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Medical Alliance for the Preservation of the Lower Extremity

Infections

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)

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.

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.

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.

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.

“If you don't like bacteria, you're on the wrong planet.”

― Stewart Brand

Above: A cross section of normal, healthy skin.

Bacterium

The Combatants

On Our side (The Defense)

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.

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.

Neutrophil
Image courtesy of UCSD School of Medicine

This is quite a formidable defense force.

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.

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.

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

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.

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.

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.

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.

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

Macrophages ingest both bacteria and damaged cells,

and so are also involved in wound healing.

The Invaders

There are many different bacteria that could infect us.

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

bacteria.

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.

The most common organism living on our skin is

staphylococcus (seen below). These organisms look

like individual spheres.

Above: Macrophage

"The 4th sort of creatures... which moved through the 3 former sorts, were incredibly small, and so small in my eye that I judged, that if 100 of them lay [stretched out] one by another, they would not equal the length of a grain of course Sand; and according to this estimate, ten hundred thousand of them could not equal the dimensions of a grain of such course Sand. There was discover’d by me a fifth sort, which had near the thickness of the former, but they were almost twice as long."

--Antonie van Leewenhoek (1632-1723)
The first description of bacteria

The name "staphylococcus" is derived from this appearance. In Greek,

staphyle, means a bunch of grapes, and kokkus, means berries.

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.

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.

Together, these two staph organisms make up over 90% of the bacteria on

our skin.

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.

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.

Each of these computer-generated bacterial images are provided courtesy of the CDC.

Less common are bacteria with other shapes, like corkscrews (as seen with Lyme disease and syphilis), 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.

The Battle Begins

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.

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.

How do our bodies react to infection?

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.

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.

Antonie van Leeuwenhoek (1632-1723)

Bacteria were discovered in 1683 by Antonie van Leeuwenhoek (1632-1723), known today as the father of microbiology.

Born in Delft, Netherlands, van Leeuwenhoek worked as a draper. He created high-quality glass lenses in order to better examine the quality of small threads in drapery material.

He was so adept at this, that he achieved a level of magnification as much as 20 times more powerful than that of anyone else of his era.

Van Leeuwenhoek soon turned his attention to viewing small creatures in pond water, thereby discovering the first microorganisms. He discovered bacteria, which no one else would be able to observe for another 100 years. He also discovered blood cells, sperm, and he was the first to describe structural details in structures like the cell, muscle, and the optic nerve.

Van Leeuwenhoek became very well known in his time, and he was visited in his lab by a variety of luminaries of his day, such as the German polymath Gottfried Leipniz (philosopher and independent discoverer of calculus), William III of Orange, the sovereign of Netherlands, Mary II, the Queen of England, James II, King of England, Peter the Great of Russia, and Frederick the Great of Prussia.

Van Leeuwenhoek was a hometown contemporary of Johannes Vermeer, the painter. There are no records of their relationship, but they were likely very well acquainted, as they were born a few days apart, lived a few blocks apart in a small town of 20,000, and van Leeuwenhoek was executor of Vermeer's estate.

How do the white blood cells move like that?

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.

Once the white cell catches the bacteria, it typically envelopes the bacteria and kills it through a combination of reactive chemicals, an acidic environment, antimicrobial peptides and digestive enzymes.

What strategies do bacteria use to fight back?

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.

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.

Bacteria may also camouflage to 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.

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.

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

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.

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.

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.

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.

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 right we see an infection originating from a routine ingrown nail.

The red colour in the skin, accompanied by warmth, swelling, and often discomfort, is known as "cellulitis."

The red colour is caused by the body increasing blood flow to the infected region to allow for more white blood cells to fight the bacteria. This extra blood flow accounts for the warmth accompanying the infection.

In the example to the right, it is ascending up the foot (red arrows) as it breaks past the body's defenses. This is known as "ascending cellulitis".

Today we routinely treat infections like these with antibiotics.

But it is sobering to think that before World War II, when the first antibiotic hadn't yet come to the market, even young, healthy people with something as simple as an ingrown nail could die from such small infections.

Infections from a relatively routine condition like an ingrown nailgetting past the body's defenses (like the example above) is not typical.

For example, to the right is a fairly severe ingrown nail involving both sides of the nail plate. There is some modest redness and inflammation adjacent to the nail, but the infection is not breaking past the body's defenses or heading up the foot or leg as in the previous example.

A case of an advancing infection in a patient not diagnosed with diabetes should give the clinician pause that there may be diabetes or an immune issue to be considered.

Diabetics and Infection

Diabetics often have a more difficult time handling infections than those without diabetes. One reason is that high blood sugar impairs white blood cell function. High sugar can be thought of as poisoning their machinery. At the same time, high sugar nourishes bacteria. You can read more about the effect of sugar on wound healing here.

Diabetics often have impaired skin barriers, which we touched on here.

Diabetics often have diminished blood flow, particularly at the level of the small vessels, and particularly in the feet, which are furthest away from the heart.

Neuropathy (impaired nerve function in diabetics) means there is a delayed detection of the infection. Patients just don't know there is an issue, delaying treatment.

Diabetics are often more likely to develop infections involving multiple bacteria, and often bacteria that are more difficult to kill.

In these examples, each infection is stemming from an ulceration. The infection is heading up the toe (right), up the foot (below left) and up the leg (below right).

Casualties of War

The casualties of this battle are evidenced by pus. Pus is a fluid, consisting of dead white blood cells, mostly neutrophils, and bacteria, and is often a creamy-yellowish white colour. When mixed with blood, pus is often a creamy-reddish colour.

To the right you can see the author using a needle to remove pus from inside the foot.

You cannot compress fluid, so when pus is produced, it tends to spread under the skin, damaging our tissues and causing tissue death. (See blackened tissue far right).

Both these infections are limb-threatening, even life-threatening.

Eventually, the pus stretches the skin so much, the skin typically breaks open. This is a good thing, as we need to get this dead tissue and poison out of the body.

Pus pocket

In this case, you can see the pressure site (black arrow), redness heading up the foot (red arrow), and pus draining through the canal (blue arrow) and out the ulcer (green arrow) near the base of the second toe.

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:

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

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).

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.

Ulcer

Canal

Cellulitis

Pressure Site

When the fluid is removed and the wound is examined, we can see the degree of tissue damage.

The foot on the right was fully salvaged and the patient returned to a weight-bearing job.

The foot on the right worsened and required amputation.

The yellow-white tissue within the wound is called slough (pronounced "sluff"), and represents dead and dying tissue.

Black tissue is necrotic and not viable.

Even in severe conditions, neuropathy may leave the foot painless, allowing the patient to remain in denial about the severity of their condition.

When the patient to the right was told his infection left part of his foot non-viable and that he would need an amputation, he ignored the discussion completely.

He instead responded by explaining that after he left the hospital he planned on buying a BMW. Whenever the topic of his foot was brought up again, he ignored the discussion, instead talking about the type of engine his desired car had, along with its features.

When the severity of the post-infection condition of the patient to the right was brought up, she denied it. She was convinced she simply had dry skin--that a skin moisturizer would resolve the issue.

Denial like this, where there is a surprising lack of concern or emotional distress about significant physical symptoms is sometimes termed "La Belle Indifférence"--a beautiful indifference.

Incidentally, the term "La Belle Indifférence" was coined by Pierre Janet, a successor of Jean-Martin Charcot at La Salpêtrière Hospital.

Charcot and Charcot Neuoarthropathy are discussed here.

Antibiotics

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

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.

Other antibiotics work by disrupting some component of bacterial cell function.

The patient to the right has a malodourous foot with serious polymicrobial infection. This patient is in need of an IV antibiotic to have a chance at viability.

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

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

Why didn't the wound heal?

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

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.

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

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

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.

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.

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.

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

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

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This page written by Dr. S A Schumacher
Podiatric Surgeon
Surrey, British Columbia Canada

www.drschumacher.ca

Unless otherwise indicated, all clinical
photographs owned and provided by
Dr. S A Schumacher.

They may be reproduced for educational
purposes with attribution to:
Dr. S A Schumacher