital tract
- N. gonorrhoeae –> gonorrhea
- C. trachomatis –> urethritis
- Human papillomavirus –> genital warts
4) Skin
- C. tetani –> tetanus
- Rabies virus –> rabies
- Plasmodium vivax –> malaria
Non-specific defenses against pathogenic microbes
Innate (non-specific) defenses protect against microorganisms in general. They can be classified
into three major categories: (1) physical barriers, such as intact skin and mucous membranes;
(2) phagocytic cells, such as neutrophils, macrophages, and natural killer cells; and (3) proteins,
such as complement, lysozyme, and interferon.
Skin and mucous membranes
- Intact skin is the first line of defense against many organisms
- Physical barrier in addition to fatty acids secreted by sebaceous glands (antibacterial
and antifungal activity) - The normal flora of the skin (propionibacteria etc.) can also provide protection
- The mucous membrane of the respiratory tract is lined with cilia and covered with mucus
- Coordinated beating of cilia drives mucus up to the nose and mouth, where the
trapped bacteria can be expelled or swallowed - Nonspecific protection in the gastrointestinal tract includes hydrolytic enzymes in saliva,
acid in the stomach, and various degradative enzymes and macrophages in the small
intestine - Additional protection is provided by defensins, highly positively charged peptides
that create pores in the membranes of bacteriae
Inflammatory response and phagocytosis
* Neutrophils predominate in the acute pyogenic infections, whereas macrophages are
more prevalent in the chronic or granulomatous infections
- Macrophages perform two functions: they are phagocytic and they produce important
proinflammatory cytokines (TNF-α and IL-1) - IFN-γ, which is produced by activated T helper cells, activates macrophages and
enhances their microbicidal action - Neutrophils are also phagocytic, but they do not present antigens to T helper cells as
macrophages and dendritic cells do - Certain acute-phase proteins also provide protection against bacteria, e.g. CRP and
mannose-binding protein which bind to the surface of bacteria and enhance activation of
the alternative complement pathway - IL-6 is the main inducer of the acute-phase response
- Chemokines are produced by tissue cells in the infected area and serve the function of
attracting neutrophils and macrophages to the infected area - IL-8 and complement component C5a are examples of important chemokines
- Phagocytosis is enhanced by the binding of IgG antibodies and complement components
(C3b) to the surface of the bacteria, a process called opsonization - Once phagocytosed, bacterial cells are killed in a two-step process that consists of
degranulation followed by production of hypochlorite (specific to neutrophils), hydrogen
peroxide, or superoxide - Neutrophils and macrophages can also kill cell extracellularly, via oxygen-dependent
methods (superoxide, hydrogen peroxide, hypochlorite, nitric oxide) or oxygenindependent methods (lactoferrins, defensins, lysozymes, cationic proteins)
Specific immune responses against pathogenic microbes
Adaptive (specific) immunity protects against a particular microorganism and results either from
exposure to the organism (active immunity) or from receipt of preformed antibody made in
another host (passive immunity)
Passive adaptive immunity
- Temporary protection against an organism
- Protective abilities are present immediately
- Can be used to prevent a disease (e.g. botulism, tetanus) and also in the treatment of
immunodeficiency diseases (e.g. hypogammaglobulinemia) - Also occurs naturally in the form of immunoglobulins passed through the placenta (IgG) or
breast milk (IgA) from mother to child.
Active adaptive immunity
* Protection based on exposure to the organism in the form of overt disease, subclinical
infection, or a vaccine
* Protective abilities have a delay of a few days to a few weeks
* Mediated by both antibodies (immunoglobulins) and T cells:
1) Antibodies
- Neutralization of toxins
- Lysis of bacteria in the presence of complement
- Opsonization of bacteria to facilitate phagocytosis
- Interference with adherence of bacteria and viruses to cell surfaces
2) T cells
- Cytotoxic destruction of virus-infected cells and bacteria
- Activation of macrophages
- Delayed hypersensitivity
- Stimulation of B cells to produce antibodies
Hypersensitivity reactions in infectious diseases, serum sickness
Hypersensitivity is the term used when an immune response results in exaggerated or
inappropriate reactions harmful to the host. Hypersensitivity reactions can be subdivided into
four main types.
Types I, II, and III are antibody-mediated, whereas type IV is cell-mediated.
Type I: Immediate (anaphylactic) hypersensitivity
- Process begins when an antigen induces the formation of IgE antibody
- IgE binds to IgE receptors on surface of basophils and mast cells
- Reexposure to the antigen causes cross-linking of cell-bound IgE
- Degranulation and release of pharmacologically active mediators occurs within
minutes of exposure (immediate phase) - Symptoms such as edema and erythema (“wheal and flare“) and itching appear
rapidly due to preformed mediators (e.g. histamine) - The late phase occur approximately 6 hours after exposure and is due to mediators (e.g.
leukotrienes) that are synthesized after the cell degranulates - These mediators cause an influx of inflammatory cells and symptoms such as
erythema and induration - Clinical manifestation can appear in various forms; e.g. urticaria, eczema, rhinitis,
conjunctivitis, bronchoconstriction (asthma), and diarrhea - The most severe form of type I hypersensitivity is systemic anaphylaxis, in which severe
bronchoconstriction and hypotension (shock) can be life-threatening - Most common causes are foods (e.g. peanuts, shellfish), bee venom, and drugs such
as penicillin - It can also be caused by rupture of hydatid cyst in Echinococcus granulosus infection
Type II: Cytotoxic hypersensitivity
- Occurs when antibody directed at antigens of the cell membrane activates complement
- Generates a membrane attack complex, which damages the cell membrane
- Also attracts phagocytes to the site, with consequent release of enzymes that also
damage the cell membrane - Occurs after group A streptococcal infections (rheumatic fever) as well as in some
hemolytic anemias, to name a few
Type III: Immune complex hypersensitivity
- Occurs when antigen-antibody complexes induce an inflammatory response in tissues
- In persistent microbial or viral infections, immune complexes may be deposited in organs
(e.g. the kidneys), resulting in damage - Wherever immune complexes are deposited, they activate the complement system
- Two typical type III hypersensitivity reactions are the Arthus reaction and serum sickness
1) Arthus reaction is the name given to the inflammation caused by the deposition of
immune complexes at a localized site
- If high enough levels of IgG antibody for a particular antigen are present and
that antigen is then injected subcutaneously or intradermally, intense edema
and hemorrhage develop, peaking in 3 to 6 hours - A clinical manifestation of the Arthus reaction is hypersensitivity pneumonitis
associated with the inhalation of actinomycetes („farmer‘s lung) found in hay - Can also occur at the site of tetanus immunization if they are given at the same
site with too short an interval between immunizations (<5 years)
2) Serum sickness is a systemic inflammatory response to the presence of immune
complexes deposited in many areas of the body
- After injection of foreign serum (or more commonly these days, exposure to
certain drugs), the antigen is excreted slowly - Antibodies are produced simultaneously, producing immune complexes which
may circulate or be deposited at various sites - Results in fever, urticaria, arthralgia, lymphadenopathy, splenomegaly, and
eosinophilia a few days to 2 weeks after exposure
Type IV: Delayed (cell-mediated) hypersensitivity
- Function of T lymphocytes, not antibody
- In certain contact hypersensitivities, such as poison oak, the pruritic, vesicular skin rash is
caused by CD8+ cytotoxic T cells that attack skin cells that display the plant oil as a foreign
antigen - In the tuberculin skin test, the indurated skin rash is caused by CD4+ helper T cells and
macrophages that are attracted to the injection site
Active and passive immunization, principles, side effects. Types of vaccines
Active immunization
* Occurs either naturally during infection or via vaccination with vaccines prepared from
microbes or their products
- Vaccines are either live attenuated or non-live types, both possessing distinct pros and
cons: - Live attenuated: mimics natural infection, single dose is sufficient, low infectious
dose required, risk of virulent reversion, storage conditions are critical, elicits
complete immunity (sIgA, cell mediated immunity) - Non-live: single dose elicits a single antigenic stimulus, multiple doses and booster
stimulations required, high amount of antigen required, cannot revert to virulence,
less specific and cheaper storage, elicits only serum IgG antibodies - Certain viral vaccines (influenza, measles, mumps, yellow fever) are grown in chick
embryos and should not be given to those who have had an anaphylactic reaction to eggs - In case of high level infectious immunity (>95-98%), the non-immune members of the
population are virtually protected due to lack of infectious source, a phenomenon known
as herd immunity
Passive immunization
- Administration of preformed antibody in preparations called immune globulins
- Can be used for treatment or prevention of diseases
- The following bacterial preparations are available:
1) Tetanus antitoxin is used in the treatment of tetanus and in its prevention
2) Botulinum antitoxin is used in the treatment of botulism
3) Diphtheria antitoxin is used in the treatment of diphtheria
- The following viral preparations are available:
1) Rabies immune globulin (RIG) is used in prevention of rabies in people who may have
been exposed to the virus
2) Hepatitis B immune globulin (HBIG) is used in the prevention of hepatitis B in people
who may have been exposed to the virus
3) Varicella-zoster immune globulin (VZIG) is used in the prevention of disseminated
zoster in people who may have been exposed to the virus and who are
immunocompromised
4) Vaccinia immune globulins (VIG) can be used to treat some of the complications of
smallpox vaccination
5) Hepatitis A or measles immune globulins can be used for the prevention of disease in
people who may have been exposed to these viruses
Types of vaccines
A. Live, attenuated vaccines
* The vaccine against tuberculosis contains a live, attenuated strain of M. bovis called
BCG (Bacillus Calmette-Guérin)
- Given to children at high risk of exposure
- One of the vaccines against typhoid fever contains live, attenuated S. typhi
- Given to persons living or traveling in high-risk areas or persons in close
contact with either infected patients or chronic carriers - The vaccine against tularemia contains live, attenuated Francisella tularensis
- Indicated for laboratory personnel, veterinarians, and hunters
- The vaccines against measles, mumps, rubella, and varicella are some examples of
viral vaccines containing live, attenuated organisms
B. Killed/inactivated vaccines
- Vibrio cholerae vaccine contains killed organisms
- Administered to persons traveling to areas where cholera is endemic
- Yersinia pestis vaccine contains killed organisms
- Indicated for persons at high risk for contracting plague
- The vaccine against typhus contains killed Rickettsia rickettsiae organisms
- Primarily given to members of the armed forces
- The vaccine against Q fever contains killed Coxiella burnetii organisms
- Given to those who are at high risk of exposure to animals infected with the
organism - The polio vaccine used for routine immunizations contains killed polio viruses,
another example is the hepatitis A vaccine
C. Toxoid vaccines
* Corynebacterium diphtheriae vaccine contains the diphtheria toxoid
- Indicated for every child
* Clostridium tetani vaccine contains tetanus toxoid
- Given to everyone both early in life and later as boosters
* Bordetella pertussis vaccine contains pertussis toxoid, but includes other proteins as
well
D. Subunit vaccines
a) Capsular polysaccharide vaccines
- Both versions of the vaccine against S. pneumoniae contain the capsular
polysaccharide of the bacteria as the immunogen - One version covers the 23 most prevalent serotypes and is
recommended for persons >60 years and susceptible adults - The second version covers 13 serotypes and is coupled to diphtheria
toxoid, it is available for young children - N. meningitidis vaccine contains capsular polysaccharide of four important
types (A, C, W-135, and Y) - Available conjugated to diphtheria toxoid or not, given when there is a
high risk of meningitis - H. influenzae vaccine contains the type b polysaccharide
- Available conjugated to diphtheria toxoid or not, given to children
between the ages of 2 and 15 months to prevent meningitis - One of the vaccines against typhoid fever contains the capsular polysaccharide
of S. typhi
b) Purified protein vaccines - One version of a B. pertussis vaccine contains inactivated pertussis toxin
(pertussis toxoid), but other proteins, such as filamentous hemagglutinin and
pertactin, are required for full protection - Indicated for every child as a protection against whooping cough
- Usually given in combination with diphtheria and tetanus toxoids (DTP
or DTaP vaccine) - Bacillus anthracis vaccine contains “protective antigen“ purified from the
organism - Given to persons with occupational risk of exposure
- The hepatitis B virus (HBV) vaccine and human papilloma virus (HPV) vaccine
are examples of viral vaccines containing purified protein antigens
Diagnostic immune reactions in microbiology
The basis of diagnostic immune reactions (a.k.a. serological reactions) is the great specificity
between antigens and their antibodies.
Serological tests are of great importance when diagnosing
infectious diseases in several situations:
- When the organism cannot be cultured (e.g. syphilis and hepatitis A, B, and C)
- When the organism is too dangerous to culture (e.g. rickettsial diseases)
- When culture techniques are not readily available (e.g. HIV, EBV)
- When the organism takes too long to grow (e.g. Mycoplasma)
One problem with this approach is that it takes time for antibodies to form (e.g. 7-10 days in the
primary response).
For this reason, acute and convalescent serum samples are taken, and a
fourfold or greater rise in antibody titer is required to make a diagnosis.
Types of diagnostic tests
1) Agglutination
* Antigen is particulate (e.g. bacteria and RBCs) or is an inert particle (latex beads)
coated with an antigen
- Antibodies cross-link the antigenically multivalent particles and forms a latticework,
and clumping (agglutination) can be seen - Can be used in the identification of pathogenic E. coli strains as well as in the diagnosis of typhus, typhoid fever, and brucellosis
2) Precipitation (precipitin)
- Antigen is in solution or in semisolid medium (agar)
- Antibodies cross-link antigen molecules in variable proportions, and aggregates
(precipitates) form where the optimal proportions of antigen and antibody combine
(zone of equivalence) - In the case of antigen excess, small immune complexes will form diffusely and
fail to produce a precipitate - Can be used in the detection of B. anthracis from animal tissues (precipitin ring test),
in the detection of diphtheria toxin (Elek-test), and in identification of T. pallidum
infection (VDRL test, RPR test
3) Enzyme-linked immunosorbent assay (ELISA)
* Based on covalently linking an enzyme to a known antigen or antibody, reacting the
enzyme-linked material with the patient‘s specimen, and then assaying for enzyme
activity by adding the substrate of the enzyme
- Useful for determining serum antibody concentrations in HIV and West Nile virus
infection - Other uses include the detection of Mycobacterium antibodies in tuberculosis and
detection of rotavirus in feces, to name a few
4) Immunofluorescence assay (IFA)
- Fluorescent dyes can be covalently attached to antibody molecules and made visible
by ultraviolet (UV) light in the fluorescence microscope - The reaction is direct when known labeled antibody interacts directly with the
unknown antigen, and indirect when a two-stage process is used (often more
sensitive) - An example is the fluorescent treponemal assay with antibody absorption (FTA-ABS),
used in the identification of syphilis
5) Complement fixation
- Consists of the following two steps:
(1) Antigen and antibody (one known and the other unknown) are mixed and a
measured amount of complement is added - If the antigen and antibody match, they will combine and use up (“fix“) the
complement
(2) An indicator system, consisting of “sensitized“ RBCs (i.e. RBCs plus anti-RBC
antibody), is added
- If the antibody matched the antigen in the first step then complement was
fixed and less (or none) is available to attach to the sensitized RBCs,
therefore the RBCs remain unhemolyzed (i.e. the test is positive) - An example is the Wasserman test (non-treponemal test) where the antigen is
cardiolipin
6) Hemagglutination tests
* Many viruses clump RBCs from one species or another (active hemagglutination) and
this can be inhibited by antibody specifically directed against the virus
* RBCs can also absorb many antigens and, when mixed with matching antibodies, will
clump (passive hemagglutination)
7) Western blot (immunoblot)
- Proteins are separated electrophoretically in a gel, resulting in discrete bands of
protein - They are then transferred from the gel (i.e. blotted) onto filter paper, and the person‘s
serum is added - If antibodies are present, they bind to the proteins and can be detected by adding
antibody to human IgG labeled with either radioactivity or an enzyme - Typically used to determine whether a positive result in a screening immunologic
test is a true-positive or a false-positive result - For example, as a follow up to a positive result in ELISA screening for HIV
infection
8) Fluorescence-activated cell sorting (flow cytometry)
- Commonly used to measure the number of the various types of immunologically
active blood cells - For example, it is used in HIV-infected patients to determine the number of CD4+ T cells (fluorescent mAb detected with a laser light beam, one cell at a time)
Entameba
- Entamoeba histolytica causes amebic dysentery (bloody, mucus-containing diarrhea) and
liver abscess - Life cycle has two stages: the motile ameba (trophozoite), which is passed in feces, and
the nonmotile cyst, which is ingested orally - The cyst has four nuclei, which is an important diagnostic criterion
- The trophozoites invade the colonic epithelium and secrete enzymes that cause localized
necrosis (“flask-shaped“ ulcer) - Progression into the submucosa leads to invasion of the portal circulation by
trophozoites
Infection by E. histolytica is found worldwide but occurs most frequently in tropical
countries
- In addition to acute dysentery, chronic amebiasis with low-grade symptoms such as
occasional diarrhea, weight loss, and fatigue also occurs - Roughly 90% of those infected have asymptomatic infections, but they may be carriers
- In some patients, a granulomatous lesion called an ameboma may form in the cecal or
rectosigmoid areas of the colon and can resemble an adenocarcinoma - Right-lobe liver abscess can penetrate the diaphragm and cause lung disease
- Diagnosis of intestinal amebiasis rests on finding either trophozoites in diarrheal stools or
cysts in formed stools - The stool O&P test is insensitive and false negatives commonly occur
- E. histolytica can be distinguished from other amoebas by the nature of the trophozoite
nucleus (small, central, fine chromatin granules) as well as by the cyst size and number of its nuclei - Detection of E. histolytica antigens and nucleic acids (via PCR) as well as serologic testing
(indirect hemagglutination) can also be useful for detection of the organism - The treatment of choice for symptomatic intestinal amebiasis or hepatic abscesses is
metronidazole or tinidazole - Asymptomatic cyst carriers should be treated with iodoquinol or paromomycin
Naegleria, Acanthamoeba
Acanthamoeba castellanii and Naegleria fowleri are free-living amoebas that cause
meningoencephalitis
- Acanthamoeba also causes keratitis, which is an inflammation of the cornea that occurs
primarily in those who wear contact lenses - Acanthamoeba is carried into the skin and eyes during trauma, and primarily causes
infections in immunocompromised individuals - Diagnosis is made by finding amoebas in the spinal fluid (in case of CNS infection) and with
corneal scrapings or biopsy (in case of eye infection) - The prognosis is poor even in treated cases
- Amphotericin B may be effective in Naegleria infections, whereas pentamidine,
ketoconazole, or flucytosine may be effective in Acanthamoeba infections
Giardia lamblia, Trichomonas
- Giardia lamblia causes giardiasis (watery, foul-smelling diarrhea)
- Accompanied by nausea, anorexia, flatulence, and abdominal cramps persisting for
weeks or months - The life cycle consists of two stages: the trophozoite and the cyst
- The trophozoite is pear-shaped with two nuclei, four pairs of flagella, and a suction
disk with which it attaches to the intestinal wall - The oval cyst is thick-walled with four nuclei and several internal fibers
- Excystation takes place in the duodenum, where the trophozoite attaches to the gut wall
but does not invade the mucosa and does not enter the bloodstream - The trophozoite causes inflammation of the duodenal mucosa, leading to
malabsorption of protein and fat - The organism is found worldwide and about half of those infected are asymptomatic
carriers - Diagnosis is made by finding trophozoites or cysts or both in diarrheal stools
- An ELISA test that detects Giardia antigen in the stool is also very useful
- If stool diagnosis and ELISA test are negative, the string test, which consists of swallowing
a weighted piece of string until it reaches the duodenum, may be useful - The trophozoites adhere to the string and can be visualized after its withdrawal
- The treatment of choice is either metronidazole or tinidazole
Trypanosoma, Leishmania
- Trichomonas vaginalis causes trichomoniasis (watery, foul-smelling, greenish vaginal
discharge accompanied by itching and burning) - T. vaginalis is a pear-shaped organism with a central nucleus and four anterior flagella that
exists only as a trophozoite - The primary locations of the organisms are the vagina and the prostate
- Trichomoniasis is one of the most common infections in the world, with roughly
25-50% if women in the US harboring the organism - Infection in men is usually asymptomatic, but about 10% of infected men have urethritis
- The treatment of choice is metronidazole and it is important to treat both partners
- Trypanosoma cruzi is the cause of Chagas‘ disease (American trypanosomiasis)
- The life cycle involves the reduviid bug (“kissing bug“) as the vector, and both humans and
animals (e.g. cats, dogs, armadillo) as reservoir hosts - Reduviid bug takes a blood meal and passes trypomastigotes in feces, which then
enter the bite wound - There, they form non-flagellated amastigotes within host cells (myocardial, glial,
and reticuloendothelial cells are most frequently affected) - Amastigotes differentiate into trypomastigotes, then burst out of the cell and enter
the bloodstream where they can infect cells at different sites and continue the
infective cycle - When the reduviid bug bites again, the trypomastigotes get taken up by the bug
- Within the insect gut, the trypomastigotes multiply and differentiate first into
epimastigotes and then into trypomastigotes - Chagas‘ disease occurs primarily in rural Central and South America
- The acute phase of Chagas‘ disease consists of facial edema and a nodule near the bite,
coupled with fever, lymphadenopathy, and hepatosplenomegaly - The acute phase resolves in about 2 months, with most individuals remaining
asymptomatic but some progressing to the chronic form (myocarditis, megacolon) - Acute disease is diagnosed by demonstrating the presence of trypomastigotes in thick or
thin films of the patient‘s blood - If diagnosis cannot be made with blood smear, then other diagnostic methods (e.g.
stained preparation of a bone marrow aspirate or muscle biopsy specimen, culture
of the organism, xenodiagnosis, or serological tests) may be required - The drug of choice for the acute phase is nifurtimox, which kills trypomastigotes in the
blood but is much less effective against amastigotes in tissue
Trypanosoma brucei
- Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause sleeping
sickness (African trypanosomiasis) - The life cycle of Trypanosoma brucei involves the tsetse fly as well as human and animal
(only T. rhodesiense) reservoirs - Metacyclic trypomastigotes are transmitted by the tsetse fly bite, from which they
enter the bloodstream where they differentiate into blood-form trypomastigotes
and multiply - The trypomastigotes are then taken up by the tsetse fly in a blood meal from the
reservoir host - Within the insect guts they multiply and migrate to the salivary glands, where they
transform into epimastigotes that multiply further and then form metacyclic
trypomastigotes - The trypomastigotes spread from the skin through the blood to the lymph nodes and the brain, where they cause the typical somnolence (sleeping sickness) and eventual coma (due to demyelinating encephalitis)
- The disease is endemic in sub-Saharan Africa, the natural habitat of the tsetse fly
- Treatment must be initiated before the development of encephalitis, because suramin, the
most effective drug, does not pass the blood-brain barrier well
Leishmania braziliensis and L. donovani
- Leishmania donovani is the cause of kala-azar (visceral leishmaniasis)
- The life cycle of L. donovani involves the sandfly as the vector and a variety of mammals
(dogs, foxes, rodents) as reservoirs - When the sandfly sucks blood from an infected host, it ingests macrophages
containing amastigotes - After dissolution of the macrophages, the freed amastigotes differentiate into
promastigotes in the insect gut and then multiply and migrate to the pharynx, where
they can be transmitted during the next bite - Shortly after an infected sandfly bites a human, the promastigotes are engulfed by
macrophages, where they transform into amastigotes - The infected cells die and release progeny amastigotes that infect other macrophages
and reticuloendothelial cells - Symptoms begin with intermittent fever, weakness, and weight loss
- Massive splenomegaly and hyperpigmentation of the skin is characteristic
- Reduced bone marrow activity, coupled with cellular destruction in the spleen, results in
anemia, leukopenia, and thrombocytopenia - Untreated severe disease is nearly always fatal as a result of secondary infection, but with
proper therapy the mortality rate is reduced to almost 5% - Recovery results in permanent immunity
- Diagnosis is usually made by detecting amastigotes in a bone marrow, spleen, or lymph
node biopsy - Leishmania tropica and L. mexicana both cause cutaneous leishmaniasis
- The initial lesion is a red papule at the bite site, which enlarges slowly to form
multiple satellite nodules that coalesce and ulcerate - The lesion can spread to involve large areas of skin in immunocompromised
- Leishmania braziliensis causes mucocutaneous leishmaniasis, which occurs only in
Central or South America - Begins with a papule at the bite site, but then the metastatic lesions form, usually at the mucocutaneous junction of the nose and mouth
- Disfiguring granulomatous, ulcerating lesions destroy nasal cartilage and heal slowly,
if at all - The life cycle and diagnosis of L. tropica, L. mexicana, and L. braziliensis is essentially the
same as for L. donovani - The treatment of choice is either liposomal amphotericin B or sodium stibogluconate in
visceral leishmaniasis, and sodium stibogluconate in cutaneous as well as mucocutaneous
leishmaniasis
Plasmodia, Babesia
Plasmodium malariae, P. vivax, P. ovale,
and P. falciparum
- Malaria is caused primarily by four plasmodia: Plasmodium vivax, Plasmodium ovale,
Plasmodium malariae, and Plasmodium falciparum - The life cycle of Plasmodium species involves the female Anopheles mosquito as the vector
and humans as the intermediate hosts
The life cycle in humans begins with the introduction of sporozoites into the blood
from the saliva of the biting mosquito
- The sporozoites are taken up by hepatocytes, where they multiply and differentiate
into a schizont filled with merozoites
§ P. vivax and P. ovale produce a latent form (hypnozoite) in the liver, which is
the cause of relapses seen with vivax and ovale malaria - Upon rupture of the schizont, merozoites are released from the liver cells and infect
RBCs, where they differentiate into ring-shaped trophozoites - The ring-form grows into an ameboid form and then differentiates into a schizont
filled with merozoites - After release, the merozoites infect other RBCs and repeat this cycle at regular
intervals - Some merozoites develop into male and others into female gametocytes
- The gametocyte-containing RBCs are ingested by the female Anopheles mosquito and,
within her gut, produce a female macrogamete and eight sperm-like male
microgametes - After fertilization, the diploid zygote differentiates into a motile ookinete that
burrows into the gut wall, where it grows into an oocyst within which many haploid
sporozoites are produced - The sporozoites are released and migrate to the salivary glands, ready to complete
the cycle when the mosquito takes her next blood meal - The periodic release of merozoites causes the typical recurrent symptoms of chills, fever,
and sweats seen in malaria patients - A very important feature of P. falciparum is chloroquine resistance
- Most of the pathologic findings of malaria result from the destruction of RBCs
(splenomegaly, fever, anemia etc.) - Malaria caused by P. falciparum is more severe than that caused by other plasmodia, which
are usually self-limited with a low mortality rate - Infects far more RBCs –> occlusion of capillaries with aggregates of parasitized RBCs
–> life-threatening hemorrhage and necrosis, particularly in the brain (cerebral
malaria) - More than 200 million people worldwide have malaria and more than 1 million die of it
each year, making it the most common lethal infectious disease - It occurs primarily in tropical and subtropical areas, especially in Asia, Africa, and
Central and South America - If blood smears do not reveal the diagnosis, then a PCR-based test for Plasmodium nucleic
acids or an ELISA test for a protein specific for P. falciparum can be useful - The main criteria used for choosing the specific treatment for malaria are the severity of
the disease and whether the organism is resistant to chloroquine - Chloroquine is the drug of choice for treatment of uncomplicated malaria caused by
non-falciparum species in areas without chloroquine resistance - Primaquine is used to kill the hypnozoites of P. vivax and P. ovale, but must not be
given to a patient with G6PD deficiency as it may induce severe hemolysis - Coartem (artemether and lumefantrine) or Malarone (atovaquone and proguanil)
can be used to treat uncomplicated, chloroquine-resistant P. falciparum - In severe, complicated cases of chloroquine-resistant falciparum malaria, IV
administration of either artesunate or quinidine is used - Chemoprophylaxis of malaria for travelers to areas where chloroquine-resistant
P. falciparum is endemic consists of mefloquine or doxycycline, whereas chloroquine
should be used in areas where P. falciparum is sensitive to that drug
Babesia spp.
- Babesia microti causes babesiosis, which is a zoonosis acquired chiefly in the coastal areas
and islands off the northeastern coast of the US - The sporozoa of the organism is transmitted by the bite of the Ixodes scapularis tick, the
same species of tick that transmits Borrelia burgdorferi - Causes influenza-like symptoms, that begin gradually and may last for several weeks, in
addition to hepatosplenomegaly and anemia - The treatment of choice for mild to moderate disease is a combination of atovaquone and
azithromycin - Patients with severe disease should receive a combination of quinidine and clindamycin
- Babesia divergens causes babesiosis as well and is endemic to Europe
- In case of splenectomy it causes hemolytic anemia with a 50% mortality rate
Toxoplasma gondii
- Toxoplasma gondii causes toxoplasmosis, including congenital toxoplasmosis
- The life cycle of T. gondii involves the domestic cat (and other felines) as the definitive host
and humans and other mammals as intermediate hosts - Infection of humans begins with the ingestion of cysts in undercooked meat or from
accidental contact with cysts in cat feces - In the small intestine, the cysts rupture and release forms that invade the gut wall,
where they are ingested by macrophages and differentiate into rapidly multiplying
tachyzoites (trophozoites), which kill the cells and infect other cells - The parasites enter host cells in the brain, muscle, and other tissues, where they
develop into cysts in which the parasites multiply slowly and differentiate into
bradyzoites - The cycle within the cat begins with the ingestion of cysts in raw meat (e.g. mice)
- Bradyzoites are released from the cysts in the small intestine, infect the mucosal cells, and differentiate into male and female gametocytes, whose gametes fuse to form oocysts that are excreted in cat feces
- Human-to-human transmission of T. gondii, other than transplacental transmission, does not occur
- Congenital infection of the fetus occurs only when the mother is infected during pregnancy
- Progression of the infection is usually limited by a competent immune system
When contained, the organisms persist as cysts within tissues with no inflammation
present, and the individual remains well unless immunosuppression allows activation of
organisms in the cysts
- Infection by T. gondii occurs worldwide and is usually sporadic
- Clinical findings vary between immunocompetent persons, immunocompromised persons,
and newborns - Immunocompetent: asymptomatic mostly, may resemble infectious mono-nucleosis
- Immunocompromised: primarily encephalitis
- Congenital: abortion, stillbirth, encephalitis, chorioretinitis, hepatosplenomegaly,
fever, jaundice, intracranial calcifications, mental retardation, blindness - Acute and congenital infections can be detected with an IFA for IgM or IgG (not in
congenital) antibody - Microscopic examination of Giemsa-stained preparations shows crescent-shaped
trophozoites during acute infections - Congenital toxoplasmosis and disseminated disease in immunocompromised patients
should be treated with a combination of sulfadiazine and pyrimethamine - Acute toxoplasmosis in immunocompetent individuals is usually self-limited, but any
patient with chorioretinitis should be treated
Cryptosporidium, Cyclospora, Cycloisospora
Cryptosporidium spp.
- Cryptosporidium hominis (formerly known as Cryptosporidium parvum) causes
cryptosporidiosis, the main symptom of which is diarrhea (most severe in immunocompromised patients) - Some aspects of the life cycle of C. hominis are uncertain, but the following stages have been
identified - Oocysts release sporozoites which form trophozoites
- Several stages ensue, involving the formation of schizonts and merozoites
- Eventually, microgametes and macrogametes form and unite to produce a zygote,
which differentiates into an oocyst - The organism is acquired by fecal-oral transmission of oocysts from either human sources
(primarily) or from animal sources (e.g. cattle) - The pathogenesis of the diarrhea is uncertain and no toxin has been identified
- Cryptosporidia cause diarrhea worldwide, with large outbreaks attributed to inadequate
purification of drinking water occurring in urban cities occasionally - The cysts are highly resistant to chlorination but are killed by pasteurization and can be
removed by filtration - Nitazoxanide is the drug of choice for patients not infected with HIV
- There is no effective drug therapy for severely immunocompromised patients, but
paromomycin may be useful in reducing diarrhea - Cryptosporidia belong to the subclass Coccidia
- Isospora belli is an intestinal protozoan that causes watery diarrhea, especially in
immunocompromised patients - Its life cycle parallels that of other members of the Coccidia
- Isospora are similar to Cryptosporidia in many ways; they also are acquired by fecaloraltransmission of oocysts from either human or animal sources and they also cause
infection of the small intestine - Unlike Cryptosporidia, however, Isospora invade the mucosa of the small intestine
and cause destruction of the brush border - Diagnosis is made by finding the typical oocysts in fecal specimens
- The treatment of choice is trimethoprim-sulfamethoxazole (TMP:SMX)
Microsporida are a group of protozoa characterized by obligate intracellular replication
and spore formation
- Enterocytozoon bienusi and Encephalitozoon intestinalis are two important
microsporidial species that cause severe, persistent, watery diarrhea in AIDS patients - The organisms are transmitted from human to human by the fecal-oral route
- Microsporidia are also implicated in infections of the CNS, the genitourinary tract,
and the eye - Diagnosis is made by visualization of the spores in stool samples or intestinal biopsy
samples - The treatment of choice is albendazole
Enterobius vermicularis, Trichuris trichiura
Intestinal nematodes
Enterobius vermicularis
- Enterobius vermicularis causes pinworm infection (enterobiasis)
- The life cycle of E. vermicularis occurs only in humans; there is no animal reservoir or vector
- The infection is acquired by ingesting the worm eggs
- The eggs hatch in the small intestine, where the larvae differentiate into adults and
migrate to the colon, where mating occurs - At night, the female migrates from the anus and releases thousands of fertilized eggs
on the perianal skin and into the environment - Within 6 hours, the eggs develop into embryonated eggs and become infectious
- Reinfection can occur if they are carried to the mouth by fingers after scratching the
itching skin - Perianal pruritus is the most prominent symptom and scratching predisposes to secondary
bacterial infection - Enterobius is found worldwide, with children younger than 12 years of age being the most
commonly affected group - The treatment of choice is mebendazole or pyrantel pamoate
Trichuris trichiura
- Trichuris trichiura causes whipworm infection (trichuriasis)
- Humans are infected by ingesting worm eggs in food or water contaminated with human feces
- The eggs hatch in the small intestine, where the larvae differentiate into immature
adults - The adults migrate to the colon, where they mature, mate, and produce thousands of fertilized eggs daily, which are passed in the feces
- Eggs deposited in warm, moist soil form embryos, and when the embryonated eggs are ingested, the cycle is completed
- Trichuris may cause diarrhea, but most infections are asymptomatic
- In children with heavy infection, Trichuris may also cause rectal prolapse, resulting from
increased peristalsis that occurs in an effort to expel the worms - Whipworm infection occurs worldwide, especially in the tropics
- Diagnosis is based on finding the typical lemon-shaped eggs with a plug at each end in the
stool - Albendazole is the drug of choice
Ascaris lumbricoides, Toxocara
Ascaris lumbricoides
- Ascaris lumbricoides causes ascariasis
- Humans are infected by ingesting worm eggs in food or water contaminated with human
feces - The eggs hatch in the small intestine, and the larvae migrate through the gut wall
into the bloodstream and then to the lungs - They enter the alveoli, pass up the bronchi and trachea, and are swallowed
- Within the small intestine, they become adults
- They live in the lumen, do not attach to the wall, and derive their sustenance from
ingested food - Thousands of eggs are laid daily, are passed in the feces, and differentiate into
embryonated eggs in warm, moist soil - Ingestion of the embryonated eggs completes the cycle
- The adults of A. lumbricoides are the largest intestinal nematodes, often growing to >25 cm
- The major damage occurs during larval migration rather than from the presence of adult
worm in the intestine - In the lungs, the larvae cause inflammation with an eosinophilic exudate (Ascaris
pneumonia), often manifesting with fever and cough - A heavy worm burden may contribute to malnutrition, especially in children in developing
countries, as well as abdominal pain and even obstruction - Most infections are asymptomatic
- Treatment of choice is mebendazole or pyrantel pamoate
Toxocara (tissue nematode)
- Toxocara canis is the major cause of visceral larva migrans
- Toxocara cati and several other related nematodes also cause
this disease - The definitive host for T. canis is the dog, with humans being an
accidental, dead-end host - The adult T. canis female in the dog intestine produces eggs
that are passed in the feces into the soil - Humans ingest soil containing the eggs, which hatch into larvae
in the small intestine - The larvae migrate to many organs, especially the liver, brain, and eyes
- The larvae eventually are encapsulated and die
- Pathology is related to the granulomas that form around the dead larvae as a result of a
DTH response to larval proteins - The most serious clinical finding is blindness associated with retinal involvement
- Fever, hepatomegaly, and eosinophilia are common
- Encephalitis, myocarditis, and pneumoniae may also occur
- Young children are primarily affected
- Serologic tests are commonly used, but the definitive diagnosis depends on visualizing the
larvae in tissue - Albendazole or mebendazole is the treatment of choice
Strongyloides stercolaris, Ancylostoma duodenale, Necator americanus
Strongyloides stercoralis
- Strongyloides stercoralis causes strongyloidiasis
- S. stercoralis has two distinct life cycles, one within the human body and the other
free-living in the soil - The life cycle in the human body begins with the penetration of the skin (usually of
the feet) by infectious filariform larvae and their migration to the lungs - They enter the alveoli, pass up the bronchi and trachea, and then are swallowed
- In the small intestine, the larvae molt into adults that produce eggs in the mucosa
- The eggs usually hatch within the mucosa, forming rhabditiform larvae that are
passed in the feces - Some larvae molt to form filariform larvae, which penetrate the intestinal wall
directly without leaving the host and migrate to the lungs (autoinfection) - Larvae that are passed in the feces and enter warm, moist soil molt through
successive stages to form adult male and female worms - After mating, the entire life cycle of egg, larva, and adult can occur in the soil
- After several free-living cycles, filariform larvae are formed and can once again
penetrate human skin to initiate the parasitic cycle within humans
Most patients are asymptomatic and most infections occur in Southeast Asia
- Adult female worms in the wall of the small intestine may cause inflammation that results
in watery diarrhea - Larvae in the lungs can produce pneumonitis similar to that caused by Ascaris
- Pruritus at the site of infection as well as cutaneous larva migrans can also occur
- Ivermectin is the drug of choice and thiabendazole is an alternative
Ancylostoma duodenale and Necator americanus
- Ancylostoma duodenale (Old World hookworm) and Necator americanus (New World
hookworm) cause hookworm infection - Humans are infected when filariform larvae in moist soil penetrate the skin (usually of
the feet or legs) - They are carried by the blood to the lungs, migrate into the alveoli and up the bronchi
and trachea, and then are swallowed - They develop into adults in the small intestine, attaching to the wall with either
cutting plates (Necator) or teeth (Ancylostoma) - They feed on blood from the capillaries of the intestinal villi and produce thousands
of eggs per day that are passed in the feces - Eggs develop first into non-infectious, feeding rhabditiform larvae and then into
third stage, infectious, non-feeding filariform larvae, which penetrate the skin to complete the cycle - The major damage is due to the loss of blood at the site of attachment in the small intestine
(weakness, pallor, microcytic anemia) - Pruritus at the site of infection as well as cutaneous larva migrans can also occur
- Pneumonia with eosinophilia can be seen during larval migration through the lungs
- Hookworm is found worldwide, especially in tropical areas
- The treatment of choice is mebendazole or pyrantel pamoate
Trichinella spiralis
Trichinella spiralis causes trichinosis
- The life cycle of T. spiralisinvolves mammal reservoirs (pigs most importantly) and humans
as end-stage hosts - Humans are infected by eating raw or undercooked meat containing larvae encysted
in the muscle - The larvae excyst and mature into adults within the mucosa of the small intestine
- Eggs hatch within the adult females, and larvae are released and distributed via the
bloodstream to many organs; however, they develop in striated muscle cells - Within these “nurse cells“, they encyst within a fibrous capsule and can remain viable
for several years but eventually calcify - Diarrhea usually develops after eating undercooked meat (usually pork), followed 1 to 2
weeks later by fever, muscle pain, periorbital edema, subconjunctival hemorrhages
(important diagnostic criterion), and eosinophilia - Signs of cardiac and CNS disease are frequent, because the larvae migrate to these tissues
as well - Death, which is rare, is usually due to congestive heart failure or respiratory paralysis
- Trichinosis occurs worldwide, especially in Eastern Europe and West Africa
- Muscle biopsy reveals larvae within striated muscle, and serologic tests become positive 3
weeks after infection - There is no effective treatment for trichinosis when the larvae have infected the muscle,
but for patients with severe symptoms, steroids plus albendazole can be useful
Hymenolepis nana, Diphyllobotrium latum
Cestodes
Diphyllobothrium latum
- Diphyllobothrium latum (fish tapeworm) causes diphyllobothriasis
- Humans are infected by ingesting raw or undercooked fish containing plerocercoid larvae
(a.k.a. spraganum larvae) - In the small intestine, the larvae attach to the gut wall and develop into adult worms
- Gravid proglottids release fertilized eggs through a genital pore, and the eggs are
then passed in the stools (must go into fresh water for life cycle to continue) - The embryos emerge from the eggs and are eaten by tiny copepod crustacea (first
intermediate host) - There the embryos differentiate and form procercoid larvae in the body cavity
- When the copepod is eaten by freshwater fish (e.g. pike, trout, perch), the larvae
differentiate into plerocercoids in the muscle of the fish (second intermediate host) - The cycle is complete when raw or undercooked fish is eaten by humans (definitive
host) - Infection by D. latum causes little damage in the small intestine and therefore most patients
are asymptomatic, but abdominal discomfort and diarrhea can occur - Megaloblastic anemia occurs in some individuals as a result of vitamin B12 deficiency
caused by the preferential uptake of the vitamin by the worm - The disease is found worldwide but is endemic in areas where eating raw fish is custom
(Scandinavia, northern Russia, Japan, etc.) - Diagnosis depends on finding the typical eggs (i.e. oval, yellow-brown eggs with an
operculum at one end) in the stools - The treatment of choice is praziquantel
Hymenolepis nana
- Hymenolepis nana (dwarf tapeworm) is the most frequently found tapeworm in the US
- It is different from other tapeworms because its eggs are directly infectious for humans (i.e.
ingested eggs can develop into adult worms without an intermediate host) - Within the duodenum, the eggs hatch and differentiate into cysticercoid larvae and
then into adult worms - Gravid proglottids detach, disintegrate, and release fertilized eggs
- The eggs either pass in the stool or can reinfect the small intestine (autoinfection)
- A possible intermediate host for H. nana are is arthropods, which can ingest the eggs
passed in human stool - Infection causes little damage, and most patients are asymptomatic
- The organism is found worldwide, commonly in the tropics
- Diagnosis is based on finding eggs in stools (characteristically have 8-10 polar filaments
between the membrane of the six-hooked larva and the outer shell) - The treatment of choice is praziquantel
Taenia solium, T. saginata
There are two important human pathogens in the genus Taenia: T. solium (pork tapeworm) and
T. saginata (beef tapeworm).
Taenia solium
* The adult form of T. solium causes taeniasis, whereas the larvae of T. solium cause
cysticercosis
* Humans are infected by eating raw or undercooked pork containing the cysticercoid
larvae
In the small intestine, the larvae attach to the gut wall and take about 3 months to grow into adult worms measuring up to 5 m
- The gravid terminal proglottids containing many eggs detach daily, are passed in the
feces, and are accidentally eaten by pigs (intermediate host) - A six-hooked embryo (oncosphere) emerges from each egg in the pig‘s intestine
- The embryos burrow into a blood vessel and are carried to skeletal muscle, where
they develop into cysticerci and remain until eaten by a human (definitive host) - In cysticercosis, a more dangerous sequence occurs when a person ingests the worm eggs
in food or water that has been contaminated with human feces - The eggs hatch in the small intestine, and the oncospheres burrow through the wall
into a blood vessel - They can disseminate to many organs, especially the eyes and brain, where they
encyst to form cysticerci - The adult tapeworm attached to the intestinal wall causes little damage and most patients
infected by them are asymptomatic, but anorexia and diarrhea can occur - The cysticerci, on the other hand, can become very large, especially in the brain, where they
manifest as a space-occupying lesion - Living cysticerci do not cause inflammation, but when they die they release
substances that provoke an inflammatory response - Eventually the cysticerci calcify
- Cysticercosis in the brain causes headaches, vomiting, and seizures
- Cysticercosis in the eyes can appear as uveitis or retinitis
- The disease occurs worldwide but is endemic in areas of Asia, South America, and Eastern
Europe - Identification of T. solium consists of finding gravid proglottids with 5-10 primary uterine
branches in the stools - Diagnosis of cysticercosis depends on demonstrating the presence of cyst in tissue
- The treatment of choice is praziquantel
Taenia saginata
* Taenia saginata causes taeniasis
* T. saginata larvae do not cause cysticercosis
* The life cycle of T. saginata follows the same steps as the life cycle of T. solium, with the
exception that consumption of raw or undercooked beef is the cause of infection and cattle
are the intermediate host
* Little damage results from the presence of adult worm in the small intestine and most
patients infected by them are asymptomatic, but malaise and mild cramps can occur
* The disease occurs worldwide but is endemic in Africa, South America, and Eastern Europe
The proglottids are motile and may cause pruritus ani as they move on the skin adjacent to
the anus
* Identification of T. saginata consists of finding gravid proglottids with 15-20 uterine
branches in the stool
* The treatment of choice is praziquantel
Echinoccocus, Dipylidium caninum
Echinococcus
- Echinococcus granulosus (dog tapeworm) causes echinococcosis
- The larvae of E. granulosus cause unilocular hydatid cyst disease
- In the typical life cycle, adult worms in the dog‘s (definitive host) intestine liberate
thousands of eggs, which are ingested by sheep (intermediate host) and humans
(dead-end intermediate host) - The oncosphere embryos emerge in the small intestine and migrate primarily to the liver but also to the lungs, bones, and brain
- The embryos develop into large fluid-filled hydatid cysts, containing many
protoscoleces - The life cycle is completed when the entrails (e.g. liver containing hydatid cysts) of
slaughtered sheep are eaten by dogs - The cyst formed by E. granulosus acts as a space-occupying lesion, putting pressure on
adjacent tissue - Many individuals are asymptomatic, but liver cysts may cause hepatic dysfunction
- Cysts in the lungs can erode into a bronchus, causing bloody sputum
- Cerebral cysts can cause headache and focal neurologic signs
- If the cyst ruptures spontaneously or during trauma or surgical removal,
life-threatening anaphylactic shock can occur - The disease is found primarily in shepherds living in the Mediterranean region, the Middle
East, and Australia - Treatment involves albendazole with or without surgical removal of the cyst
- Echinococcus multilocularis shows many of the same features as those of
E. granulosus, but the definitive hosts are mainly foxes and the intermediate hosts are
various rodents - Within the human liver, the larvae form multiloculated cysts with few protoscoleces
- The clinical picture usually involves jaundice and weight loss and the prognosis is
poor
Dipylidium caninum
- Dipylidium caninum is the most common tapeworm of dogs and cats
- It occasionally infects human, usually young children, when dog or cat fleas carrying
cysticerci are ingested - The cysticerci develop into adult tapeworms in the small intestine
- Most human infections are asymptomatic, but diarrhea and pruritus ani can occur
- Diagnosis is made by observing the typical “barrel-shaped“ proglottids in the stool or
diapers - Niclosamide is the drug of choice
Infections caused by Trematodes (Schistosoma, Paragonimus, Clonorchis, Fasciola)
Trematodes
Schistosoma
* Schistosoma (blood fluke) causes schistosomiasis
* Schistosoma mansoni and Schistosoma japonicum affect the gastrointestinal tract, whereas
Schistosoma haematobium affects the urinary tract
In contrast to other trematodes, which are hermaphrodites, adult schistosomes exist as
separate sexes but live attached to each other
- Humans are infected when the free-swimming, fork-tailed cercariae penetrate the skin
- They differentiate to schistosomula larvae, enter the blood, and are carried via the
veins into the arterial circulation - Those that enter the sup. mesenteric artery pass into the portal circulation and reach
the liver, where they mature into adult flukes - In the definitive venous site (mesenteric venules for S. mansoni and
S. japonicum, bladder veins for S.
haematobium) the female lays fertilized eggs, which
penetrate the vascular endothelium and enter the gut or bladder lumen, respectively - The eggs are excreted in the stools or urine and must enter fresh water where they
release ciliated, swimming larvae called miracidia - The miracidia then penetrate snails (intermediate host) and undergo further
development and multiplication to produce many cercariae - Cercariae leave the snails, enter fresh water, and complete the cycle by penetrating
human skin - Most of the pathologic findings are caused by the presence of eggs in the liver, spleen, or
wall of the gut or bladder - Eggs in the liver induce granulomas, which lead to fibrosis, hepatomegaly, and portal
hypertension that leads to splenomegaly - S. mansoni eggs damage the wall of the distal colon, whereas S. japonicum eggs
damage the walls of the small and large intestine, leading to infection and GI
hemorrhage - The eggs of S. haematobium in the wall of the bladder induce granuloma and fibrosis,
which can lead to carcinoma of the bladder - Most patients are asymptomatic, but chronic infections may become symptomatic
- The acute stage, which begins shortly after cercarial penetration, consists of itching and
dermatitis followed 2 to 3 weeks later by fever, chills, diarrhea, lymphadenopathy, and
hepatosplenomegaly - “Swimmer‘s itch“, which consists of pruritic papules, is a frequent problem in many lakes
in the US and occurs due to an immunologic reaction to the presence in the skin of the
cercariae of non-human schistosomes - S. mansoni is found in Africa and Latin America, S. haematobium is found in Africa and the
Middle East, and S. japonicum is found only in Asia - The three species can be distinguished by the appearance of their eggs in the microscope
- S. mansoni: prominent lateral spine
- S. japonicum: very small lateral spine
- S. haematobium: terminal spine
- The treatment of choice is praziquantel
Paragonimus
- Paragonimus westermani (lung fluke) causes paragonimiasis
- Humans are infected by eating raw or undercooked crab meat (or crayfish) containing the
encysted metacercariae larvae - After excystation in the small intestine, immature flukes penetrate the intestinal
wall and migrate through the diaphragm into the lung parenchyma - There, they differentiate into hermaphroditic adults and produce eggs that enter the
bronchioles and are coughed up or swallowed - Eggs in either sputum or feces that reach fresh water hatch into miracidia, which
enter snails (first intermediate hosts) - There, they differentiate first into rediae larvae and then into many free-swimming
cercariae - The cercariae infect and encyst in freshwater crabs (second intermediate host) and
the cycle is complete when undercooked infected crabs are eaten by humans - The main symptom is a chronic cough with bloody sputum, accompanied by dyspnea,
pleuritic chest pain, and recurrent attacks of bacterial pneumonia - The disease can resemble tuberculosis
- Paragonimiasis is endemic in Asia and India
- The treatment of choice is praziquantel
Clonorchis
- Clonorchis sinensis causes clonorchiasis (Asian liver fluke infection)
- Humans are infected by eating raw or undercooked fish containing the encysted
metacercariae larvae - After excystation in the duodenum, immature flukes enter the biliary ducts and
differentiate into adults - The hermaphroditic adults produce eggs, which are excreted in the feces
- Upon reaching fresh water, the eggs are ingested by snails (first intermediate host)
- The eggs hatch within the gut and differentiate first into rediae larvae and then into
many free-swimming cercariae - Cercariae encyst under the scales of certain freshwater fish (second intermediate
host), which are then eaten by humans - Most infections are asymptomatic, but upper abdominal pain, anorexia, hepatomegaly, and
eosinophilia can occur in patients with a heavy worm burden - In some infections, the inflammatory response can cause hyperplasia and fibrosis of the
biliary tract, but often there are no lesions - Chlonorchiasis is endemic in China, Japan, Korea, and Indochina
- The treatment of choice is praziquantel
Fasciola
- Fasciola hepatica (sheep liver fluke) causes disease primarily in sheep and other domestic
animals in Latin America, Africa, Europe, and China - Humans are infected by eating watercress (or other aquatic plants) contaminated by
metacercariae larvae that excyst in the duodenum, penetrate the gut wall, and reach the
liver, where they mature into adults - Hermaphroditic adults in the bile ducts produce eggs, which are excreted in the feces
- The eggs hatch in fresh water, and miracidia enter the snails
- Miracidia develop into cercariae, which then encyst on aquatic vegetation
- Sheep and humans eat the plants, thus completing the life cycle
- Symptoms are primarily due to the presence of adult worm in the biliary tract
- In early infection, right-upper-quadrant pain, fever, and hepatomegaly can occur, but
most infections are asymptomatic - Months or years later, obstructive jaundice can occur
- Halzoun is a painful pharyngitis caused by the presence of adult flukes on the
posterior pharyngeal wall, acquired by eating raw sheep liver - Diagnosis is made by identification of eggs in the feces
- The drug of choice is triclabendazole
Tissue infecting filarial Nematodes (Wuchereria, Loa, Onchocerca, Dracunculus)
Tissue nematodes
Wuchereria
* Wuchereria bancrofti causes filariasis
* Humans are infected when the female mosquito deposits infective larvae on the skin while
biting
- The larvae penetrate the skin, enter a lymph node, and, after 1 year, mature to adults
that produce microfilariae - These circulate in the blood, chiefly at night, and are ingested by biting mosquitoes
- Within the mosquito, the microfilariae produce infective larvae that are transferred
with the next bite - Early infections are asymptomatic, but later, fever, lymphangitis, and cellulitis develop
- Adult worms in the lymph nodes cause inflammation that eventually obstructs the
lymphatic vessels, causing massive edema of the legs (elephantiasis) - Microfilariae in the lung elicit an immediate hypersensitivity reaction that causes tropical
pulmonary eosinophilia, characterized by coughing and wheezing, especially at night - The disease occurs in the tropical areas of Africa, Asia, and Latin America
- Diethylcarbamazine is effective only against microfilariae; no drug therapy for adult worms
is available
Loa
* Loa loa causes loiasis
- Humans are infected by the bite of the deer fly, which deposits infective larvae on the skin
- The larvae enter the bite wound, wander in the body, and develop into adults
- The females release microfilariae that enter the blood, particularly during the day
- The microfilariae are taken up by the fly during a blood meal and differentiate into
infective larvae, which continue the cycle when the fly bites the next person - There is no inflammatory response to microfilariae or adults, but a hypersensitivity
reaction causes transient, localized, non-erythematous, subcutaneous edema - The most dramatic finding is an adult worm crawling across the conjunctiva of the eye, a
harmless but disconcerting event - The disease is found only in tropical Central and West Africa
- The drug of choice is diethylcarbamazine
Onchocerca
- Onchocerca volvulus causes onchocerciasis
- Humans are infected when the female blackfly, deposits infective larvae while biting
- The larvae enter the wound and migrate into the subcutaneous tissue, where they
differentiate into adults (usually within dermal nodules) - The female produces microfilariae that are ingested when another blackfly bites
- The microfilariae develop into infective larvae in the fly to complete the cycle
- Inflammation occurs in subcutaneous tissue, and pruritic papules and nodules form in
response to the adult worm proteins - Thickening, scaling, and dryness of the skin accompanied by severe itching are the
manifestations of a dermatitis often called “lizard skin“ - Microfilariae migrate through subcutaneous tissue, ultimately concentrating in the eyes
where they cause lesions that can lead to blindness (river blindness) - The disease is a major cause of blindness in Africa and Central America
- Diagnosis is based on identifying microfilariae in biopsy of the affected skin
- Ivermectin is effective against microfilariae but not adults, therefore suramin, which kills
adult worms but is quite toxic, can be given in addition
Dracunculus
- Dracunculus medinensis (guinea fire worm) causes dracunculiasis
- Humans are infected when tiny crustaceans containing infective larvae are swallowed in
drinking water - The larvae are released in the small intestine and migrate into the body, where they
develop into adults that cause the skin to ulcerate and then release motile larvae into
fresh water - Crustaceans eat the larvae, which molt to form infective larvae
- The adult female produces a substance that causes inflammation, blistering, and ulceration
of the skin, usually of the lower extremities - The inflamed papule burns and itches, and the ulcer can become secondarily infected
- Diagnosis is usually made clinically by finding the worm in the skin ulcer
- Thiabendazole and metronidazole can be given, but ultimately treatment relies on slow
extraction of the worm from the skin ulcer
Pneumocystis jiroveci
- Pneumocystis jirovecii is classified as a yeast on the basis of molecular analysis, but it has
many characteristics of a protozoan and is therefore medically thought of as one - P. jirovecii is an important cause of pneumonia in immunocompromised individuals
- Transmission occurs by inhalation and infection is predominantly in the lungs, although
the organism does not invade the lungs - The presence of cysts in the alveoli induces an inflammatory response consisting primarily
of plasma cells, resulting in a frothy exudate that blocks oxygen exchange - The sudden onset of fever, non-productive cough, dyspnea, and tachypnea is typical
of Pneumocystis pneumonia - Bilateral rales and ronchi are heard, and the chest X-ray shows a diffuse interstitial
pneumonia with “ground glass“ infiltrates bilaterally - Extrapulmonary infections occur in the late stages of AIDS and affect primarily the liver,
spleen, lymph nodes, and bone marrow - The mortality rate of untreated Pneumocystis pneumonia approaches 100%
- P. jirovecii is distributed worldwide and it is estimated that 70% of people have been
infected - Diagnosis is typically made by finding the cysts of Pneumocystis in bronchial lavage
specimens - The drug of choice is TMP-SMX
Fungal cell structure. Diagnostic procedures in fungal infections
Fungal cell structure
- Fungi (yeasts and molds) and bacteria differ in several aspects due to the fact that fungi are
eukaryotic organisms, whereas bacteria are prokaryotic - Two fungal cell structures are important medically:
(1) The fungal cell wall consists primarily of chitin (not peptidoglycan as in bacteria), but
also contains other polysaccharides, such as β-glucan (site of action of the anti-fungal
drug caspofungin)
(2) The fungal cell membrane contains ergosterol (except for P. jirovecii, which contains
cholesterol), which is the site of action of the amphotericin B and azole drugs
(fluconazole, ketoconazole)
- There are two types of fungi: yeasts and molds
- Yeasts grow as single cells that reproduce by asexual budding
- Molds grow as long filaments (hyphae) and form a mat (mycelium)
§ Some hyphae form transverse walls (septate hyphae), whereas others do not
(non-septate hyphae) - Several medically important fungi are thermally dimorphic, i.e. they form different
structures at different temperatures - They exist as molds in the environment at ambient temperature and as yeasts (or
other structures) in human tissues at body temperature - Some fungi reproduce sexually by mating and forming sexual spores (e.g. zygospores,
ascospores, and basidiospores) - Fungi that do not form sexual spores are termed “imperfect“ (fungi imperfecti)
- Most fungi of medical interest propagate asexually by forming conidia (asexual spores; e.g.
arthrospores, chlamydospores, blastospores, and sporangiospores) from the sides or ends
of specialized structures - Fungi do not have endotoxin in their cell walls and do not produce bacterial-type exotoxins
- Certain factors, such as the ALS (agglutinin-like sequence) family and secreted
phospholipases, aid in the colonization of fungi - Secreted phospholipases can be found e.g. in C. albicans, A. fumigatus, and
C. neoformans - Other factors, such as hydrophobic-hydrophobic interaction and co-aggregation with
aerobic and anaerobic bacteria, also aid in colonization - During infection, the phenotypic switch between blastoconidia and hyphae is a virulence
trait of C. albicans
Diagnostic procedures in fungal infections
- There are four approaches to the laboratory diagnosis of fungal diseases
1) Direct microscopic examination of clinical specimen
- Sputum, lung biopsy specimen, and skin scrapings can be used
- Depends on finding characteristic asexual spores, hyphae, or yeasts in the light
microscope
- Specimen is either treated with 10% potassium hydroxide (KOH) to dissolve
tissue material or stained with special fungal stains - F.x. spherules of C. immitis and the wide capsule of Cryptococcus neoformans
seen in India ink preparations of spinal fluid
2) Culture of the organism
- Fungi are frequently cultured on Sabouraud‘s agar, which facilitates the
appearance of the slow-growing fungi by inhibiting the growth of bacteria in
the specimen (due to low pH and added antibiotics)
- The appearance of the mycelium and the nature of the asexual spores are
frequently sufficient to identify the organism
3) DNA probe tests
- Identify colonies growing in culture at an earlier stage of growth than can tests
based on visual detection of the colonies, leading to a more rapid diagnosis
- Available for Coccidioides, Histoplasma, Blastomyces, and Cryptococcus
4) Serologic tests
- Tests for the presence of antibodies in the patient‘s serum or spinal fluid are
useful in diagnosing systemic mycoses but less so in diagnosing other fungal
infections - The complement fixation test is most frequently used in suspected cases of
coccidioidomycosis, histoplasmosis, and blastomycosis - In cryptococcal meningitis, the presence of polysaccharide capsular antigens of
C. neoformans in the spinal fluid can be detected by the latex agglutination test
Cutaneous mycoses
Dermatophytoses
- Dermatophytes are fungi that infect only superficial keratinized structures (skin, hair,
nails) and cause dermatophytoses (tinea, ringworm) - The most important dermatophytes are classified in three genera: Trichophyton,
Epidermophyton, and Microsporum
Dermatophytes are spread from infected persons by direct contact, and Microsporum is also
spread from animals such as dogs and cats
- Typical ringworm lesions have an inflamed circular border containing papules and vesicles
surrounding a clear area of relatively normal skin - The disease is usually named after the affected body part, such as tinea capitis for the head,
tinea corporis for the body, tinea cruris for the groin, and tinea pedis for the foot - Tinea unguium, also called onychomycosis, is a disease of the nails (especially toe nails),
where they become thickened, broken, and discolored - In some infected persons, hypersensitivity causes dermatophytid (“id“) reactions (e.g.
vesicles on the fingers), which are a response to circulating fungal antigens and do not
contain hyphae - Scrapings of skin or nail placed in KOH on a glass slide show septate hyphae under
microscopy - Cultures on Sabouraud‘s agar at room temperature develop typical hyphae and conidia
- Microsporum species can be detected by seeing fluorescence when the lesions are exposed
to ultraviolet light from a Wood‘s lamp - Topical terbinafine is the first-line therapy for tinea infections, but oral treatment with
griseofulvin or itraconazole can also be used - Onychomycosis can be treated with efinaconazole solution applied topically to the nails
- Lecture slides say that first-line therapy for onychomycosis is terbinafine (oral +/-
topical) and the second-line therapy should consist of azoles (oral +/- topical)
Malassezia furfur : Pityriasis versicolor
Tinea versicolor
- Tinea versicolor (pityriasis versicolor) is a superficial skin infection of cosmetic importance
only and is caused by Malassezia species - The lesions are usually noticed as hypopigmented areas, especially on tanned skin in the
summer - There might be slight scaling or itching, but usually infection is asymptomatic
- It occurs more frequently in hot, humid weather
- The lesions contain both budding yeast cells and hyphae
- Diagnosis is usually made by observing this mixture in KOH preparations of skin scrapings
- The treatment of choice is topical miconazole, but fluconazole or itraconazole can be used
to treat recurrences - Selenium sulfide lotion can also be used
Tinea nigra
- Tinea nigra is an infection of the keratinized layers of the skin and is caused by
Cladosporium werneckii - It appears as a brownish spot, caused by the melanin-like pigment in the hyphae, with
abnormal thickening of the cornified epidermis (hyperkeratosis) - It can also manifest with pruritus
- C. werneckii is typically found in the soil in tropical climates and transmitted during injury
- Diagnosis is made by microscopic examination with KOH and culture of the skin scrapings
- The infection is treated with a topical keratolytic agent (e.g. salicylic acid) as well as topical
antifungal agents (itraconazole, terbinafine)
Superficial and subcutaneous mycoses
Sporothrix schenckii
Sporotrichosis
- Sporothrix schenckii is a dimorphic fungus
- The mold form lives on plants and the yeast form occurs in human tissue
- When spores of the mold are introduced into the skin, typically by a thorn, it causes a local
pustule or ulcer with nodules along the draining lymphatics
The lesions are typically painless, and there is little systemic illness
- Some patients may present with arthritis and tenosynovitis
- In HIV-infected patients with low CD4 counts, disseminated sporotrichosis can occur
- Round or cigar-shaped budding yeasts are seen in tissue specimens
- The drug of choice for skin lesions is itraconazole
Chromomycosis
- Chromomycosis is a slowly progressive granulomatous infection that is caused by several
soil fungi (most often due to Fonsecaea pedroso, but also by Phialophora verrucosa and
Cladosporium spp.) when introduced into the skin through trauma - Wart-like lesions with crusting abscesses extend along the lymphatics
- After many years, the lesions may resemble the head of a cauliflower
- Bacterial superinfection can lead to lymphedema and elephantiasis, and occasionally
to squamous cell carcinoma at affected sites - The disease occurs mainly in the tropic and is found on bare feet and legs
- In the clinical laboratory, dark brown, round fungal cells are seen in leukocytes or giant
cells - The disease is treated with cryosurgery and itraconazole
Systemic mycoses
Coccidioides immitis
Coccidioides
• Coccidioides immitis causes coccidioidomycosis
• C. immitis is a dimorphic fungus that exists as a mold in soil and as a spherule in tissue
• The fungus is endemic in the southwestern US and Latin America
• It forms hyphae with alternating arthrospores in soil, which can be inhaled and infect the
lungs
- In the lungs, arthrospores form thick-walled spherules that are large (30 mm in
diameter) and filled with endospores
- Upon rupture of the wall, endospores are released and differentiate to form new
spherules
- Dissemination from the lungs to other organs (primarily bones and CNS) occurs in
people who have a defect in cell-mediated immunity
• Most infections of the lung are asymptomatic, but some infected persons develop an
influenza-like illness with fever and cough
- ~50% show changes in the lungs on X-ray and 10% develop erythema nodosum
• Disseminated disease most commonly produces meningitis, osteomyelitis and skin nodules
(NB: erythema nodosum is not a sign of disseminated disease, and is actually an indicator
of good prognosis)
• Diagnosis can be done microscopically (shows spherules), with culture (shows hyphae with
arthrospores), with serology, or with PCR
No treatment is needed in asymptomatic or mild primary infection
• Amphotericin B or itraconazole is used for persisting lung lesions or disseminated disease
• Fluconazole is the drug of choice for meningitis and is also effective in lung disease
Histoplasma capsulatum
Histoplasma
• Histoplasma capsulatum causes histoplasmosis
• This fungus occurs in many parts of the world, and is endemic in central and eastern US
states
• H. capsulatum is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue
- It forms two types of asexual spores: (1) tuberculate macroconidia, which are
important for laboratory identification; and (2) microconidia, which transmit the
infection if inhaled
• Inhaled spores are engulfed by macrophages and develop into yeast forms - The yeasts survive within the phagolysosome of the macrophage by producing
alkaline substances, such as bicarbonate and ammonia, which inactivate the
degradative enzymes of the phagolysosome - The organisms spread widely throughout the body, especially to the liver and spleen
- Most infections remain asymptomatic, with small granulomatous foci healing by
calcification - Intense exposure produces pneumonia and cavitary lung lesions that may manifest
with clinical problems - Disseminated histoplasmosis develops in infants and individuals with reduced cellmediated
immunity
• Pancytopenia and ulcerated lesions on the tongue are typical of disseminated
histoplasmosis
• Erythema nodosum may occur in immunocompetent people
• Diagnosis can be done with microscopic examination of tissue biopsy specimens or bone
marrow aspirates (show yeast cells within macrophages), with culture (shows hyphae with
macroconidia at 25°C and yeast at 37°C), and serologic tests
• No therapy is needed in asymptomatic or mild primary infections
• Oral itraconazole is effective against progressive lung disease, and parenteral itraconazole
or amphotericin B is the treatment of choice in disseminated disease
• Fluconazole is often used in meningitis because it penetrates the spinal fluid well
Blastomyces dermatitidis
Blastomyces
• Blastomyces dermatitidis causes blastomycosis (a.k.a. North American blastomycosis)
• B. dermatitidis is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue
- The yeast is round with a doubly refractive wall and a single broad-based bud
• This fungus is endemic primarily in the eastern US, where it grows in moist soil and forms
hyphae with small pear-shaped conidia
• Inhalation of the conidia causes human infection
- Asymptomatic or mild cases are rarely recognized
- Dissemination may result in ulcerated granulomas of skin, bone, or other sites
• Diagnosis can be done microscopically with tissue biopsy specimens (show thick walled
yeast cells with single broad-based buds), with culture (shows hyphae with small
pear-shaped conidia), or with PCR
• Itraconazole is the drug of choice for most patients, but amphotericin B should be used to
treat severe disease
Paracoccidioides brasiliensis
Paracoccidioides
• Paracoccidioides brasiliensis causes paracoccidioidomycosis (a.k.a. South American
blastomycosis)
• P. brasiliensis is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue
- The yeast is thick-walled with multiple buds
• This fungus grows in the soil and is endemic in rural Latin America, which is the only region
where the disease occurs
• The spores are inhaled, and early lesions occur in the lungs
- Asymptomatic infection is common
- Alternatively, oral mucous membrane lesions, lymph node enlargement, and
sometimes dissemination to many organs develop
• Diagnosis can be done with microscopic examination of pus or tissues (shows yeast cells
with multiple buds resembling a “ship captain‘s wheel“), with culture (2-4 weeks produces
typical organisms), or with serologic test
• The drug of choice is itraconazole taken orally for several months
Opportunistic mycoses I (Candida, Cryptococcus, Penicillium)
Candida albicans
Candida
• Candida albicans, the most important species of Candida, causes thrush, vaginitis,
esophagitis, diaper rash, and chronic mucocutaneous candidiasis
- It also causes disseminated infections such as right-sided endocarditis (especially in
IV drug users), bloodstream infections (candidemia), and endophthalmitis
- Other important Candida species include C. glabrata (second most common, th.
echinocandins), C. tropicalis (th. same as C. albicans), C. parapsilosis (th. same as
C. albicans), C. krusei (th. echinocandins), and C. auris (th. echinocandins)
• C. albicans is an oval yeast with a single bud - It is part of the normal flora of mucous membranes of the upper respiratory,
gastrointestinal, and female genital tracts - In tissues it appears most often as yeasts or as pseudohyphaes, which are elongated
yeasts that visually resemble hyphae - True hyphae are also formed when C. albicans invades tissues
• When local or systemic host defenses are impaired, disease may result - Overgrowth of C. albicans in the mouth produces white patches called thrush
- Vaginitis with itching and discharge with itching and discharge can occur due to high
pH, diabetes, or use of antibiotics - Skin invasion occurs in warm, moist areas, which become red and weeping
§ Dishwashers in restaurants are commonly affected on fingers and nails
§ Diaper rash in infants occurs when wet diapers are not changed promptly
In immunosuppressed individuals, Candida may disseminate to many organs or
cause chronic mucocutaneous candidiasis
- IV drug abuse, indwelling IV catheters, and hyperalimentation also predispose to
disseminated candidiasis, especially right-sided endocarditis and endophthalmitis
(infection within the eye)
- Candida esophagitis, often accompanied by involvement of the stomach and small
intestine, is seen in patients with leukemia and lymphoma
• Diagnosis can be made with microscopic analysis (budding yeast and pseudohyphae appear
Gram(+) and can be visualized with calcofluor-white staining), with culture (resemble large
staphylococcal colonies, form germ tubes at 37°C), and with a laboratory test that utilizes
magnetic resonance technology to detect the presence of yeast DNA and then to identify
the species
• The drug of choice for most candidal infections is fluconazole, but an echinocandin (e.g.
caspofungin, micafungin) can also be used
• Treatment of skin infections consists of topical antifungal drugs, such as clotrimazole or
nystatin
• Disseminated infection is usually treated with fluconazole or echinocandins, but
amphotericin B may also be used
Cryptococcus neoformans
Cryptococcus
• Cryptococcus neoformans causes cryptococcosis, especially cryptococcal meningitis
- Cryptococcosis is the most common, life-threatening invasive fungal disease
worldwide
• C. neoformans is an oval, yeast with a narrow-based bud and surrounded by a wide
polysaccharide capsule
• This fungus occurs widely in nature and grows abundantly well in soil containing bird
(especially pigeon) droppings
• Human infection results from inhalation of the organism
- Lung infection is often asymptomatic or may produce pneumonia
- Disease occurs mainly in patients with reduced cell-mediated immunity, in whom the
organism disseminates to the CNS (meningitis) and other organs
§ Note, however, that roughly half the patients with cryptococcal meningitis fail
to show evidence of immunosuppression
- Subcutaneous nodules are often seen in disseminated disease
• Diagnosis can be made with microscopic analysis of spinal fluid mixed with India ink,
showing yeast cells surrounded by a wide, unstained capsule
- Stains such as periodic acid-Schiff (PAS stain), methenamine silver, and mucicarmine
will also allow the organism to be visualized
• Other diagnostic options include culturing, serologic tests, and latex particle agglutination
• Combined treatment with amphotericin B and flucytosine is used in meningitis and other
disseminated disease
Penicillium marneffei
• Penicillium marneffei is a dimorphic fungus that causes penicilliosis, a tuberculosis-like
disease, in AIDS patients, particularly in Southeast Asian countries such as Thailand
- The disease can manifest as fever with or without pulmonary infiltrates, as well as
hepatosplenomegaly, lymphadenopathy and skin lesions
- Other clinical findings include oropharyngeal lesions in addition to intestinal and
musculoskeletal involvement
- Fungaemia occurs in 50-64% of patients
• It grows as a mold that produces a rose-colored pigment at 25°C but at 37°C grows as a
small yeast that resembles H. capsulatum
• Bamboo rats are the only other known hosts
• The diagnosis is made either by growing the organism in culture or by using fluorescent
antibody staining of affected tissue
• The treatment of choice consists of amphotericin B for 2 weeks followed by oral
itraconazole for 10 weeks (may be needed lifelong)
- Untreated penicilliosis is almost uniformly fatal
Opportunistic mycoses II (Aspergillus, Zygomycosis)
Apergillus fumigatus, A. flavus
Aspergillus
• Aspergillus species, especially Aspergillus fumigatus, cause (1) infections of the skin, eyes,
ears, and other organs; (2) “fungus ball“ in the lungs; and (3) allergic bronchopulmonary
aspergillosis
Aspergillus species exist only as molds
- They have septate hyphae that form V-shaped branches, with walls that are more or
less parallel and conidia that form radiating chains
• These molds are widely distributed in nature
• Transmission is by airborne conidia that colonize and later invade abraded skin, wounds,
burns, the cornea, the external ear, or paranasal sinuses
- In immunocompromised persons, it can invade the lungs producing hemoptysis and
the brain causing an abscess
• Aspergilli can grow in cavities within the lungs, especially cavities caused by tuberculosis,
where they produce an aspergilloma (fungus ball)
• Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the
presence of Aspergillus in the bronchi
- Patients have asthmatic symptoms and a high IgE titer against Aspergillus antigens,
and they cough up brownish bronchial plugs containing hyphae
• Aspergillus flavus growing on cereals or nuts produces aflatoxin, which may be carcinogenic
or acutely toxic
Biopsy specimens show septate, branching hyphae invading tissue, and cultures show
colonies with characteristic radiating chains of conidia
• Voriconazole is the drug of choice for invasive aspergillosis
- Amphotericin B, posaconazole, and caspofungin are alternative drugs
Mucormycetes (Zygomycetes)
Zygomycosis
• Mucormycosis (zygomycosis, phycomycosis) is a disease caused by saphrophytic molds
(e.g. Mucor, Rhizopus, and Absidia) found widely in the environment
• These organisms are transmitted by airborne asexual spores and invade tissues of patients
with reduced host defenses
- They proliferate in the walls of blood vessels, particularly of the paranasal sinuses,
lungs, or gut, and cause infarction and necrosis of tissue distal to the blocked vessels - Patients with diabetic ketoacidosis, burns, bone marrow transplants, or leukemia are
particularly susceptible
§ Diabetic patients are particularly susceptible to rhinocerebral mucormycosis
• In biopsy specimens, organisms are seen microscopically as non-septate hyphae with
broad, irregular walls and branches that form more or less at right angles
• Cultures, although difficult to grow, show colonies with spores contained within a
sporangium
• Early diagnosis in combination with treatment consisting of amphotericin B administration
and surgical removal of necrotic infected tissue has resulted in some remissions and cures - Posaconazole can also be used
• Prophylactic use of voriconazole is an option for those at risk of infection
Antifungal agents, mechanisms of action
The most effective antifungal drugs, amphotericin B and the various azoles, exploit the presence
of ergosterol in fungal cell membranes that is not found in bacterial or human cell membranes.
Another class of antifungal drugs, echinocandins, inhibit the synthesis of β-glucan, which is found
in fungal cell walls but not in bacterial cell walls.
Alteration of fungal cell membranes
1) Amphotericin B
- Used in the treatment of a variety of disseminated fungal diseases
- It is a polyene with a series of seven unsaturated double bonds in its macrolide ring
structure
- Disrupts the cell membrane of fungi because of its affinity for ergosterol (fungicidal)
- Fungi resistant to amphotericin B have rarely been recovered from patient
specimens
- Significant renal toxicity; measurement of serum creatinine levels is used to monitor
the dose
§ Nephrotoxicity is significantly reduced when the drug is administered in
liposomes, but liposomal amphotericin B is expensive
- Fever, chills, nausea, and vomiting are common side effects
2) Nystatin
- Another polyene antifungal agent, which, because of its toxicity, is used only topically
for infections caused by the yeast Candida
3) Terbinafine
- Blocks ergosterol synthesis by inhibiting squalene epoxidase
- Used in the treatment of dermatophyte infections of the skin, fingernails, and
toenails.
4) Azoles
- Block cytochrome P-450-dependent demethylation of lanosterol, the precursor of
ergosterol (fungistatic)
- Fluconazole, ketoconazole, voriconazole, posaconazole, and itraconazole are used to
treat systemic fungal diseases
§ Fluconazole: candidal and cryptococcal infections
§ Ketoconazole: blastomycosis, chronic mucocutaneous candidiasis, coccidioidomycosis,
and skin infections caused by dermatophytes
§ Voriconazole: invasive aspergillosis, prophylaxis for mucormycosis
§ Posaconazole: oropharyngeal candidiasis, mucormycosis, Candida and
Aspergillus prophylaxis in immunocompromised individuals
§ Itraconazole: histoplasmosis and blastomycosis - Clotrimazole and miconazole are used only topically because they are too toxic to be
given systematically
§ Topical therapy of Candida infections and dermatophytes - Fungi resistant to the azole drugs have rarely been recovered from patient specimens
Inhibition of fungal cell wall synthesis
1) Echinocandins
- Caspfoungin and micafungin are the most commonly used
- Lipopeptides that block fungal cell wall synthesis by inhibiting the enzyme that
synthesizes β-glucan (fungicidal against Candida, fungistatic against Aspergillus)
- Caspofungin is used for the treatment of disseminated candidiasis and for the
treatment of invasive aspergillosis that does not respond to amphotericin B
Additional drug mechanisms
1) Griseofulvin
- Binds to tubulin in microtubules and may act by preventing the formation of the
mitotic spindle
- Useful in the treatment of hair and nail infections caused by dermatophytes
2) Pentamidine
- Inhibits DNA synthesis by an unknown mechanism
- Active against fungi and protozoa
- Widely used to prevent or treat pneumonia caused by Pneumocystis jirovecii
3) Fluoropyrimidin
- Inhibits DNA or RNA synthesis
- Active in vitro against Candida spp. and Cryptococcus spp.
- Rapid emergence of resistance limits clinical utility
- Most common clinical use is in combination with amphotericin B for cryptococcal
infections
Staphylococci
Staphylococcus aureus
Staphylococcus aureus
• Staphylococcus aureus causes abscesses, various pyogenic infections (e.g. endocarditis,
septic arthritis, and osteomyelitis), toxic shock syndrome, and food poisoning
- It is also one of the most common causes of hospital-acquired pneumonia, septicemia,
and surgical wound infections
- It is an important cause of skin and soft tissue infections, such as folliculitis, cellulitis,
impetigo and conjunctivitis
• Staphylococci are spherical gram-positive cocci arranged in irregular grapelike clusters
• S. aureus can be differentiated from the other staphylococci on the basis that it produces
coagulase, ferments mannitol, hemolyzes RBCs, and produces staphyloxanthin (carotenoid
pigment, important virulence factor)
• >90% of S. aureus strains contain plasmids that encode β-lactamase, making them resistant
to most penicillins - Some strains (e.g. MRSA) are resistant to β-lactamase-resistant penicillins, such as
methicillin and nafcillin, by virtue of changes in the penicillin-binding proteins - Strains of S. aureus with intermediate resistance to vancomycin (VISA) and with full
resistance to vancomycin (VRSA) have also been detected
• S. aureus has several important cell wall components and antigens
1) Protein A – major protein in the cell wall, binds to Fc portion of IgG (prevents
activation of complement)
2) Teichoic acids – mediate adherence to mucosal cells, lipoteichoic acids play a role in
the induction of septic shock
3) Polysaccharide capsule – 11 serotypes based on the antigenicity of the capsular
polysaccharide (types 5 and 8 cause 85% of infections)
4) Surface receptors – for specific staphylococcal bacteriophages
5) Peptidoglycan – endotoxin-like properties
• Humans are the reservoir for staphylococci and the nose is the main site of colonization for
S. aureus
- S. aureus can also be found on the skin, especially of hospital personnel and patients,
and in the vagina of ~5% of women
- Reduced humoral immunity, diabetes, IV drug use, and chronic granulomatous
disease (CGD) predispose to infection
• The three clinically important exotoxins of S. aureus are enterotoxin, toxic shock syndrome
toxin, and exfoliatin
a) Enterotoxin: causes food poisoning (vomiting, watery diarrhea), acts as a
superantigen, fairly heat-resistant, resistant to stomach acid and digestive enzymes
§ The toxin is preformed and hence has a short incubation period (1-8 hours)
b) Toxic shock syndrome toxin (TSST): causes toxic shock (especially in
tampon-using menstruating women), produced locally and enters the bloodstream
to cause toxemia, superantigen
§ Toxic shock syndrome is characterized by fever, hypotension, rash
(sunburn-like, desquamates), and organ involvement (liver, kidney, GI tract,
CNS, muscle, or blood)
c) Exfoliatin: causes “scalded skin“ syndrome in young children, acts as a protease that
cleaves desmoglein in desmosomes –> separation of the epidermis at the granular
cell layer
§ Scalded-skin syndrome is characterized by fever, large bullae, and an
erythematous macular rash, with recovery usually within 7-10 days
• Several other exotoxins of S. aureus can kill leukocytes (leukocidins) and of these, the two
most important are alpha toxin and P-V leukocidin
• β-lactamase resistant S. aureus strains can be treated with β-lactamase-resistant penicillins
(e.g. nafcillin), some cephalosporins, vancomycin, or a combination of a β-lactamasesensitive
penicillin (e.g. amoxicillin) and a β-lactamase inhibitor (e.g. clavulanic acid)
• The drug of choice for methicillin-resistant or nafcillin-resistant strains is vancomycin, to
which gentamicin is sometimes added
• VISA and VRSA strains can be treated with daptomycin or quinupristin-dalfopristin
(Synercid)
Staphylococcus epidermidis and S. saprophyticus
• Staphylococcus epidermidis causes prosthetic valve endocarditis and prosthetic joint
infections
- It is the most common cause of CNS shunt infections and an important cause of sepsis
in newborns as wells as peritonitis in patients with renal failure
- Found primarily on the human skin (normal flora) and can enter the bloodstream at
the site of IV catheters - Infections are almost always hospital-acquired
- Does not produce exotoxins
- Vancomycin is the drug of choice
• Staphylococcus saprophyticus causes UTIs, especially cystitis - Found primarily on the mucosa of the genital tract in young women
- Infections are almost always community-acquired
- Does not produce exotoxins
- Can be treated with TMP-SMX or a quinolone
Streptococcus pyogenes
Streptococcus pyogenes (GAS)
• Streptococcus pyogenes(group A streptococcus) is the leading bacterial cause of pharyngitis
and cellulitis
- It is an important cause of impetigo, necrotizing fasciitis, and streptococcal toxic
shock syndrome
- It is also the inciting factor of rheumatic fever and acute glomerulonephritis
• Streptococci are spherical gram-positive cocci arranged in chains or pairs
• α-Hemolytic streptococci form a green zone around their colonies (incomplete lysis of
RBCs), whereas β-hemolytic streptococci form a clear zone around their colonies (complete
lysis of RBCs)
• There are two important antigens of β-hemolytic streptococci
1) C carbohydrate is located in the cell wall and determines the group of β-hemolytic
streptococci
2) M protein protrudes from the outer surface of the cell to block phagocytosis, and also
determines the type of group A β-hemolytic streptococci
• Most streptococci are part of the normal flora of the human throat, skin, and intestines but
produce disease when they gain access to tissues or blood
• S. pyogenes causes disease by three mechanisms
a) Pyogenic inflammation – induced locally
b) Exotoxin production – can cause widespread systemic symptoms
§ Erythrogenic toxin causes the rash of scarlet fever and has a similar mechanism
of action to TSST
§ Streptolysin O (antigenic) and streptolysin S (not antigenic) cause
β-hemolysis, anti-streptolysin O (ASO) titers are used in detection of rheumatic
fever
§ Pyrogenic exotoxin A is responsible for most cases of streptococcal toxic shock
syndrome and has the same mode of action as staphylococcal TSST
§ Exotoxin B is a protease that rapidly destroys tissues, causing necrotizing
fasciitis
c) Immunologic – cross-reaction of antibody with normal tissue
• S. pyogenes produces three important inflammation-related enzymes: (1) hyaluronidase,
which degrades hyaluronic acid and facilitates rapid spread in skin infections; (2)
streptokinase (fibrinolysin), which activates plasminogen and dissolves fibrin; and (3)
DNase (streptodornase), which degrades DNA in exudates or necrotic tissue
• Since the culture of S. pyogenes takes at least 18 hours, rapid antigen tests have been
developed that can give results in ~10 minutes
• Infections are treated with either penicillin or amoxicillin
- Erythromycin is used in case of penicillin allergy
I decided not to write about the poststreptococcal disease (acute GN, rheumatic fever) since they are
also covered in Internal and Pathology. The only thing I want to mention is that the JONES criteria
stand for the following:
J – joint involvement
♡ – myocarditis
N – nodules, subcutaneous
E – erythema marginatum
S – Sydenham chorea
Alpha hemolytic streptococci (S. pneumoniae, viridans group)
Strep. pneumoniae, S. viridans
Streptococcus pneumoniae
• Streptococcus pneumoniae causes pneumonia, bacteremia, meningitis, and infections of the
upper respiratory tract such as otitis media, mastoiditis, and sinusitis
- It is the most common cause of community-acquired pneumonia, meningitis, sepsis
in splenectomized individuals, otitis media, and sinusitis
• Pneumococci are gram-positive lancet-shaped cocci arranged in pairs (diplococci) or short
chains
- On blood agar, they produce α-hemolysis and are lysed by bile or deoxycholate
- Their polysaccharide capsule has >85 antigenically distinct types
• Humans are the natural hosts for pneumococci, and about 5-50% of the healthy population
harbors the organisms in the oropharynx
• S.pneumoniae has several virulence factors, the most important of which is the capsular
polysaccharide
- IgA protease enhances the organism‘s ability to colonize the mucosa of the upper
respiratory tract by cleaving IgA
- Lipoteichoic acid in the cell wall can induce inflammatory cytokine production
- Pneumolysin, the hemolysin that causes α-hemolysis, may also contribute to
pathogenesis
• Factors that lower resistance and predispose persons to pneumococcal infection include
alcohol or drug intoxication, abnormality of the respiratory tract (e.g. viral infections,
bronchial obstruction), abnormal circulatory dynamics (e.g. heart failure), splenectomy,
and certain chronic diseases such as sickle cell anemia and nephrosis
• Aside from microscopic analysis and culture, diagnosis can also be made with rapid latex
agglutination
• Most pneumococci are susceptible to penicillins and erythromycins, but resistant strains
have emerged and can be treated with vancomycin (severe infection) or ceftriaxone (less
severe infection)
• Two types of vaccines are available, one for children under the age of 5 years and
immunocompromised individuals (13-valent pneumococcal conjugate vaccine), and the
other for healthy individuals age 50 years or older (23-valent pneumococcal unconjugated
vaccine)
Viridans group
• Viridans group streptococci are the most common cause of infective endocarditis
- They enter the bloodstream (bacteremia) from the oropharynx, typically after dental
surgery
- The signs of endocarditis are fever, heart murmur, anemia, and embolic events such
as splinter hemorrhages, subconjunctival petechial hemorrhages, and Janeway
lesions
- It is 100% fatal unless effectively treated with antimicrobial agents
• Streptococcus mutans synthesizes polysaccharides (dextrans) that are found in dental
plaque and lead to dental caries
• Viridans streptococci, especially S. anginosus, S. milleri, and S. intermedius, also cause brain
abscesses, often in combination with mouth anaerobes
• Pathogenesis of the viridans streptococci is uncertain, but many produce a glycocalyx that
enables the organisms to adhere to the heart valve
• Endocarditis caused by most viridans streptococci is curable by prolonged penicillin
treatment
Streptococcus agalactiae, Enterococcus genus, anaerobic streptococci
Streptococcus agalactiae
• Streptococcus agalactiae (group B streptococcus) is the leading cause of neonatal sepsis
and meningitis, as well as an important cause of neonatal pneumonia
• The main predisposing factor is prolonged (longer than 18 hours) rupture of the
membranes in women who are colonized with the organism
• Group B streptococci are characterized by their ability to hydrolyze hippurate and by the
production of a protein that causes enhanced hemolysis on sheep blood agar when
combined with β-hemolysins of S. aureus (CAMP test)
• A rapid test is available for the detection of group B streptococci in vaginal and rectal
samples, and results are obtained in ~1 hour
• The drug of choice is either penicillin G or ampicillin
Enterococcus genus
• Enterococcus faecalis (group D streptococcus) is an important cause of hospital-acquired
urinary tract infections and endocarditis
- Indwelling urinary catheters and urinary tract instrumentation are important
predisposing factors for UTIs
- Patients who have undergone GI or urinary tract surgery or instrumentation are at
increased risk of endocarditis caused by enterococci
• Enterococci are members of the normal flora of the colon
• Group D streptococci hydrolyze esculin in the presence of bile (i.e. they produce a black
pigment on bile-esculin agar)
Enterococcus
- Enterococci can be differentiated from other group D streptococci on the basis that
they grow in hypertonic (6.5% NaCl), whereas nonenterococci do not
• Enterococcal endocarditis can be eradicated only by a penicillin or vancomycin combined
with an aminoglycoside
• Enterococci resistant to multiple drugs have emerged (e.g. VRE), and are treated with
linezolid and daptomycin
Anaerobic streptococci
• Peptostreptococci grow under anaerobic or microaerophilic conditions and produce
variable hemolysis
- They are members of the normal flora of the gut, mouth, and female genital tract and
participate in mixed anaerobic infections
Urine sample
