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Charles Bryan MD


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Mankind has three great enemies, fever, famine, and war. And of these by far the greatest, by far the most terrible, is fever.

―William Osler, 1897 

Infectious disease is one of the few genuine adventures left in the world. . . however secure and well regulated civilized life may become, bacteria, protozoa, viruses, infected fleas, lice, ticks, mosquitoes and bedbugs will always lurk in the shadows ready to pounce when neglect, poverty, famine or war lets down the defenses.

―Hans Zinsser, 1935 


Figure 1
This graph illustrates the trends in infectious disease mortality in the United States from 1900 to 1996. With exception of the influenza pandemic of 1918, death rates due to infectious diseases decreased until around 1980, at which time several factors (including HIV-related mortality and antibiotic resistance) caused these rates to rise. This increasing trend in infectious disease mortality continued throughout the 1980s and 1990s.


Figure 2
Propionibacterium acnes is a very common obligate anaerobic, non-spore forming rod, and the etiologic pathogen responsible for acne vulgaris, or pimples. It normally resides in the sebaceous glands of the skin.
CDC/Bobby Strong


Infections still cause about one-third of all deaths worldwide and are the leading cause of death, mainly because of disease in developing countries. In developed countries including the United States, improvements in sanitation and hygiene during the 19th century lowered the death rates from infectious diseases even before the dramatic impact of antimicrobial agents and new vaccines. However, recent data suggest that mortality due to infectious diseases in the United States is actually increasing. Between 1980 and 1992, mortality from infections increased by 58% and age-adjusted death rates increased by 39% (figure 1), so that taken as a group infectious diseases became the third leading cause of death (up from fifth in 1980). The epidemiology and pathogenesis of infection can be discussed in several complementary ways.

First, consider the formula for infection:

Likelihood of infection  ≈ virulence of microorganism X number of microorganisms
  host resistance 

Microorganisms are virulent to the extent that they cause disease in previously healthy individuals; that is, when host resistance is high. Virulence is sometimes defined in terms of the percentage of infected persons who develop serious disease or, in some instances, as the case-fatality rate. Host resistance can be reduced because of localized or systemic disease or injury. Damaged or abnormal tissue that is easily infected is sometimes called a locus minoris resistentiae (place of least resistance).

A second framework for understanding infections is the epidemiologic triad or chain of infection:

Reservoir à Means of transmission à Susceptible host

A third framework for understanding infections concerns exogenous versus endogenous microorganisms. Exogenous infections arise from the animate or inanimate environment, whereas endogenous infections arise from the patient's flora.

Infectious disease is usually an accidental event in a world in which each of us lives intimately with billions of microorganisms. In many cases we depend on them, as they on us, for survival. Death is undesirable from the microbe’s perspective as well as ours.


Figure 3
Diphtheria is an acute bacterial disease caused by toxigenic strains of Corynebacterium diphtheriae and occasionally C. ulcerans. It is transmitted through respiratory droplets and personal contact. Diphtheria affects the mucous membranes of the respiratory tract, known as “respiratory diphtheria”, the skin, termed “cutaneous diphtheria”, and occasionally other sites including the eyes, nose, or vagina
CDC/ Dr. P.B. Smith

Figure 3
In respiratory infections, viral infection facilitates invasion by colonizing aerobic bacteria such as S. pneumoniae and H. influenzae, which in turn facilitates superinfection by “normal flora” anaerobes

Normal and Colonizing Bacterial Flora

Colonization begins at birth and is of two types:

  • Permanent colonization by bacteria that are more-or-less expected to be part of the normal flora at all times

  • Transient colonization by potential pathogens.

    Examples of the former include “diphtheroid” bacteria (Propionibacterium and Corynebacterium species) (figures 2 and 3) on the skin, viridans streptococci in the oral cavity, and E. coli, enterococci, and Bacteroides species in the colon. Examples of the latter include Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis in the upper respiratory tract. Colonization is by no means a haphazard event. Microorganisms have on their surfaces specialized molecules called adhesins that bind with specific receptors on host epithelial cells or with extracellular matrix materials. An appreciation of the major components of the body
    s normal and colonizing bacterial flora promotes understanding of many of the common infections encountered in clinical medicine.

In respiratory infections, for example, viral infection facilitates invasion by colonizing bacteria such as S. pneumoniae and H. influenzae, which in turn facilitates superinfection by “normal flora” anaerobes such as Prevotella, Fusobacteria, and Peptostreptococcus species (figure 3).


Figure 4
Methicillin-resistant Staphylococcus aureus bacteria, commonly referred to by the acronym, MRSA; Magnified 9560x.
CDC/ Janice Haney Carr/ Jeff Hageman, M.H.S.

Figure 5
Dynamics of colonization and infection by Staphylococcus aureus.

Figure 6
Cutaneous abscess located on the thigh caused by methicillin-resistant Staphylococcus aureus bacteria (MRSA). A clinician had lanced the lesion in order to allow the pus contained therein, to be released.
CDC/ Bruno Coignard, M.D.; Jeff Hageman, M.H.S.

Staphylococcus aureus 

Potential sites of colonization by S. aureus (figure 4) include the skin, the perineal area, and the gastrointestinal tract, but by far the most important site is the nasal mucosa (anterior nares). S. aureus nasal carriage is extremely common. At a given time, 20% to 40% of adults are likely to have positive nasal swab cultures for S. aureus. Many persons (up to 25% of the population) are permanent nasal carriers of S. aureus. Most people (about 60% of the population) exhibit intermittent colonization with S. aureus, while some persons never show colonization. Because most of us (whether we admit it or not) put our fingers in our noses on a regular basis, person-to-person transmission of S. aureus by hand contact is a universal phenomenon. Viral upper respiratory infection in patients with S. aureus nasal colonization sometimes results in wide dispersal of the organism in the immediate environment; this phenomenon has long been recognized in pediatrics as “cloud babies,” but recently “cloud adults” have also been reported. Some persons with staphylococcal nasal colonization are prone to develop styes, folliculitis, or furunculosis (boils). Most, however, remain asymptomatic until the organism is given the opportunity to invade the skin on account of a wound, abrasion, vascular access line, or surgical procedure. Occasional persons develop S. aureus pneumonia, especially during influenza epidemics since influenza A increases the density of staphylococcal colonization. Staphylococcal bacteremia can arise from colonization, local infection, trauma, foreign bodies, or pneumonia. Complications of staphylococcal bacteremia, which often presents as a nonspecific flu-like illness, include septic shock, endocarditis, and metastatic infection (figure 5).           

Of great current concern is the spread in communities throughout the United States of S. aureus strains that are resistant to antibiotics (these are commonly called “methicillin-resistant” or MRSA strains) and that are associated especially with skin abscesses (figure 6) and furuncles and with severe necrotizing pneumonia. These strains typically express the Panton-Valentine leukocidin, an exotoxin that induces pore formation in polymorphonuclear neutrophils and monocytes, leading to activation, degranulation, and release of inflammatory mediators.


Figure 7
Brain abscess
In this aspirate, gram-positive cocci form chains with peculiar configurations resembling balls of yarn. Organisms of the Streptococcus anginosus group (historically known as Streptococcus milleri) grew on this culture. The S. anginosus group is commonly isolated from brain abscesses
© Rebecca Buxton and
The Microbelibrary (Used with permission)
Viridans Streptococci

Most of the α-hemolytic streptococci present in the normal flora are loosely known as “viridans” (Latin viridis, “green”) because they cause green hemolysis on blood agar plates, but numerous individual species are now recognized on the basis of physiological, biochemical, and molecular typing methods. Under normal circumstances these bacteria comprise the major aerobic component of the flora of the human mouth, making up nearly 50% of all bacteria that can be cultured from saliva. Individual species of viridans streptococci occupy distinct ecologic niches. Streptococcus sanguis and S. mitis adhere preferentially to the buccal mucosa; S. salivarius and S. mitis to the dorsal surface of the tongue; while S. sanguis, S. mitis, S. oralis, S. gordonii, and S. anginosus are frequently found in dental plaques. S. mutans, which adheres to teeth in large numbers and ferments dietary sugars into acids, is strongly associated with dental caries―no doubt the world’s most prevalent bacterial infection. One group of viridans streptococci, variably known as the “S. milleri group” or “S. anginosus,” is associated with purulent infections including brain abscess (figure 7). Nearly all of the viridans streptococci occasionally cause endocarditis, usually in persons with diseased heart valves. With these 3 exceptions, colonization by viridans streptococci is nearly always harmless; indeed, it is highly beneficial since it provides resistance to colonization by more virulent microorganisms.


Figure 8
Acute group A streptococcal pharyngitis in an 8-year-old female patient. Note the acute inflammation of the right tonsil. It is enlarged with adherent plaque
© Lewis Tomalty and
The Microbelibrary

Figure 9
 Mechanisms of disease due to Streptococcus pyogenes

Streptococcus pyogenes (group A streptococcus) 

S. pyogenes is a major pathogen not only because of the frequency of streptococcal pharyngitis (figure 8) and impetigo but also because of the potential for life-threatening complications. Complacency engendered by the declining incidence of acute rheumatic fever has given way to renewed concern because of the streptococcal toxic shock syndrome and necrotizing fasciitis. S. pyogenes is a frequent colonizer of the human pharynx, especially in children where carriage rates of up to 20% have been reported. Asymptomatic colonization is less common in adults. Streptococcal M protein enables the organism to resist phagocytosis and multiply in blood. The development of antibodies against M protein confers lasting immunity, but unfortunately the immunity is type-specific and more than 90 types of M protein have been identified. The diverse manifestations of S. pyogenes infection are summarized in figure 9. 

The streptococcal toxic shock syndrome is, simply put, any streptococcal infection associated with the sudden onset of shock and organ failure. Portals of entry are apparent in most cases. Some cases are associated with necrotizing fasciitis. Both pyrogenic exotoxins and certain M proteins seem to be capable of acting as “superantigens,” causing massive release of monocyte cytokines and lymphokines.


Figure 10
Gram stain of a sputum specimen from a patient with pneumonia. The Gram stain shows encapsulated lancet-shaped gram-positive cocci associated with the polymorphonuclear leukocytes. Note the clear zone surrounding the organisms. This zone is consistent with a large polysaccharide capsule that is not picked up by the Gram stain. These Gram stain findings are consistent with Streptococcus pneumoniae
© Gloria Delisle, Lewis Tomalty and The Microbelibrary

Streptococcus pneumoniae 

Increasing resistance to β-lactam antibiotics and other drugs makes the pneumococcus a common cause of otitis media, sinusitis, pneumonia, meningitis, and other serious infections more dangerous today than at any time since the pre-antibiotic era. Most humans are intermittently colonized in the nasopharynx by this organism, especially during midwinter. Prevalence studies indicate that 20% to 40% of children and 5% to 10% of adults are colonized at a given time. From the nasopharynx, pneumococci have access to the eustachian tubes, the ostia to the paranasal sinuses, and the tracheobronchial tree.


Figure 11
Percentage of Nosocomial Enterococci Reported as Resistant to Vancomycin in Intensive Care Units and non-ICUs, 1989-1994  CDC

Figure 12
Gram-positive Group D Streptococcus bacteria magnified 320X.
Streptococci are subdivided into groups based on what antibodies recognize their surface antigens. Group D contains five species, S. faecalis, S. faecium, S. durans, S. avium, and S. bovis. CDC/Dr. Richard Facklam


Enterococci, Streptococcus bovis, and Group B Streptococci

Group D streptococci formerly included the enterococci, S. bovis, and S. equinus. Newer classifications give enterococci their own genus with at least 12 species, of which Enterococcus faecalis (80% to 90%) and E. faecium are the major isolates from humans. Enterococci form a major part of the normal flora of the lower gastrointestinal tract, being the predominant aerobic gram-positive bacteria in stools. Enterococci occasionally cause community-acquired urinary tract infection and endocarditis. However, the ability of enterococci to cause disease by themselves (that is, as sole pathogens) is limited. Enterococci are commonly involved in hospital-acquired infections are frequently isolated from urine of patients with obstructive uropathy and from wounds including decubitus ulcers. Resistance to numerous antibiotics complicates treatment of enterococcal infection (figure 11).

Streptococcus bovis (figure 12) is occasionally found in the human gastrointestinal tract, especially in patients with cancer or precancerous lesions of the bowel; documented S. bovis bacteremia is an indication for colonoscopy. Group B streptococci (S. agalactiae), found in genital tract or colon in 5% to 40% of women, are of concern primarily because of neonatal and puerperal sepsis but also cause disease in adults with impaired host defenses.


  Neisseria meningitidis

The meningococcus is one of the few microorganisms capable of killing a previously-healthy person within a few hours. However, asymptomatic colonization is relatively common, being found in 18% of “normal” family members over a 32-month period. Asymptomatic carriage of meningococci leads to the development of protective antibodies directed against the organism’s polysaccharide capsule. Most cases of invasive meningococcal disease occur among the newly colonized. Studies suggest that adult males often bring the organism into a household; respiratory transmission leads to colonization of other family members, with children being the most likely victims of invasive disease.


  Haemophilus influenzae and Moraxella catarrhalis

Haemophilus influenzae is a small, pleomorphic, aerobic, gram-negative coccobacillus found mainly in the upper respiratory tract. Some strains contain a polysaccharide capsule, the major virulence factor, and are typed (a through f) according to the nature of the capsule. Most instances of life-threatening disease such as meningitis are caused by type b strains. Wide deployment of the conjugate vaccine against Haemophilus influenzae type b has greatly diminished the importance of this scourge of early childhood. Non-encapsulated strains are frequently associated with sinusitis, otitis media, exacerbations of chronic bronchitis in patients with COPD, and conjunctivitis. About 30% to 80% of healthy persons have nasopharyngeal colonization by non-encapsulated strains of H. influenzae. About 2% to 4% of children were colonized by type B strains prior to the vaccine. H. influenzae, like N. meningitidis, preferentially colonizes non-ciliated epithelial cells in the nasopharynx.

Moraxella catarrhalis, previously known as Neisseria catarrhalis and then Branhamella catarrhalis is a gram-negative diplococcus associated with upper and lower respiratory infections in both children and adults. Up to two-thirds of infants, but only 1% to 5% of healthy adults, are colonized by this microorganism, which causes a spectrum of disease similar to that caused by H. influenzae.


Figure 13
Gram Stain of Urine
These short to medium-long gram-negative bacilli look like typical enteric gram-negative bacteria; isolation of Proteus mirabilis confirmed that impression
© Rebecca Buxton and
The Microbelibrary (Used with permission)

E. coli and Other Aerobic Gram-Negative Rods 

Escherichia coli, the major aerobic gram-negative rod (bacillus) found in the lower gastrointestinal tract, is of enormous importance in primary care because of its role in:

  • the great majority of cases of community-acquired urinary tract infection (UTI)

  • occasional deep tissue infectious such as vertebral osteomyelitis in patients with underlying medical problems

  • rare cases of colitis caused by enteropathogenic or enterohemorrhagic strains

  • the well-publicized problem of hemorrhagic colitis and hemolytic syndrome due to strains belonging to the 0157:H7 serotype.

All humans (excepting those who have received broad-spectrum antimicrobial therapy) are probably colonized with E. coli, but asymptomatic colonization with enteropathogenic or enterohemorrhagic strains is rare if it occurs at all.

Proteus mirabilis causes up to 10% of community-acquired UTIs and presumably colonizes the normal human gastrointestinal tract. Other aerobic gram-negative rods cause infections in patients with underlying diseases who have received broad-spectrum antimicrobial therapy. Klebsiella, Enterobacter, and Serratia species are often found in the stool flora of patients who have received broad-spectrum antibiotics. Pseudomonas aeruginosa can be part of the normal fecal flora but, unlike E. coli or Proteus mirabilis, is rarely associated with community-acquired UTI in the absence of a predisposing factor such as urologic instrumentation. Acinetobacter species, which often resist the action of soap, can be found in the skin flora in up to 25% of persons but rarely cause community-acquired disease. Salmonella and Shigella species are not considered part of the normal intestinal flora.



Anaerobic Bacteria 

Anaerobic bacteria are operationally defined by their failure to grow on solid media in the presence of 10% carbon dioxide (or 18% oxygen). Most of the common aerobic bacteria encountered in medicine can grow under anaerobic conditions as well, and are therefore sometimes called “facultative” (that is, they can grow either aerobically or anaerobically). The term “anaerobic” is usually reserved for strict anaerobes. Quantitatively, these bacteria are the most important component of the normal human flora. Thus, saliva contains 107 to 108 anaerobic bacteria/mL; the terminal ileum 104 to 106/mL; and the colon, where anaerobes outnumber aerobes by a ratio of about 1000:1, 1011 or more per gram of stool (dry weight). Anaerobes are also highly prevalent in the normal flora of the skin, vagina, and periurethral tissues. Anaerobic bacteria are commonly found in odontogenic infections including infected root canals, chronic sinusitis, chronic otitis media, and pelvic inflammatory disease. Otherwise, anaerobic bacteria rarely assume importance in primary care unless the patient has serious underlying disease or  the infection is of such severity that hospitalization is clearly indicated. This is the case because anaerobic bacteria cause serious infection only when there has been a major disruption of tissue (for example, a wound or perforated bowel) or when the oxidation-reduction potential has been lowered (for example, by ischemia, necrotic tumors, or foreign bodies). To the contrary, anaerobic bacteria are of major importance to human well being since they protect against colonization by more pathogenic organisms.

When anaerobic bacteria cause disease, they generally arise from the indigenous body flora. The major exception is the clostridial syndromes such as tetanus (Clostridium tetani) and botulism (Cl. botulinum). The species most commonly isolated from deep tissue infections include peptostreptococci ("anaerobic streptococci"), which are normally present in all of the sites mentioned above; Prevotella, Porphyromonas, and Fusobacterium species, which are normally present in the oral cavity; and the Bacteroides fragilis group of bacteria, which make up the bulk of the normal fecal flora. The most important clue to an anaerobic infection is its foul odor. This finding is diagnostic though present in only about one-half of cases. Other clues include tissue gas (observed as bullae or as crepitation on physical examination, or found on x-ray); tissue necrosis, the presence of multiple bacterial morphologies on Gram’s stain of a specimen, and the failure of bacteria to grow on a routine aerobic culture (“sterile pus”). Settings in which anaerobic bacteria should always be suspected include bite wounds, aspiration pneumonia, lung abscess, pleural empyema, brain abscess, necrotizing fasciitis, myonecrosis (gas gangrene), diabetic foot ulcers, decubitus ulcers, and septic thrombophlebitis.

Figure 14
When the prevalence of a disease in a population is extremely low, the probability that a positive test is a false -postive is very high even when the test is a good one

From Bayes’s theorem, it follows that the relationship between the prevalence of a disease and the probability that a screening test result is false-positive rather than true-positive is hyperbolic rather than linear.     

Diagnosis and Clinical Reasoning

Diagnosis is of two types: presumptive and definitive. Presumptive diagnosis is usually based on the history and physical examination, sometimes supported by laboratory and radiographic findings. Definitive etiologic diagnosis usually requires cultures and serologic methods. In primary care, most diagnoses of infectious diseases are presumptive. This is understandable, since the conditions most commonly encountered tend to be self-limited and often involve the upper respiratory tract. For seriously ill patients including hospitalized patients, definitive diagnosis is usually desirable although sometimes difficult to achieve. Some principles of diagnosis include the following:

  • Assume the worst-case scenario

  • Search for a syndrome

  • Look for atypical features

  • Pay attention to the peripheral blood smear 

  • Perform diagnostic testing only when the results will alter patient management, but arrange for close follow-up

  • Arrange for follow-up ("tincture of time")

  • Document the level of diagnostic certainty

  • "Think" tuberculosis and endocarditis

The major categories of clinical reasoning are, in ascending order of importance: (1) pattern recognition; (2) probabilistic thinking; and (3) pathophysiology. Consider, for example, an 18-year-old woman with chief complaint of burning on urination. Pattern recognition and probabilistic thinking suggests uncomplicated UTI and hence a quick prescription for a 3-day course of antimicrobial therapy. The pathophysiologic approach, however, would be to ask further questions directed at determining whether the dysuria is external rather than internal and whether risk factors for sexually transmitted disease (STD) are present. One then determines whether to perform a pelvic examination and obtain studies for STD as well as a urine culture before beginning therapy.

What diagnostic tests should be obtained, and when? Generations of medical students have learned such gems as:

  • Sutton’s law ("Go where the money is," after Willie Sutton, the bank robber)

  • Occam’s razor ("Seek the one, simplest explanation," after William of Occam, the philosopher)

  • and Anselm’s ass ("Do something; don’t just stand there in the middle" - the animal was tethered between 2 bales of hay, both just out of reach).

A better and more sophisticated approach is to consider the properties of tests within the context of probability theory.

All clinicians must be familiar with “sensitivity,” “specificity,” and related terms. Sensitivity basically means “positive in disease”―we say a test is 99% sensitive if positive test results are obtained in 99% of persons to have the disease by one or another gold standard, such as biopsy or autopsy. Specificity basically means “negative in health”―we say that a test is 99% specific if positive test results are obtained in only 1% of persons who clearly do not have the disease. However, it is extremely important to consider “sensitivity,” “specificity,” and related concepts in the context of pre-test probability―the likelihood that the patient has the disease.

This concept is best captured by Bayes’s theorem, which holds that the likelihood that a positive test result is actually false-positive rather than true-positive varies inversely with the prevalence of the disease in the population. This concept can be grasped by careful study of figure 14. The likelihood that a positive test result is false-positive rather than true-positive is 100% if nobody in the population represented by the patient has the disease, but 0% if everybody has the disease. Between these extreme cases, the relationship is described not by a straight line but rather than by a hyperbolic curve. The upshot is that if the pre-test probability is extremely low, then the chances are overwhelming that a positive screening test result is actually a false-positive result even if the sensitivity and specificity of the test are superb.        

Increasingly, the concept of pre-test probability is being expressed as the likelihood ratio, and nomograms are available for evaluating of the usefulness of a test.



Infection Control  

Rigorous infection control is a moral imperative and legal requirement. All medical personnel should know the basic principles of disease transmission and control. Let us briefly review disease transmission as it applies to preventing infection in the office setting:

·        Contact transmission involves person-to-person or object-to-person touching of mucous membranes or open skin. This is an important means of transmission of staphylococci, Clostridium difficile, and some respiratory viruses including respiratory syncytial virus. Frequent hand washing is the major defense against contact transmission, but attention should also be paid to routine disinfection of stethoscopes, toys, bathroom fixtures, and other objects with patient care areas.

·        Droplet transmission involves coughing, sneezing, or suctioning procedures (as in bronchoscopy), resulting in a spray of secretions capable of contacting conjunctiva, nasal mucosa, and lips within a 3-foot radius. This is an important means of transmission of meningococci, influenza viruses, and pertussis. The use of eye protection including goggles and shields during certain procedures is a defense against droplet transmission.

·        Airborne transmission involves inhalation of particles that are much smaller than droplets, often referred to as “droplet nuclei.” This is an important means of transmission when organisms remain suspended in the air after coughing in the form of “droplet nuclei,” as in tuberculosis (pulmonary and laryngeal), chickenpox, and measles (rubeola). Masks, ultraviolet lights, and immunization constitute some of the defenses.

·        Vehicle transmission by contaminated items, although now uncommon in health care settings as a result of tight regulations, still occurs and can cause outbreaks of even epidemics. Causes include use of expired medications or antiseptics, irrigation fluids that have been left in open containers, and use of diluted bleach solution that is over 24 hours old. Disease frequently involved organisms that survive well in water such as Pseudomonas species. Defenses include monitoring refrigerator temperatures, checking for expired medications, discarding irrigation solutions without preservatives at the end of the day of opening, and selecting disinfectants that do not require dilution.

·        Vector transmission by insects or animals is extremely rare in today’s health care facilities.


All health care workers should  know their tuberculin skin status and their immunization status against measles (rubeola), mumps, rubella, hepatitis B, and varicella-zoster virus. It is important to protect both our patients and ourselves—primum non nocere!


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