Infections

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The number of cells in the human body varies considerably,
depending upon one's size, but recent estimates suggest
our cells number in the tens of trillions.  Yet as vast as this
number is, we host thousands of species of bacteria, and
the total number of bacterial cells we host on and within
our bodies actually surpasses the number of our own
human cells. (1,2,3)   

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This may sound alarming, but the truth is that we couldn't
exist without bacteria.  They help digest our food and
allow us to absorb vitamins.  

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They also keep our immune system finely tuned.  For

example, every square millimeter of our skin is covered

with uncountable numbers of bacteria.  And enormous

numbers reside in our intestines and respiratory tracts. 

Our immune system monitors them and keeps them at

bay.  And for the most part, they don't cause problems. 

Like people, when bacteria are stable and happy, they

behave.  

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However, when there is a break in the skin, as seen with

a foot ulcer, bacteria have the opportunity to spread. 

In most cases, the body will defend the invasion without

issue.  But when bacteria breach that immune system

and start to spread beyond their normal boundaries,

you develop an infection.  

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To the right we see redness (erythema) as the infection

begins to spread up the foot.  Even simple infections

can quickly become limb- or life-threatening.  So let's

examine what happens in our bodies as we deal with

infection.

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The Combatants

 

On Our side (The Defense)

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The Wall

 

The defense of the human body against bacterial

attack begins with our skin.  This is our castle wall

—our barrier against foreign invaders. 

 

The skin averages about 2-3mm in thickness, though

it is much thicker on the soles of our feet and the

palms of our hands, and it’s much thinner on our

eyelids.  The outermost layer, the stratum corneum,

consists of a tight shell of about 15-20 layers of

flattened dead cells.

 

Bacteria can range in size, with some 20x larger than

others, but the most common bacteria on our skin

range in size from 0.0005 - .002 mm (0.5-2 microns). 

This means in order to enter our body, the bacteria

need to breach a wall 1000-6000 times their size. 

It would be like our trying to get through a wall a

kilometer thick at its narrowest.

 

Of course, the bacteria has to get to the wall first.  And this, itself is a problem because living on that outside barrier are billions of bacteria that have happily colonized our skin.  They cause us no harm; in fact, these bacteria, themselves, serve as a barrier to infection.  Well-adapted to our environment, the natural bacteria on our skin are usually able to out-compete an invading organism, making it harder for virulent organisms to take root.  Some of those bacteria living naturally on our skin produce enzymes that inhibit the functions of invading bacteria.  They also produce a moisturizing film that acts to keep our skin smooth and free of cracks and fissures through which bacteria may penetrate.

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Occasionally, however, there may be a break in the skin.  A blister may form.  A cut may develop.  An ulcer may form from pressure or shear.  And then bacteria may get through the wall.

 

Our Troops  

 

Inside our skin, we have as our next line of defense, white blood cells (WBCs).  These are also known as leukocytes, (from the Greek Leukos “white” and –cyte “cell”).   White cells are our body’s major defense force. We normally have somewhere between 3,500 and 11,000 WBCs in each cubic millimeter (1/50th of a drop) of blood.  This makes a total fighting force in our body of approximately 50 billion WBCs.  And this force can be expanded in very short order.

 

This is quite a formidable defense force.

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There are several types of WBCs, each with specialized functions. 

Accounting for 50-75% of our WBCs, neutrophils are the most

abundant WBC, and thus, the most important members of our

defense force. 

 

Produced in our bone marrow, neutrophils are highly-mobile killers. 

They travel through the blood, constantly patrolling, looking for

invaders.  When an infection occurs, local cells produce cytokines--

proteins that trigger and regulate our body's response.  The

neutrophils, drawn towards the area by those chemical signals, pass

out of the blood and into the fluid around the cells, towards the 

site of infection.  

 

Irregularly-shaped and able to move independently, neutrophils aggressively defend our body against the bacterial attack with speed and vigor.  Each neutrophils may kill and digest 5-20 bacteria in its life.  Or the neutrophil may stick to a bacterium, immobilizing and incapacitating it.  They also release cytokines of their own to draw in more of our body’s defenses.

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However, neutrophils don't live long--just 5-90 hours.  The short life span is an advantage, however, as it limits the damage neutrophils can do to our tissues, and if bacteria manage to survive being ingested by a neutrophil, the

neutrophils death allows the bacteria to be attacked by our immune system once again. 

 

To make up for the short lifespan of neutrophils, our body produces tens of billions of neutrophils per day.  That's hundreds of thousands per second.  And we can ramp up production even more if there is an infection.  

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Interestingly, neutrophils prefer ingesting sugar to bacteria, and this may be one reason diabetes patients have a diminished immune response.

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Neutrophils aren't the only sort of WBC we have at our disposal.  Lymphocytes are another form.  The two main types, T-cells (made in our thymus) and B-cells (made in our bone marrow) are involved in recognizing specific bacteria and viruses to which we’ve already been exposed.  They recognize these bacteria by identifying antigens (a molecule on an invading organism that the body recognizes as alien.   This allows the body to form a quicker reaction to subsequent infections.

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Some lymphocytes, called natural killer cells, attack bacteria directly by injecting chemicals toxic to bacteria.  Others release cytokines to draw in more cells.  Others assist the lymphocytes involved in killing bacteria by tagging them with chemicals that make them more easily identified by other white blood cells.

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Cytokines released by lymphocytes also elicit a reaction in the body to create a fever that helps our body kill bacteria.  In fact, besides fever, the other markers of inflammation—redness, swelling, pain, diminished function—are also designed to help us.  An infected limb becomes red because of increased blood flow.  We swell to immobilize that body part.  Pain and a diminished ability to function is our body’s way of telling us to rest.

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Another major form of WBC is the macrophage, a name of

Greek origin meaning "big eater".  Macrophages are born

in the marrow as monocytes.  They travel through our

blood, but don't linger there.  They rather quickly set up

long-term residence in the tissues of the body, where they

mature into macrophages. 

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And there they lie, for weeks or months, in wait for any

invaders.  

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Macrophages ingest both bacteria and damaged cells,

and so are also involved in wound healing.  

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The Invaders

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There are many different bacteria that could infect us. 

In fact, we're home to over a thousand species of

bacteria. 

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The majority of bacteria have a structure based on

a variation of three basic shapes--a sphere, a rod,

and a spiral.  The spheres may be in a group, such

as a group of two, four, or eight spheres.  They
could be organized as a chain of spheres, or some

other combination.  Other organisms with a rod-like

structure will have similar variations.

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The most common organism living on our skin is

staphylococcus (seen below).  These organisms look

like individual spheres. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The name "staphylococcus" is derived

from this appearance.  In Greek,

staphyle, means a bunch of grapes,

and kokkus, means berries. 

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Staphlococcus (often just called staph)
organisms are so common that one

species alone--staph epidermidis--

accounts for 75-90% of the bacterial

population on our skin, especially in

the drier regions of our body. 

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The second most common organism

on our body is also a staphylococcus--

Staph Aureus.  This organism can be

found anywhere, but is more common
in the nose, the armpits and the groin. 

 

Staph aureus is the most common

bacteria found in foot wounds.  Food

poisoning is also commonly caused by

staph aureus.

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Together, these two staph organisms

make up over 90% of the bacteria on

our skin.

 

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Another common organism is streptococcus (right).  "Strep throat" is a

well-known example of a strep infection. 

 

Streptococcus looks like a chain of berries, often with a bend or a twist. 

Indeed, strepto- comes from the Greek for flexible and twisted, like a chain, and kokkus meaning berries.   

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Other very common bacteria on our skin, are shaped like rods, and are called bacilli (Greek for a staff or walking stick).  Examples of bacteria with this shape are pseudomonas (below left), clostridia (below center) and E. Coli (below right).  These are common organisms found in wounds.

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Less common are bacteria with

other shapes, like corkscrews

(as seen with Lyme disease and
syphillis), macaroni or commas
(as with cholera), and helical
shapes (as with the bacteria

causing stomach ulcers). 

 

Even rarer are bacteria shaped

like long strings, boxes, and

stars. 

 

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The Battle Begins

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Irrespective of their shape, bacteria are much smaller than most human cells, including the cells that defend us.  But a small size and enormous numbers mean a lot of bacteria can get through very small spaces.  If there is a compromise to the skin--a scratch, a crack, a blister--this may be enough for bacteria to get through our skin barrier and start

an infection.  In the case with ulcers, the opening can be much bigger than a scratch or a crack.

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What can bacteria so tiny do to hurt us?

 

The bacteria attack our cells  by secreting enzymes to break down our cell wall and ingest the contents.  They may also secrete toxins to damage our tissues.  And they secrete waste that also damages our tissues.  And because of their ability to reproduce so fast--to millions, billions and beyond--an unchecked infection could kill us rather quickly.

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How do our bodies react to infection?

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In most cases, invading bacteria are grossly outnumbered by our 50 billion white blood cells early, and the WBCs usually deal with the invaders without issue.  Neutrophils rush to the site of infection to meet the threat.

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Shown to the right is a movie of our white blood cell chasing

the smaller bacterial cell among the stationary red blood cells

(which carry oxygen).   If you look closely, you see that each

bacterium appears to be two cocci stuck together--called a 

diplococci.  Neisseria gonorrhea (the bacterium that causes

gonorrhea) and haemophilus influenzae (often causing

meningitis and ear infections) have this appearance.

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How do the white blood cells move like that?

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The white blood cell is able to move like this because the

chemical signal from the bacteria is transferred to the proteins

that make up the white cell's internal structure called its

cytoskeleton.  The cytoskeleton is a  network of interlocking

filaments that extend throughout the white blood cell.  The

cytoskeleton can be arranged, then rearranged very quickly

and repeatedly, allowing the white cell to move towards the

bacteria.

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Once the white cell catches the bacteria, it typically envelopes the bacteria and uses digestive enzymes to kill it.

 

 

How does a WBC with no eyes recognize and chase an alien bacterium?

 

One way neutrophils recognize bacteria is that bacteria have a cell wall that has a different structure from our own. 

 

Further, bacteria release chemical signatures that our cells don't make, allowing our white blood cells to identify them.

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Assisting in this identification, we have antibodies and defense cells that tag the bacteria with markers (a process called opsonization) to enhance that signal and make it easier for the white blood cells that kill bacteria to work.

 

 

If our bodies have a defense force of 50 billion white blood cells, why do we still get infections?

 

50 billion is a lot of white blood cells.  But some patients--the elderly, the very young, the immunosuppressed (such as those on chemotherapy or infected with HIV), diabetics, and those on steroids, may not have so large an army of white blood cells.  Or they may not mount so vigorous a response.  

 

And even in the healthy, our WBCs already have a pretty big job managing any potential infections from the billions of bacteria already inside our bodies in our intestines and respiratory tracts.   Further, if bacteria can get inside our bodies somehow, they have some strategies to cope with our large WBC army. 

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What strategies do bacteria use to fight back?

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One major tactic bacteria use against us is in speed of replication.  Bacteria can

double their numbers every 4 to 20 minutes, and their numbers thus multiply

exponentially.  So even starting from a single invading organism, the total

bacterial invading force can number in the billions in a matter of hours. 

 

Because bacteria reproduce so quickly, time is of the essence for us to react. 

So bacteria have evolved several methods of avoiding detection for as long as

possible.  And the techniques they've devised may be the same techniques you

might devise if you had to invent ways to survive against overwhelming numbers
of individuals looking for you.

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One tactic bacteria use is hiding.  We've already discussed how tiny bacteria are.  Their being small makes it easier to hide and harder for our WBCs to find them.  Finding out-of-the-way locations to settle is another way to hide.

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Bacteria may also disguise themselves.  Some bacteria have evolved a cell wall that mimics carbohydrates found in our bodies, making them difficult to be detected by WBCs.  Other bacteria purposefully coat their cell wall with proteins found in our body to disguise themselves.

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And a number of others have found a way to live (and hide) inside our own cells.  Leprosy, gonorrhea, chlamydia, and tuberculosis are well known examples.  In fact, some bacteria can actually hide inside our own WBCs, thereby eluding the attack.  This is one reason it's good our neutrophils don't live more than a few days.  When the neutrophils die, they release any hidden bacteria, giving other WBC troops the chance to track down that bacterium.

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Other bacteria have found a way to inhibit our immune system by chemically inhibiting WBCs from reacting. 

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Another mechanism of avoiding our WBCs is misdirection.  Some bacteria release numerous small bacterial fragments our body recognizes as foreign.  The bacteria hopes our WBCs chase the scent of these foreign fragments and lose sight of the bacterium itself, allowing it to make a getaway.

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Many bacteria don't so much hide or misdirect as they make themselves difficult to get rid of.  Many bacteria, for example, produce a slimy, sticky cell coating called glycocalyx (pronounced "Gly-Ko-Kay-Licks").  Glycocalyx can delay and inhibit the WBC's ability to digest it, and it can allow the bacteria to stick to hard surfaces, making it difficult to be removed.

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Once a bacterium is caught by a WBC, it may fight back.  Some bacteria puncture our WBCs.  Some release enzymes that destroy our WBCs.  Or it may destroy the attachment point WBCs use to grab the bacteria.

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​​Each infection is fought one on one, mano a mano, with each bacterial species using its own strategy.  Now multiply these battles by the millions, even billions, and you see the scope these battles may take. 

 

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​Casualties of War

 

The casualties of this battle are evidenced by pus. Pus consists of dead white blood cells, mostly neutrophils, and bacteria.  And when the body is unable to clean up this debris, the pus tends to find an exit.  Pus is often creamy-yellowish white (below left), and often has an odour.  When pus is mixed with blood, it develops a creamy reddish colour (below right).  

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Pus is a good example of why debridement is important. 

 

In order for a wound to heal, it is best to get dead cells and bacteria found in pus out of the wound.  This is true for a few reasons: 

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First, dead cells are a defenseless food source for bacteria.  We want to eliminate that food supply.

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Second, regions of thick, dead tissue and fluid are areas without normal blood supply.  Its presence makes it difficult for our body to deliver fresh leukocytes (white blood cells). 

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And third, pus is a fluid.  And fluids can't be compressed like a gas or solid can.  So with the compressive force of walking, the pus simply spreads out along tissue planes, causing tearing of the surrounding normal, healthy skin and connecting soft tissues, further damage. 

 

 

 

 

We're constantly exposed to bacteria, and our defenses win the vast majority of these battles. 

 

However, once in a while, the speed with which the bacteria reproduce overwhelms our body and the infection spreads.  To the left is an infection originating from an ingrown nail.

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The red streak heading up the foot and ankle is known as

"ascending cellulitis."  This literally means inflamed cellular tissue heading up the extremity, and it's a visual representation of the spread of the bacteria into the body after breaking through our defenses.

 

The spread of bacteria like this is more common in diabetic patients who often cannot muster a normal response to an advancing infection.  

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It's sobering to think that before World War II, when the first antibiotic hadn't yet come to the market, even young, healthy people would die from such small infections.

 

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To the right is an example where an ulcer has developed under

the big toe joint.  Pus is draining through a channel out towards
the 2nd toe. 

 

As the infection spreads up the foot, the body, in response, 
increases blood flow to the site of active infection, creating the
erythema (redness) we see mid arch.

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In many cases, the infection is associated with more casualties--

in the form of dead cells (necrosis). In the photo to the right,

note the  wet, yellow-white tissue within the wound.  This is

called slough, (pronounced "sluff"), and represents dead and
dying tissue.

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Below we see two examples of deep tissue infection with significant tissue death and disrupted circulation. 

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In the case below left, the infection advanced very quickly.  The infection was drained and the non-viable portion of the foot (the 4th and 5th toes and metatarsals) was amputated.  In the case on the right, a trans-metatarsal amputation (the entire forefoot) was required.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Here we see two examples where the infection spreading up the foot.  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                       

 

 

 

 

                           

 

 

 

 

 

 

 

To the right we see the infection heading up towards the knee.  

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Infections like these can progress very quickly, particularly in 

patients compromised by high sugar, poor nutrition, a weakened 

immune system, and diminished blood supply.

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As the infection spreads, systemic effects like fever, chills, fatigue,

and a generalized feeling of being ill develop.  The patient may
become confused, and may not seek medical help.

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These infections are at least limb threatening and often life
threatening.  

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Antibiotics

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When infections like this develop, however, we do have another weapon at our disposal: Antibiotics.  And whether delivered orally or through IV, in serious infections, they become the single most important factor in treatment.

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Antibiotics work by creating or targeting a weakness in the bacteria.  For instance, penicillin inhibits normal production of bacterial cell walls, causing the bacteria to rupture.  The cell wall of our cells is constructed differently, and is immune from the effect.  

 

Since penicillin was discovered (on September 3, 1928), antibiotics have been amazingly successful.  Just a couple of generations ago, many people died of even minor infections.  

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However, because bacteria can reproduce so quickly, bacteria have evolved a response.  They've developed an immunity to many of our antibiotics.  For example, many bacteria can now produce an enzyme that destroys penicillin's ability to disrupt their cell wall, making it ineffective.  This is why the original penicillin is almost never used anymore. 

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Further, some bacteria can transfer this immunity to other bacteria.  

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We've also made our own situation worse by over prescribing antibiotics, and for prescribing antibiotics for viruses that aren't affected by antibiotics, and we've used them indiscriminately in agriculture.  The effect has been that we have more and more virulent bacteria resistant to many antibiotics.  

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The foot below left developed after the patient celebrated the healing of a wound by going fishing--standing in wading boots in a cold river.    He could not feel the cold and developed frostbite.   The toe became infected.  The patient's antibiotic-resistant infection went septic, and he died as a result of the infection.  

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The patient below right became septic from this deep foot infection and passed away three days later.  

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So, we want to be certain to use antibiotics when they are necessary.  But we don't want to use them when they are not.  

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If you're not sure you have an infection, look for redness, warmth, swelling, and pain (less so in neuropathic patients) compared to the other limb.  Is there discharge coming from the foot?  These all suggest infection and need to be investigated.

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These images courtesy of UCSD Medical School.

 

 

If you're feeling ill, have chills, sweats, a fever, or confusion, these are signs the infection may be spreading throughout your body.  Seek immediate medical attention.  

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When there is no infection present, however, antibiotics don't work.

Antibiotics don't heal wounds.

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The patient pictured to the right was treated with 18 straight months
of antibiotics.

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Why didn't the wound heal?

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Because there is no infection.  And what the patient needed most,
offloading, wasn't performed.  

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Certainly, we could culture the wound and grow some bacteria that
are living on the wound (colonizing the wound).  The same is true if
you cultured any surface on your body, or any surface in your room. 

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But an organisms simply living on the wound and not actively invading
the body doesn't represent an infection.  

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If you have no infection, antibiotics will not help your ulcer, and you'll
likely need to be treated with debridement, offloading and dressings.  

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1. Alison Abbott for Nature News. 8 January 2016 Scientists bust myth that our bodies have more bacteria than human cells

2. Sender, R; Fuchs, S; Milo, R (January 2016). "Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans". Cell. 164 (3): 337–40. doi:10.1016/j.cell.2016.01.013. PMID 26824647.

3. https://www.bodyandsoul.com.au/health/health-news/billions-of-bacteria-live-on-your-skin/news-story/0a23868c33945f26d4250c00058f494c  

 

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