Ebook Cases in medical microbiology and infectious diseases Part 2

(BQ) Part 2 book Cases in medical microbiology and infectious diseases presentation of content: Skin and soft tissue infections, central nervous system infection, systemic infections, advanced cases.

SKIN AND SOFT TISSUE INFECTIONS SECTION

FOUR

256 Skin and Soft Tissue Infections

INTRODUCTION TO SECTION IV

The resistance of skin to infection is due to the integrity of the keratinized skin, the

pres-ence of inhibitory fatty acids produced by sebaceous glands, the dryness of the skin, and

the inhibitory effect of the resident normal skin microbiota Skin and soft tissue infections

can be caused by either direct penetration of a pathogen through the skin or

hematoge-nous spread of the pathogen to the site The normal skin microbiota includes organisms

that may cause infection in the setting of a disruption in the integrity of the skin (such as

the presence of a surgical suture or an insect bite) In the setting of severe damage to the

skin, as occurs with burns, even normally innocuous organisms, including endogenous

bacteria, can cause severe disease Similarly, when the skin is no longer dry, as may occur

in moist intertriginous spaces or when occlusive dressings are present, the patient is at

increased risk of infection

Cutaneous manifestations of systemic disease are common Rocky Mountain spotted

fever, meningococcemia, enteroviral infection, and toxic shock syndrome can all present

with fever and a diffuse erythematous macular rash Other systemic infections that can

present with a diffuse rash include scarlet fever, measles, and German measles The

char-acteristic rash of Lyme disease, erythema migrans, is specific enough to establish the

diagnosis The nature of the lesion (macular, papular, vesicular, pustular, or bullous) may

help to narrow the differential diagnosis For example, varicella-zoster virus infection

typically results in vesicular skin lesions The rash of secondary syphilis, on the other hand,

may present clinically as macular, papular, maculopapular, or pustular skin lesions but does

not present as a vesicular rash

Skin and soft tissue infections can be classified on the basis of the anatomic level at

which infection occurs The more superficial infections, such as folliculitis caused by

Staphylococcus aureus or cellulitis caused by Streptococcus pyogenes, are important to treat at

an early stage Delay in treatment may result in invasion of the deeper structures, as in

necrotizing fasciitis, which has a high mortality rate

Damage to the skin and soft tissues, as occurs in traumatic injuries, may allow the

entry into the wound of soil organisms such as Clostridium perfringens, an anaerobic,

Gram-positive rod Under favorable conditions, potentially fatal soft tissue infections

(myositis, gas gangrene) may occur

New technologies such as 16S rRNA gene sequencing and matrix-assisted laser

desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) allow us to

identify to the species level Gram-positive bacilli recovered from soft tissue infections

Rapidly growing mycobacteria including Mycobacterium abscessus, Mycobacterium chelonae,

and Mycobacterium fortuitum have been found to cause infection secondary to cosmetic

surgery and pedicures Other environmental mycobacteria such as Mycobacterium marinum

have been associated with soft tissue infection following traumatic injury involving water

exposure Cornyebacterium kroppenstedtii has been associated with mastitis Three species of

Actinomyces—A neuii, A radingae, and A turicensis—are now recognized to cause skin and

soft tissue infections These three organisms are also indigenous flora on skin, so the

find-Skin and Soft Tissue Infections 257

ing of these organisms in clinical specimens should be accompanied by evidence of mation such as the presence of white blood cells on direct Gram stain of the patient’s specimen

inflam-Important agents of skin and soft tissue infection are listed in Table 4 The presence

of ectoparasites, such as lice and bedbugs, is not designated an infection but rather an infestation Ectoparasites are, however, included for completeness

TABLE IV SELECTED SKIN AND SOFT TISSUE PATHOGENS

ORGANISM

GENERAL CHARACTERISTICS SOURCE OF INFECTION DISEASE MANIFESTATION

Bacteria

Actinomyces neuii Short, Gram-positive

bacillus Endogenous (skin flora) Cellulitis, skin abscess, superficial wound

infections

Actinomyces radingae Short, Gram-positive

bacillus Endogenous (skin flora) Cellulitis, skin abscess, superficial wound

infections

Actinomyces turicensis Short, Gram-positive

bacillus Endogenous (skin flora) Cellulitis, skin abscess, superficial wound

infections

Bacillus anthracis Spore-forming, aerobic,

Gram-positive bacillus Exogenous; livestock or animal products;

bioterrorism agent

Cutaneous, gastrointestinal, and inhalation anthrax;

meningitis; bacteremia

Bartonella henselae Fastidious,

Gram-negative bacillus Exogenous; cats appear to be primary

host

Cat scratch disease, bacillary angiomatosis (in immunocompromised individuals)

Borrelia burgdorferi Spirochete Tick-borne Lyme disease; rash,

arthritis, nervous system and cardiac manifestations

Clostridium tetani Anaerobic,

Gram-positive bacillus Exogenous (wounds) Tetanus

fasciitis, pharyngitis, pneumonia, rheumatic fever, poststreptococcal

258 Skin and Soft Tissue Infections

TABLE IV SELECTED SKIN AND SOFT TISSUE PATHOGENS (continued)

ORGANISM

GENERAL CHARACTERISTICS SOURCE OF INFECTION DISEASE MANIFESTATION

(diabetics)

Mycobacterium

abscessus Acid-fast bacillus, environmental Exogenous (water) Surgical wounds, chronic lung infections in cystic

fibrosis patients, related sepsis

Direct sexual contact;

vertical, mother to child

Genital tract involvement, pharyngeal infection, ocular infection, bacteremia, arthritis with dermatitis

Neisseria meningitidis Oxidase-positive,

Gram-negative diplococcus

Endogenous (from colonization) Meningitis, bacteremia, pneumonia

Pasteurella multocida Oxidase-positive,

Gram-negative bacillus Zoonosis (often animal bite or scratch) Cellulitis, bacteremia, osteomyelitis, meningitis,

pneumonia

Pseudomonas

aeruginosa Lactose-nonfermenting, oxidase-positive,

Gram-negative bacillus

Exogenous Skin infections in burn

patients, community and health care-associated UTI, health care-associated pneumonia, health care- associated bacteremia, ecthyma gangrenosum

Staphylococcus aureus Catalase-positive,

coagulase-positive, Gram-positive coccus

Endogenous Cellulitis, bacteremia,

endocarditis, septic arthritis, abscesses, pneumonia

Treponema pallidum Spirochete (does not

Gram stain) Direct sexual contact; vertical, mother to

child

Primary (painless chancre), secondary (diffuse rash), latent, and late syphilis; can affect any organ

Skin and Soft Tissue Infections 259

TABLE IV SELECTED SKIN AND SOFT TISSUE PATHOGENS (continued)

ORGANISM

GENERAL CHARACTERISTICS SOURCE OF INFECTION DISEASE MANIFESTATION

Fungi

Blastomyces

dermatitidis Dimorphic mold Exogenous Cutaneous infection, pneumonia, meningitis,

bone infection

Candida albicans Yeast, often germ tube

positive Endogenous Thrush, vaginal yeast infection, diaper rash,

esophagitis, health associated UTI, health care-associated bloodstream infection

care-Candida spp.,

non-albicans Yeasts, germ tube negative Endogenous Thrush, vaginal yeast infection, health

care-associated UTI, health care-associated bloodstream infection

Cryptococcus

neoformans Encapsulated yeast Exogenous (environmental, rarely

zoonotic)

Meningitis, pneumonia, bloodstream infection, cellulitis

Epidermophyton

floccosum KOH-positive skin lesions; club-shaped

macroconidia, absent microconidia

Anthropophilic Dermatophyte infection of

keratinized tissue (rarely nails)

Microsporum spp. KOH-positive skin

lesions; fluoresce yellow-green under Wood’s light

May be zoophilic (e.g.,

Trichophyton spp. KOH-positive skin

lesions May be zoophilic (e.g., T mentagrophytes) or

anthropophilic (e.g., T

schoenleinii)

Dermatophyte infection of keratinized tissue

(including nails) Parasites

Ancylostoma

braziliense Hookworm of dog Exogenous Cutaneous larva migrans

Ancylostoma caninum Hookworm of dog Exogenous Cutaneous larva migrans

Cimex lectularius Ectoparasite Exogenous Bedbug; itching skin

lesions

Leishmania tropica,

Leishmania

braziliensis

Protozoans Exogenous (sand fly) Ulcerative skin lesions

(continued next page)

260 Skin and Soft Tissue Infections

TABLE IV SELECTED SKIN AND SOFT TISSUE PATHOGENS (continued)

ORGANISM

GENERAL CHARACTERISTICS SOURCE OF INFECTION DISEASE MANIFESTATION

Sarcoptes scabiei Ectoparasite Exogenous; zoonotic

varieties less common than human varieties

Scabies infestation

Viruses

Enteroviruses Nonenveloped, ssRNAb Usually fecal-oral Aseptic meningitis, rash,

myocarditis Herpes simplex virus

1 and 2 Enveloped, dsDNA

c Person to person;

reactivation of latent infection; during passage of the neonate through the birth canal

Genital ulcers; oral, ocular infections; encephalitis;

neonatal infection;

esophagitis (immunocompromised individuals)

HIV Enveloped RNA

retrovirus Blood-borne and sexual transmission;

vertical, mother to child

AIDS, mononucleosis-like syndrome with rash in primary infection

(measles) Enveloped, ssRNA Respiratory spread Measles, pneumonia, encephalomyelitis, subacute

sclerosing panencephalitis Papillomavirus Nonenveloped, dsDNA Person to person Warts

Varicella-zoster virus Enveloped, dsDNA Respiratory spread Chicken pox; zoster (may

disseminate) Variola virus Enveloped, dsDNA Person to person,

respiratory spread;

bioterrorism agent

Smallpox; vesicular, pustular, hemorrhagic rash

a UTI, urinary tract infection.

b ssRNA, single-stranded RNA.

c dsDNA, double-stranded DNA.

261

The patient was a 45-year-old male who was in his usual state

of good health when he awoke at 3 a.m with pain in the lateral aspect of his left calf He looked at his calf and thought that the pain was due to an ingrown hair and went back to sleep At 10 a.m., he expressed a small amount of pus from the ingrown hair

Over the next 8 hours, the patient developed an area of cellulitis on the lateral

aspect of the calf of approximately 5 by 10 cm At that time, a small amount of pus

was again expressed from the area of the ingrown hair The next morning, the area

of cellulitis extended from just below the knee to just above the ankle The patient

visited his physician His vital signs at that visit, including pulse, respirations,

blood pressure, and temperature, were all within normal limits Physical exam was

signifi cant for an area of cellulitis as described that was red and warm to the touch

but with no area of obvious fl uctuance No lymphadenopathy was observed The

central area of the cellulitis, near the area that the patient described as where the

ingrown hair had been, was punctured three times with a 20-gauge needle but no

pus was drained The patient was referred to the surgery service The surgeons

examined the patient and said they would follow him The patient was given 2 g

of ceftriaxone intramuscularly and begun on oral cephalexin

The patient returned to the surgical clinic 48 hours later with an obvious area of

fl uctuance in the center of the area of cellulitis Over the preceding 48 hours, the

patient reported low-grade fevers Approximately 1 ml of pus was aspirated and was

sent for Gram stain and culture (Fig

36.1 and 36.2) When pus was aspirated

from the lesion, the surgeon decided to

excise and drain the lesion (Fig 36.3)

1 Describe what you observed in Fig 36.1 and 36.2 The organ-ism is catalase and coagulase positive What organism was causing his infection?

2 Why were incision and age necessary to treat this infection? Why would antimi-crobial agents alone not be effective in treatment of this infection?

drain-3 Susceptibility results for this organism are seen in Fig 36.4

How do you interpret these susceptibility results? Explain

The patient was a 45-year-old male who was in his usual state

aspect of his left calf He looked at his calf and thought that the pain was due to an ingrown hair and went back to sleep At 10 a.m., he expressed a small amount of pus from the ingrown hair

CASE

36

Figure 36.1

Figure 36.2

262 Skin and Soft Tissue Infections

the likely reasons for the results seen with drugs 2 and 4 How do results

of the testing of drug 2 explain the progression of his infection despite a large intramuscular dose of ceftriaxone followed by oral cephalexin?

Also explain the fi ndings for drugs 7 and 8 How should the isolate infecting this patient be treated?

4 What test is being used to test vancomycin (drug 5)? Why is this test being used and what does it show?

5 What virulence factor is particularly associated with skin and soft tissue infections (SSTIs)? Explain its mechanism of action This virulence fac-tor and this type of antibiogram are associated with a particular strain of this organism Briefl y discuss the evolving epidemiology of this strain

6 What infection control precautions would be necessary for this patient?

What are some of the potential unintended consequences of ized patients who are colonized with this organism?

hospital-7 Why are these organisms viewed as a global threat?

Figure 36.3

Figure 36.4

Case 36 263

CASE DISCUSSION

1. The fi nding of Gram-positive cocci in clusters on Gram stain is

consistent with staphylococci The fi nding of a yellowish colony that is

beta-hemolytic on 5% sheep blood agar is consistent with Staphylococcus

aureus The staphylococci are divided into two groups based on the biochemical test called the coagulase test; S aureus is positive, while a group of >30 other staphylococcal

species are negative This group of organisms is referred to as the coagulase-negative staphylococci (CoNS) Three of the CoNS species are frequently encountered clini-

cally Staphylococcus epidermidis can infect implanted foreign bodies, such as

pacemak-ers, cerebrospinal fl uid shunts used to treat hydrocephalus, intravascular cathetpacemak-ers,

and artifi cial joints Staphylococcus lugdunensis has been associated with skin and soft tissue infections (SSTIs) as well as native valve endocarditis Although S lugdunensis can cause SSTIs, it is less common than S aureus The other frequently encountered CoNS species is Staphylococcus saprophyticus, which causes urinary infections primarily

in young, sexually active women The isolate recovered from this patient was

coagu-lase positive and was identifi ed as S aureus.

The patient’s infection began as a folliculitis at the site of the ingrown hair, gressed to a cellulitis, and ultimately evolved into an abscess Approximately 20% of

pro-adults are chronic nasal carriers of S aureus, while an additional 60% may carry the

organism intermittently From the nose, the skin can become colonized Studies have shown intermittent skin carriage rates as high as 40%, although most studies target the skin carriage rate at 10 to 15% In all likelihood this individual’s initial folliculitis was a

result of the infecting S aureus coming from skin colonization Manipulation of the skin

resulted in the spread of the organism to the dermis, leading to cellulitis and abscess formation

2. The standard of care for an abscess is 2-fold: incision and drainage (Fig 36.3) and antimicrobial therapy The reason why antibiotics alone would not be suffi cient is that abscess formation results in a loss of blood fl ow to the center of the infected area (the abscess) As a result, antibiotic levels in the center of the abscess would be low or, in a large abscess, completely absent, allowing the survival of the infecting organisms pres-ent there Incision and drainage removes a large number of organisms and reduces the infected area, making penetration of much higher levels of antimicrobial agents to the infected tissue and killing of the infecting organism more likely

Staphylococcus

CASE

36

264 Skin and Soft Tissue Infections

3. The susceptibility test that was performed on this patient is a disk diffusion test for

seven drugs and an E-test for one drug The basis for disk diffusion susceptibility testing

is described in the introductory chapter of this text, and the reader is referred there for

further details The antibiogram for this organism is as follows:

Drug 1: trimethoprim-sulfamethoxazole, to which the organism is susceptible

Drug 2: cefoxitin, to which the organism is resistant

Drug 3: doxycycline, to which the organism is susceptible

Drug 4: penicillin G, to which the organism is resistant

Drug 5: vancomycin with an MIC of 2 μg/ml by E-test (see answer 3 for more details)

Drug 6: gentamicin, to which the organism is susceptible

Drug 7: clindamycin, to which the organism is susceptible

Drug 8: erythromycin, to which the organism is resistant

This S aureus strain is expressing two different resistance mechanisms against the β-lactam

drugs One is evidenced by its resistance to penicillin G This resistance is due to the

organism’s ability to produce an enzyme, β-lactamase, that degrades the β-lactam ring of

penicillin G, rendering this and the related widely used antimicrobials ampicillin,

amoxicillin, and piperacillin inactive Approximately 90 to 95% of S aureus strains

produce a β-lactamase that is encoded on the bacterial chromosome Almost as soon

as penicillin G was put into widespread therapeutic use, recognition of S aureus

strains resistant to penicillin G by virtue of β-lactamase production emerged New

agents including penicillinase-stable penicillins (oxacillin, nafcillin, and the oral agent

dicloxacillin); first-, second-, and third-generation cephalosporins; and carbapenems were

developed over the following decades A characteristic all these drugs shared was that they

were relatively stable in the presence of β-lactamase-producing S aureus However, a

sec-ond resistance mechanism to β-lactam drugs soon emerged The presence of this

resis-tance is predicted by the cefoxitin result Although cefoxitin is not a drug that is used to

treat S aureus infections, S aureus strains expressing cefoxitin resistance predictably have

alteration of a specific penicillin-binding protein, PBP2 The altered penicillin-binding

protein, PBP2a, is encoded by mecA All β-lactam antimicrobials have significantly reduced

affinity for PBP2a relative to PBP2 This altered affinity is the basis for what we call

meth-icillin resistance in S aureus This term is obviously a bit of a misnomer since this PBP

alteration confers resistance to all β-lactam drugs, just not methicillin The reason the

term “methicillin-resistant S aureus,” or MRSA, became widespread is that methicillin

was the drug used to treat serious S aureus infections when this resistance was first

encountered It is critical to remember that no β-lactam antimicrobial has clinical efficacy

against MRSA with the exception of a newly developed cephalosporin, ceftaroline,

although some β-lactams may appear to have activity against S aureus in vitro

The only other antimicrobial to which this isolate is resistant is erythromycin If the

placements of the clindamycin (disk 7) and erythromycin (disk 8) disks are closely

exam-ined, it should be noted that they are closer together than the other disks in order to

determine whether there is formation of a D-shaped zone of inhibition around the

clin-Case 36 265

damycin The D-zone occurs when erythromycin induces the production of an rRNA

methylase encoded by the erm gene Expression of this methylase can be either

constitu-tive (always on) or inducible (on only in the presence of an inducer such as erythromycin)

erm-specific methylation of the rRNA results in both erythromycin and clindamycin resistance The D-zone test is assessing whether the inducible form of erm is present The

bacteria growing closest to the erythromycin disk are in the presence of an inducer, and therefore will be resistant to clindamycin; this resistance causes a “flattening” of the zone

of inhibition in the area between the two disks, creating a characteristic D-shaped zone

around the clindamycin disk (Fig 36.3) If the constitutive form of erm was present, the

organism would test as resistant to clindamycin independent of the presence of

erythro-mycin Clinical failures of clindamycin therapy for infections due to S aureus strains with inducible erm genes are well documented in the literature Mild SSTIs can be treated with

oral antimicrobials Because his isolate was resistant by virtue of altered PBPs to both of the drugs he was given initially, ceftriaxone and cephalexin (an oral cephalosporin), this patient next was given oral clindamycin Some studies suggest that incision and drainage

is all that is necessary to clear the infection, but the physician was being cautious

4. Vancomycin is a key drug in treating MRSA infections, particularly severe ones as seen in this patient Vancomycin (drug 5) is being tested using a special antimicrobial- impregnated strip called an E-test The strip is designed to release a gradient of a specific antimicrobial agent into the agar The point where the elliptical zone of bacterial growth inhibition (thus the name “E-test”) meets the strip determines the MIC of the antimicro-bial for the organism being tested The vancomycin MIC is 2 μg/ml, which is at the upper level of susceptibility for this organism Strains with vancomycin MICs of 4 or 8 μg/ml are

referred to as vancomycin-intermediate S aureus, or VISA, and are more likely to result

in treatment failures VISA strains are not reliably detected by disk diffusion techniques; thus the need for a MIC technique The reduced susceptibility of VISA isolates is due to

a thickening of the cell wall, resulting in “trapping” of vancomycin, a large, highly charged

molecule VISA strains should not be confused with vancomycin-resistant S aureus, or

VRSA VRSA strains are still quite rare worldwide Their resistance is due to the

acquisi-tion of the vanA gene from Enterococcus faecium VRSA strains have high-level vancomycin

resistance (MICs of 16 to ≥128 μg/ml)

5. Panton-Valentine leukocidin is a virulence factor that is specifically associated with SSTIs It is a cytolytic pore-forming hexameric protein that can lyse a variety of cell types

It has particular affinity for polymorphonuclear cells and macrophages (thus the name

“leukocidin”) With increasing frequency, S aureus strains with a specific molecular

signa-ture have been documented to be responsible for significant SSTIs causing individuals to seek care in emergency departments These strains are called community-associated MRSA,

or CA-MRSA CA-MRSA strains carry the lukS-PV and lukF-PV genes encoding Valentin leukocidin and a small staphylococcal chromosomal cassette (SCCmec type IV) that

Panton-266 Skin and Soft Tissue Infections

called USA300 predominates Infections with this strain have attracted significant

atten-tion in the popular media because of outbreaks among a variety of athletic teams, day care

centers, schools, and military units More ominously, severe cases of pneumonia are being

documented with increasing frequency Cases of CA-MRSA necrotizing pneumonia have

significant morbidity and mortality One of the interesting things about CA-MRSA is that

it remains susceptible to a variety of oral agents, in this case, clindamycin, doxycycline, and

trimethoprim-sulfamethoxazole This is in stark contrast to another group of MRSA

strains that are classified as health care-associated MRSA, or HA-MRSA Typically

acquired in a health care setting, these strains are often resistant to oral agents and

ami-noglycosides, making vancomycin the primary therapeutic option, while three newer

agents, daptomycin, linezolid, and ceftaroline, are important second-line drugs For

HA-MRSA, linezolid is often the only susceptible oral drug, and it is poorly tolerated and

expensive Thus, serious HA-MRSA infections are almost always treated with intravenous

vancomycin Because of its oto- and nephrotoxicity, vancomycin is complicated to give,

since drug levels must be monitored to ensure that toxic levels are not accumulating

6. MRSA, vancomycin-resistant enterococci, and Clostridium difficile are the most

import-ant bacterial causes of health care-associated infections Patients who are colonized with

MRSA are more likely to develop serious HA-MRSA infections, including postoperative

wound infections, central venous catheter-related bacteremia, and ventilator-associated

pneumonia They may also spread MRSA to other patients directly or via common

care-givers A number of strategies have been advocated for preventing HA-MRSA

infec-tions, although evidence to support some of them is often contradictory Strict adherence

to hand washing is essential in preventing the spread of all health care-associated

patho-gens Isolation and contact precautions for patients colonized or infected with MRSA is

standard practice Contact precautions include wearing gloves and gowns when entering

the rooms of MRSA-colonized or -infected patients Proper disposal of gloves and

gowns coupled with hand hygiene is essential One of the areas of controversy in the

prevention of HA-MRSA infections is who should be screened for MRSA carriage and

what laboratory method should be used for screening This discussion is quite complex

and is in a state of flux, so we will not attempt to cover it here However, patients who

are in isolation and on contact precautions often do not get the same level of care as

patients who are not This translates into fewer visits from health care providers, missed

medicine doses, fewer assessments of vital signs, increased risks of falls, and not

surpris-ingly, poorer satisfaction with health care Additionally, patients who are admitted from

long-term health care facilities may get “stuck” in the hospital if they are colonized with

MRSA or vancomycin-resistant enterococci because a particular facility may not accept

individuals with these multidrug-resistant infections

Another issue of note is decolonization of MRSA-colonized individuals Decolonization

is done by applying a topical antimicrobial, mupirocin, to the nares to eliminate nasal

carriage and bathing in either dilute solutions of chlorhexidine or bleach to decrease skin

colonization, including inguinal sites

Case 36 267

In the community, CA-MRSA has been associated with a variety of sports activities Most of the evidence to date suggests that this organism is spread from person to person either by direct contact (as in the case of football players, wrestlers, and fencers) or via fomites such as by sharing towels with colonized/infected individuals or by contact with training equipment that has been previously used by CA-MRSA carriers Strict attention

to personal hygiene, including good hand-washing practices, not sharing towels, and ing down exercise equipment with disinfectant following use, could help reduce these infections

wip-7. CA-MRSA is now recognized as an important emerging human pathogen A recent report in JAMA indicates that in the United States, MRSA is a more important cause of

mortality than HIV CA-MRSA has made a significant contribution to this mortality, and its importance as a human pathogen appears to be increasing This strain’s predilection to cause serious pulmonary infections made this organism of particular concern because it was feared that secondary bacterial superinfection due to CA-MRSA would greatly increase morbidity and mortality during any future influenza pandemic CA-MRSA was found to be widespread in the United States by the early 2000s Importantly, there is cur-rently no evidence to suggest that increased numbers of secondary CA-MRSA pneumonia occurred during the influenza A/H1N1 pandemic of 2009 to 2011

REFERENCES

1 Daum RS 2007 Clinical practice Skin and soft-tissue infections caused by methicillin-

resistant Staphylococcus aureus N Engl J Med 357:380–390.

2 Deresinski S 2012 Methicillin-resistant Staphylococcus aureus and vancomycin: minimum inhibitory concentration matters Clin Infect Dis 54:772–774.

3 Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK; Active Bacterial Core surveillance (ABCs) MRSA Investigators

2007 Invasive methicillin-resistant Staphylococcus aureus infections in the United States

JAMA 298:1763–1771.

4 Platt R Time for a culture change? N Engl J Med 364:1464–1465.

5 Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson-Dunn B, Tenover FC, Zervos MJ, Band JD, White E, Jarvis WR; Glycopeptide-Intermediate

Staphylococcus aureus Working Group 1999 Emergence of vancomycin resistance in

Staphylococcus aureus N Engl J Med 340:493–501.

This 65-year-old woman was bitten by her cat on the dorsal aspect of the right middle fi nger at 8:00 a.m She rinsed the bite with water, and at 4:30 p.m she noted pain and swelling in the

fi nger and the dorsum of the right hand She then noted pain in the axilla, red streaking up the forearm, and chills On examination she had a temperature of 38°C and her right upper extremity was notable for

swelling, erythema, warmth, and tenderness on the dorsum of the hand Two small

puncture wounds were seen on the proximal phalanx of the long fi nger, and

ery-thema was visible over the extensor surface of the forearm Axillary tenderness was

also noted Laboratory studies demonstrated an elevated white blood cell count of

12,000/μl with a left shift (the presence of immature neutrophils in the peripheral

blood) Aspiration of an abscess on her fi nger was sent for culture, and the patient

was taken to the operating room for incision and drainage of the abscess A Gram

stain of the organism causing this woman’s infection is seen in Fig 37.1, and Fig

37.2 shows cultures on sheep blood and chocolate agars The organism failed to

grow on MacConkey agar, and spot tests from the blood agar plate were oxidase

and spot indole positive

1 Which organism was isolated on culture of the abscess? If this had been

a human bite, what organisms might cause an infection?

2 What is the reservoir of this organism? How do humans most monly become infected by this organism?

com-3 How can infection with this organism be prevented?

4 What other clinical syndromes can be caused by this organism?

5 If this patient had been scratched by a young cat rather than bitten and had subsequently developed regional lymphadenitis, what would be the likely organism?

This 65-year-old woman was bitten by her cat on the dorsal

with water, and at 4:30 p.m she noted pain and swelling in the

fi nger and the dorsum of the right hand She then noted pain in the axilla, red streaking up the forearm, and chills On examination

CASE

37

Figure 37.1

Case 37 269

Figure 37.2

6 Domestic animals such as cats and dogs are vaccinated against what pathogen in order to protect humans? When should humans be vacci-nated against this pathogen?

270 Skin and Soft Tissue Infections

C canimorsus on the basis of two characteristics First, P multocida is a Gram-negative

coccobacillus, while C canimorsus is a long, thin bacillus Additionally, P multocida is spot

indole positive, while C canimorsus is negative A key feature of this case, which is typical

of P multocida, was the rapid onset of clinical signs of infection following the animal bite

One point worth emphasizing is that infections following cat and dog bites are commonly

polymicrobial, often including both aerobic and anaerobic bacteria, with a median of fi ve

different bacterial isolates per culture when appropriate techniques are employed for the

isolation of anaerobes

Like those from cat and dog bites, human bite wound infections are typically due to

a mixture of aerobic and anaerobic organisms that are part of the oral microbiota Key

organisms include facultative Gram-positive cocci in the Streptococcus anginosus group, the

facultative Gram-negative bacillus Eikenella corrodens, and anaerobic Gram-negative

bacilli within the genera Prevotella and Fusobacterium Another important organism is

Staph ylococcus aureus, which likely arises from the skin microbiota of the injured individual

The emergence of community-associated methicillin-resistant S aureus (MRSA)

infec-tions means that these infecinfec-tions must also be considered when choosing antimicrobials

Interestingly, facultative Gram-negative bacilli such as Pasteurella and C canimorsus are not

present in human bite wounds

2. P multocida is widely distributed throughout nature and is part of the normal fl ora in

the nasopharynx of many mammals (both wild and domestic) and birds Human infection

is most likely to be associated with cat bites or scratches and less likely (though still quite

commonly) to be caused by dog bites Infections following bites by other members of the

cat family, including lions, have been reported to cause P multocida wound infections In a

minority of human infections, the patients have had no known animal exposure Particular

organisms are often associated with bites from specifi c animals For example, C canimorsus

(cani = “dog”; morsus = “bite”) infection may be transmitted by dog bites, and both

Streptobacillus moniliformis and Spirillum minus are transmitted by rat bites It is important

to note that bites of domestic animals are responsible for hundreds of thousands of

emer-gency department visits annually in the United States

3. Infection can be prevented by limiting contact with cats and dogs If a person is

bit-ten or scratched by a cat or dog, the wound should be thoroughly cleaned as soon as

possible The animal should also be observed for sign of rabies, especially if rabies

vacci-nation is not well documented

Pasteurella multocida

CASE

37

Case 37 271

4. In addition to soft tissue infection with rapid onset, other clinical syndromes seen with this organism following animal bites include osteomyelitis, tenosynovitis, abscess formation, and arthritis Serious infections are more frequent after cat bites than after dog bites It is speculated that the cat tooth, which is long and narrow, is more likely to cause puncture wounds that penetrate the tendon sheath (causing tenosynovitis) or periosteum (causing osteomyelitis) These infections are particularly problematic because they often occur on the hands and wrists Because of the extraordinarily complex anatomy involved, infections of the hand and wrist, if neglected, can require complicated surgical debride-ment and loss of important motor function for the patient, either temporarily or perma-nently Other uncommon complications include bacteremia with septic shock, meningitis, brain abscess, and peritonitis Interestingly, there have been a fair number of reported

cases of peritonitis due to P multocida in which a cat bit into the tubing that was being used

during peritoneal dialysis Pneumonia due to cat exposure, rather than a bite, occurs as well

5. Cat scratch disease is characterized by the development of a small lesion 1 to 2 weeks after a cat scratch, usually on the hand, wrist, or forearm This lesion is followed 1 to 3 weeks later by regional lymphadenopathy, typically of a single or multiple nodes, most commonly in the axilla but sometimes in the cervical or epitrochlear region Multiple sites are infrequently involved The nodes may remain enlarged for several months and then resolve without treatment The etiologic agent is a fastidious Gram-negative bacillus,

Bartonella henselae Although this organism can be grown from the blood of cats, it is rarely

if ever recovered from the tissue of infected individuals Diagnosis is likely to be sought in order to rule out other potential causes of lymphadenopathy such as malignancy There are limited diagnostic tools clinically available to diagnose cat scratch disease Although the antibodies that are tested for when using serology cross-react with similar organisms, the detection of a 4-fold rise in titer from acute- to convalescent-phase sera is diagnostic

in the appropriate clinical setting However, serology only provides a retrospective nosis Multiple nucleic acid amplification tests have been described in the literature, but sensitive detection from human tissue often requires culture enrichment prior to molecu-lar amplification, and this technique remains a research tool Although the organism can

diag-be visualized in lymph node tissue with silver staining early in the disease course, this method is nonspecific and its sensitivity is unknown

6. Both dogs and cats should be vaccinated against the neurotropic, single-stranded- RNA, enveloped virus rabies Rabies is transmitted by the bite of a mammal, typically a dog However, in the United States, cats are more likely to have rabies than dogs This is probably because rabies vaccination is a requirement for dog licensure, and this licensure

is required in most locales in the United States On the other hand, only one state, Rhode Island, requires cat licensure, suggesting that cats are much less likely to receive rabies vaccination

272 Skin and Soft Tissue Infections

Rabies is endemic in many regions of the world, with travelers to Africa, South Asia,

India, and certain regions of South and Central America at greatest risk of exposure

Rabies vaccination is recommended for individuals who are traveling to these regions and

are likely to come in contact with dogs More than 95% of cases that are imported into

Europe and North America are due to dog bites Of the small number of cases in the

United States that are acquired in the absence of foreign travel, bats are often the source

of the infection In particular, parents are encouraged to have their children vaccinated if

they may be exposed to dogs during their travels since they may be less careful about

approaching these animals Only 12% of travelers to regions where rabies is endemic are

vaccinated The reason for this low rate is thought to be the expense of the human rabies

vaccine The importance of this vaccine is illustrated by a case of rabies obtained by a U.S

soldier serving in Afghanistan who was bitten by a dog, was not offered postexposure

pro-phylaxis, and developed rabies several months later and died Unvaccinated people visiting

countries where rabies is endemic should have a plan to get postexposure prophylaxis

consisting of rabies immune globulin and vaccine if bitten by a dog, cat, monkey, bat, wolf,

fox, or other mammal This may include traveling to a place where such treatment is

avail-able In the industrialized world, there is not as great a need to start postexposure

prophy-laxis immediately, since this risk is lower, especially if the animal responsible for the

exposure can be observed or tested for the presence of rabies

REFERENCES

1 Centers for Disease Control and Prevention (CDC) 2012 Imported human rabies in

U.S Army soldier—New York, 2011 MMWR Morb Mortal Wkly Rep 61:302–305.

2 Chomel BB, Boulouis HJ, Maruyama S, Breitschwerdt EB 2006 Bartonella spp in

pets and effect on human health Emerg Infect Dis 12:389–394.

3 Gautret P, Parola P 2012 Rabies vaccination for international travelers Vaccine 30:126–

133

4 Talan DA, Abrahamian FM, Moran GJ, Citron DM, Tan JO, Goldstein EJ; Emergency

Medicine Human Bite Infection Study Group 2003 Clinical presentation and

bacteri-ologic analysis of infected human bites in patients presenting to emergency departments

Clin Infect Dis 37:1481–1489.

5 Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJ; Emergency

Medicine Animal Bite Infection Study Group 1999 Bacteriologic analysis of infected

dog and cat bites N Engl J Med 340:85–92.

6 Weber DJ, Wolfson JS, Swartz MN, Hooper DC 1984 Pasteurella multocida infections

Report of 34 cases and review of the literature Medicine (Baltimore) 63:133–154.

273

An 18-month-old female presented to the emergency ment with fever, a diffuse rash (onset 5 days before), and a swollen right hand On examination she was irritable but alert

depart-Her temperature was 39°C and her heart rate was increased at

180 beats/min She had diffuse vesiculopustular lesions over her entire body (Fig 38.1), with some areas showing older, crusted lesions She had

cellulitis of the right hand manifested by marked erythema, swelling, and

tender-ness There were no mouth lesions, the lungs were clear, and the liver and spleen

were not enlarged Laboratory data were signifi cant only for leukocytosis with a

white blood cell count of 15,800/μl with 88% neutrophils The chest radiograph

was clear A radiograph of the right hand showed only soft tissue swelling The

patient was treated with intravenous cefazolin Improvement in the condition of

her right hand was notable within 48 hours This patient had a systemic viral

infection with a complication of bacterial superinfection (cellulitis)

1 This patient had a characteristic rash (Fig 38.1) at various stages of evolution What was her underlying viral illness? What other causes of her skin rash should be considered in the differential diagnosis?

2 How is the diagnosis of infection with this pathogen made?

3 Describe the epidemiology of this viral infection and how it has changed since 1995

4 What complications other than bacterial superinfection (as seen in this case) can occur as a result of this viral infection?

5 After acute primary infection with this virus, latent infection develops

What illness may occur years later as a result of viral reactivation? How

do the clinical manifestations of this reactivation infection differ from those of primary infection?

6 What specifi c antiviral therapy has been shown to be effi cacious? Are there any concerns about resis-

tance?

7 What are the infection control issues related to this patient’s illness?

8 Two different vaccines exist against this agent How do they differ in terms of vaccine com-position, target population, and effi cacy?

An 18-month-old female presented to the emergency

depart-swollen right hand On examination she was irritable but alert

Her temperature was 39°C and her heart rate was increased at

180 beats/min She had diffuse vesiculopustular lesions over her

CASE

38

Figure 38.1

274 Skin and Soft Tissue Infections

stages of evolution, including vesicular, pustular, and crusted

The differential diagnosis in this case includes impetigo (group A streptococcal

infec-tion), disseminated enteroviral infection, and disseminated herpes simplex virus infection

in a child with underlying skin disease (e.g., eczema) This child had no history of a

pre-existing dermatologic disorder Other viruses that cause “pox”-like lesions are in the

Poxviridae family and include the orthopoxviruses and molluscum contagiosum virus

Molluscum contagiosum was unlikely in this case; in immunocompetent individuals, it

remains localized and does not cause a sudden-onset systemic infection However, the

orthopoxviruses are important to consider, including monkeypox and smallpox Although

monkeypox is endemic in Central and West Africa and is rarely seen in the United States,

there was an outbreak of monkeypox in the Midwest in 2003 This outbreak affected 72

individuals, all of whom had exposure to prairie dogs that had been housed at the same

facility with imported, monkeypox-infected Gambian rats Because of concerns about

bioterrorism, the specter of smallpox must also be considered Smallpox lesions, unlike

those of chicken pox, are all at the same stage of development, whereas this patient’s

lesions simultaneously included vesicular, pustular, and crusted lesions Smallpox lesions

often occur on the palms and soles of the feet and are most concentrated on the face and

extremities This is in contrast to chicken pox lesions, which are rarely on the palms and

soles and are more concentrated on the torso If the patient had recently been vaccinated

against smallpox, then disseminated vaccinia should also be in the differential Noninfectious

causes of skin rashes that may be confused with varicella include contact dermatitis, drug

reactions, and insect bites

2. In immunocompetent children, the

diagnosis of chicken pox is often made on the

basis of clinical fi ndings alone For adults and

immunocompromised children, laboratory

confi rmation of VZV infection is frequently

sought A method that combines rapidity

with sensitivity is direct fl uorescent-antibody

staining of scrapings taken from vesicular

lesions Culture techniques for detection of

VZV include rapid centrifugation culture

(i.e., shell vial) (Fig 38.2) and standard tissue

culture Shell vial cultures, which take 2 to 4

is a member of the herpesvirus family These are enveloped, double-stranded

CASE

38

Figure 38.2

Case 38 275

days, are both more rapid and more sensitive than standard tissue culture, which may take as long as 3 weeks to recover VZV Nucleic acid amplification tests have also been developed, including quantitative assays A recent study compared the sensitivity of direct fluorescent-antibody assay, shell vial culture, and two PCR assays and demon-strated 87.8, 46.3, and 97.6 and 100% sensitivity, respectively Although highly sensitive and relatively rapid, nucleic acid amplification tests have not been approved by the FDA and therefore have limited availability

3. VZV has a worldwide distribution Disease is more common in temperate regions, with annual epidemics in the late winter and spring in areas with low vaccination rates The virus is spread by the respiratory route and is highly infectious, with ~90% of non-immune household contacts and 10 to 35% of nonimmune classroom contacts becoming infected VZV can also be spread by direct contact with skin lesions and fomites In 1995,

a live attenuated vaccine was approved in the United States for prevention of primary varicella In the prevaccine era, there were ~4 million cases of varicella annually in the United States, which translates to 15 to 16 cases per 1,000 In the first 5 years after intro-duction of the vaccine, the incidence dropped 76 to 87% in the United States

4. In general, varicella causes much more severe illness in adults than in children Immunocompromised children and nonimmune, pregnant women also are more prone to complications with this virus than is the general population The severe illness seen with VZV in these patient populations is due in large part to the significant morbidity and mortality associated with varicella pneumonia Other complications include hepatitis, arthritis, glomerulonephritis, myocarditis, pericarditis, pancreatitis, encephalitis, and cer-ebellar ataxia Multiorgan involvement is associated with high mortality Primary varicella during pregnancy can also cause intrauterine infection leading to fetal loss or an infant born with congenital varicella syndrome, which may include dermatomal scarring, limb hypoplasia, ocular defects, low birth weight, and mental retardation

In addition, secondary bacterial infections of the skin lesions, as was seen in this case (cellulitis of the right hand), can also occur These bacterial infections are most commonly

caused by Streptococcus pyogenes and Staphylococcus aureus VZV infections are associated with S pyogenes-induced necrotizing fasciitis, as VZV skin lesions have been well recog- nized as an important portal of entry for S pyogenes Reye’s syndrome, with encephalopa-

thy, elevated transaminase levels, and elevated serum ammonia levels, can occur in children with varicella or influenza who take aspirin It should be remembered that patients with VZV infection can have a prodrome characterized by fever, malaise, headache, and abdominal pain that is indistinguishable from many other viral illnesses Therefore, infants and children with febrile illnesses should not be given aspirin

5. Herpes zoster (shingles) is a reactivation of a latent VZV infection The dorsal root ganglia are latently infected following primary infections Cell-mediated immunity (CMI),

276 Skin and Soft Tissue Infections

and not VZV antibody, is necessary to maintain latency A loss in CMI, as is seen with

increasing age, is associated with reactivation Other risk factors for reactivation include

CMI dysfunction (transplant, hematologic malignancies, HIV), diabetes, and even recent

physiologic stress

In herpes zoster, skin lesions appear in a single dermatomal distribution innervated by

the specific dorsal root or extramedullary cranial ganglia where VZV had been latent

There are four groups of herpes zoster complications—cutaneous, visceral, neurological,

and ocular Perhaps the most debilitating complication is the persistent pain that can occur

with the rash and persist even after the lesions heal This persistent pain is called

posther-petic neuralgia

Rarely, skin lesions disseminate beyond the primary dermatome involved In

immu-nosuppressed patients, however, complicating viremia can occur, with dissemination to

extradermatomal skin sites, lungs, liver, and the central nervous system This condition,

with extradermatomal sites of infection, is called disseminated herpes zoster Patients with

zoster are also infectious, although apparently not as infectious as patients with varicella

6. Acyclovir is beneficial in treating VZV (both varicella and herpes zoster) In

immu-nocompetent adults ≥50 years of age, treatment with both analgesics and antivirals is

recommended, particularly in patients with ocular involvement In immunocompetent

patients <50 years old, antivirals are not necessary but can shorten the duration of illness

Because of its cost, acyclovir is often not used in uncomplicated cases Thymidine kinase

mutations in VZV conferring resistance to acyclovir have been described, though almost

exclusively in immunocompromised patients In one report, 27% of hematopoietic stem

cell transplant recipients with persistent VZV infection had mutations possibly associated

with resistance Interestingly, in patients with disseminated disease, all infected sites may

not harbor the resistant virus Therefore, it is prudent to test multiple specimen types

when screening for resistance mutations Acyclovir-resistant VZV in immunocompetent

patients appears to be rare, but has been reported

7. Patients with varicella are very contagious Secondary cases are frequently more

severe The increased severity is believed to be due to high viral inoculum Hospitalized

patients with varicella must be placed in respiratory isolation (airborne precautions), and

strict infection control measures regarding skin contact (hand washing, use of gloves and

gowns, etc.) must be implemented (contact precautions) Precautions must remain in place

until lesions are dry and crusted Only individuals who are nonimmune, including health

care personnel, need to wear a mask Ideally, nonimmune health care personnel should not

care for a VZV-infected patient Seronegative health care personnel who do come in

con-tact with these infected patients should not have concon-tact with other patients, especially

immunocompromised ones, for a minimum of 2 weeks after exposure, the incubation

period of this viral infection

Case 38 277

There are also infection control considerations when a nonimmune person has been exposed to VZV Postexposure vaccine should be administered within 120 hours of expo-sure For exposed individuals who cannot receive the live vaccine, a varicella-zoster immune globulin preparation (i.e., VariZIG) should be administered within 96 hours This would apply to immunocompromised individuals, infants, and pregnant women

8. There are two VZV vaccines—one to prevent varicella and one to prevent herpes zoster Both are live, attenuated vaccines made from the same vaccine strain, but the dif-ference is the titer of the virus in each vaccine The herpes zoster vaccine has a much higher titer than that of the varicella vaccine (~14 times higher) A higher titer is needed

to provide an immune booster to prevent herpes zoster reactivation or at least decrease the severity of disease Because these are live virus vaccines, they should not be used in immunocompromised individuals, including those with a hematologic malignancy, con-genital immunodeficiency, or symptomatic HIV infection Persons receiving high-dose immunosuppressive drugs and pregnant women should also not receive these live vac-cines

The varicella vaccine is licensed for use in the United States for all children >12 months of age Current recommendations call for the vaccine to be given in two doses—the first dose at 12 to 15 months of age and the second dose at 4 to 6 years of age Adolescents and adults with no previous evidence of disease should receive two doses of the vaccine 4 to 8 weeks apart The vaccine is very efficacious, vaccine failures are rare, and

it has been shown to be particularly effective at preventing severe VZV disease Postlicensure vaccine safety surveillance using the Vaccine Adverse Event Reporting System of the Centers for Disease Control and Prevention has shown the vaccine to be remarkably safe Both vaccine-associated and natural infections have been noted postvac-cination Serious infections and deaths due to infection caused by the vaccine strain have been observed but are quite rare (1 death/1,000,000 doses of vaccine administered)

The herpes zoster vaccine is licensed for individuals ≥50 years of age and only requires one dose The target population for vaccination is individuals ≥60 years of age due to the higher rate of herpes zoster and its complications in this population The initial clinical trial data (≥60-year-olds) showed that the vaccine reduced the incidence of herpes zoster

by 51% and the incidence of postherpetic neuralgia by 67%

Two questions remain unanswered concerning the effect of these vaccines on the ural progression of disease First, will individuals who receive the varicella vaccine be at risk for herpes zoster due to the vaccine strain later in life? Limited data suggest that they may, but that the rates and severity of herpes zoster are reduced compared with those in individuals who have natural disease Second, will immunity wane in adults who received the varicella vaccine as a child? As natural disease declines, this could result in an at-risk population Since adults are most vulnerable to severe varicella disease, this is a legitimate concern Twenty-year follow-up data suggest that immunity persists, but these studies

nat-278 Skin and Soft Tissue Infections

were done in settings where natural disease continues to be common, offering the

oppor-tunity for immunized individuals to receive a “booster” effect from exposure to infected

individuals

REFERENCES

1 Gershon AA, Gershon MD, Breuer J, Levin MJ, Oaklander AL, Griffiths PD 2010

Advances in the understanding of the pathogenesis and epidemiology of herpes zoster

J Clin Virol 48:S2–S7.

2 van der Beek MT, Vermont CL, Bredius RG, Marijt EW, van der Blij-de Brouwer

CS, Kroes AC, Claas EC, Vossen AC 2013 Persistence and antiviral resistance of

vari-cella zoster virus in hematological patients Clin Infect Dis 56:335–343.

3 Wilson DA, Yen-Lieberman B, Schindler S, Asamoto K, Schold JD, Procop GW

2012 Should varicella-zoster virus culture be eliminated? A comparison of direct

immuno-fluorescence antigen detection, culture, and PCR, with a historical review J Clin Microbiol

50:4120–4122.

4 Wise RP, Salive ME, Braun MM, Mootrey GT, Seward JF, Rider LG, Krause PR

2000 Postlicensure safety surveillance for varicella vaccine JAMA 284:1271–1279.

279

A 44-year-old female was transferred to the hospital by air ambulance after suffering a respiratory arrest in her doctor’s offi ce She arrived intubated after being resuscitated Her past medical history was signifi cant for her having suffered a dislo-cated left thumb 3 days previously at work while assisting a patient into a wheelchair When she got home from work, a family member reduced the

dislocation Over the next 2 days she had gradually increasing ascending pain and

swelling in her left arm She visited her local emergency department on each of

those 2 days Both times she was given analgesics and sent home On her third day

of illness, she was visiting her primary care physician, where she had a

cardiopul-monary arrest

On physical examination she had a temperature of 39.1°C, heart rate of 197 beats/min, and blood pressure of 95/45 mm Hg Her white blood cell count was

4,700/μl, her hemoglobin was 11.7 g/dl, and she had a creatinine of 1.9 mg/dl, a

blood urea nitrogen of 32 mg/dl, and a creatine kinase of 3,307 units/liter

Physical examination of her left arm was consistent with a nonperfused extremity

including a cold, cyanotic hand, blisters with skin necrosis between the wrist and

elbow, and arm warm to the touch at the elbow and above

She was begun on clindamycin and penicillin G and taken to the operating room, where an incision was made over her left humerus, which revealed necrotic

tissue and dishwater fl uid between tissue planes at the fascial level Her arm was

amputated at the shoulder She had additional chest wall debridement down to the

pectoralis major Tissue Gram stain showed 4+ Gram-positive cocci in pairs and

short chains (Fig 39.1) Postoperatively the patient became increasingly

hemody-namically unstable, had a cardiac arrest, and could not be resuscitated It was

subsequently learned that the individual with whom the patient was working

when she suffered the thumb dislocation had been admitted with septic shock to

another hospital The organism recovered from the patient is shown in Fig 39.2

1 What organism caused this patient’s infection?

2 What syndrome did this patient have? How does it explain the physical

fi nding of a cold, cyanotic extremity on admission? What virulence tors does this organism produce that played a role in her clinical disease course? What is the typical outcome of this infection? What might have been done to make her case less severe?

fac-3 How did this patient become infected? How can this be proven?

4 Two other individuals in the community had a similar illness to the case patient in the same week There was no direct epidemiologic link among the three How do you explain this observation?

A 44-year-old female was transferred to the hospital by air

offi ce She arrived intubated after being resuscitated Her past medical history was signifi cant for her having suffered a dislo-cated left thumb 3 days previously at work while assisting a patient CASE

39

280 Skin and Soft Tissue Infections

5 What is the key risk factor for this syndrome in children? Why is this risk factor unusual in adults? What is being done to try to eliminate this risk factor in children?

6 Why was clindamycin part of the therapy for this patient? What tibility test would you need to do to ensure that the clindamycin might

suscep-be active in this patient?

Figure 39.2 Isolate recovered from patient

Figure 39.1 Direct Gram stain from tissue

necro-of fl uid resuscitation), and evidence necro-of failure in two or more organ systems (this patient had evidence of renal, cardiac, and pulmonary failure based on laboratory fi ndings) STSS

is caused by the physiological response to the production of superantigens by GAS Streptococcal pyogenic exotoxin A (SpeA) is the superantigen most commonly associated with STSS This molecule binds nonspecifi cally to antigen-presenting cells and T lym-phocytes, causing the T lymphocytes to produce massive amounts of proinfl ammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-2, and gamma interferon These high levels of cytokines activate the complement, coagulation, and fi bri-nolysis cascades, which are responsible for the abnormal physiological response that is characteristic of STSS

In necrotizing fasciitis, highly virulent strains of GAS (see answer 4 for greater details) attach to the skin and penetrate through the dermis to the underlying soft tissue and mus-

cle The particular isolate infecting this patient was emm type 1 or M1 M1 organisms are more likely to cause invasive disease than most other emm types, with the possible excep- tion of M3 M1 strains that are invasive have mutations in covRS, an operon that controls

~10% of the GAS genome, including a large number of virulence factor genes When these mutations occur, there is downregulation in SpeB SpeB is a cysteine protease that regulates the activity of several GAS virulence factors by degrading them In addition, there is upregulation of a variety of virulence factors that allow it to evade the innate immune system locally as well as producing a variety of factors that either directly or indirectly destroy tissue M protein, hyaluronic acid capsule, and extracellular streptodor-nase appear to be the key virulence factors in the organism’s ability to evade phagocytosis

In Fig 39.2, the colony of the organism recovered from this patient is highly mucoid as a result of high levels of hyaluronic acid production This phenotype is a hallmark of GAS strains associated with invasive disease

The manner in which streptodornase contributes to immune evasion has recently been delineated Neutrophils secrete a substance known as NETs (neutrophil extracellular nets), which contain a complex of DNA, histones, proteases, and antimicrobial peptides These NETs “trap” bacteria and are involved in neutrophil extracellular killing Streptodornase is a DNase that degrades DNA, thus destroying the NET

GAS also produces proteases, including C5a peptidase, that either directly or rectly degrade complement components or cytokines This reduces the migration of phagocytes to the site of infection

indi-CASE

39

282 Skin and Soft Tissue Infections

GAS produces a variety of histotoxic molecules that allow the organism to spread

along fascial tissue planes, causing massive tissue destruction These include streptolysin

S and O, pore-forming cytolysins that can lyse a wide variety of tissue types Once cells

are killed, the organism produces several different DNases and plasmin, a host-derived

protease that can further degrade these tissues The organism also produces at least two

virulence factors that facilitate its spread through tissue Hyaluronidase degrades

hyal-uronic acid found in ground substance, which acts as the “cement” in connective tissue,

and streptokinase, which dissolves fibrin clots In addition, streptokinase has high affinity

for human plasminogen, degrading it to plasmin

The patient’s cold, cyanotic arm was characteristic of the massive tissue destruction,

including thrombosis of the vascular bed, incurred during necrotizing fasciitis, resulting

in nonviable tissue STSS coupled with necrotizing fasciitis has a mortality ranging in

some studies to as high as 60%, so the outcome in this case was, sadly, not unexpected

One of the difficulties in diagnosing necrotizing fasciitis is that the pathology occurs

in subcutaneous tissue As a result, in the absence of an obvious injury, the skin may appear

normal in as many as 50% of patients in the early stages of this illness The clues in this

case were her progressive arm swelling and continued arm pain, both of which were severe

enough to warrant two trips to her local emergency department Necrotizing fasciitis,

because of its ability to spread rapidly along fascial planes, is a true surgical emergency If

surgical debridement and antimicrobial therapy are not implemented in the first 12 to 24

hours of symptomatic disease, the likelihood of a fatal outcome greatly increases By the

time she presented to her personal physician on the third day of illness, her disease had

progressed beyond the point where she could survive Perhaps the reason this disease has

such a high mortality is that, as with this patient, it may not be recognized or considered

until infection with this highly virulent organism has progressed beyond the point where

the patient can be saved

3. After the death of this patient (patient A), it was learned that she had dislocated her

thumb while helping an individual (patient B) into a wheelchair It was subsequently

learned that patient B had impetigo-like lesions on her face at the time of patient A’s injury

and that patient B was admitted to a second hospital with septic shock the day after patient

A died GAS was isolated from the blood of patient B The two organisms were serotyped,

and both patients were infected with the M1 serotype M1 is the either the first- or second-

most-common serotype associated with invasive GAS and necrotizing fasciitis Although

this strain was serotyped, the current standard method for typing GAS is to do sequence

analysis of the amino-terminal region of the M protein Using this approach, >150

geno-types of GAS have been recognized Pulsed-field gel electrophoresis confirmed these two

isolates to be the same genotype The conclusion was that patient A was infected by

patient B, most likely at the time patient A dislocated her thumb helping patient B into a

wheelchair

Invasive GAS infections in health care workers obtained from infected patients have

been described Fortunately, these events are rare

Case 39 283

4. It is well recognized that community and regional outbreaks of invasive GAS disease primarily due to M types 1, 3, 12, and 28 occur M typing of the isolates from these other two individuals revealed that one of the patients had M1 strain of the same pulsotype as the case patient while the other patient was infected with a different M type During out-breaks of invasive disease, the level of GAS disease activity in the community or region increases but the great majority of patients have localized infections, typically pharyngitis and skin infections It is believed that people who develop invasive GAS disease and espe-cially those who develop STSS do not have antibodies to the specific M type that is circu-lating in the community nor do they have antibodies against SpeA, putting them at risk for this most severe manifestation of GAS disease It may also be true that the individuals

who become infected are unfortunate to have isolates with mutations in the covRS regulon

that result in the upregulation of GAS virulence factors, while the vast majority of viduals who have localized skin and throat infections are not infected with these mutants

indi-5. Approximately 30% of children who develop necrotizing fasciitis have had a recent case of chicken pox (varicella-zoster virus), usually within the past 1 to 3 weeks Children either with chicken pox or recovering from it have a 6-fold-increased risk of necrotizing fasciitis Chicken pox lesions are “itchy,” and children can inoculate GAS on their skin into their lesion by scratching these itchy lesions; in a small percentage of children, GAS nec-rotizing fasciitis can result Unlike in adults, GAS necrotizing fasciitis in children has a low mortality: <10% Most adults had chicken pox as children, so they are no longer prone to having this risk factor We have seen one case of fatal necrotizing fasciitis secondary to chicken pox in an adult The deceased was infected by his young child, who developed chicken pox during an outbreak in his day care center

Beginning in 1995, a live, attenuated varicella-zoster vaccine has been used in children

in the United States This vaccine has proven to have an efficacy of 85% and has the likely added benefit of reducing the number of cases of necrotizing fasciitis secondary to chicken pox, although there are no organized studies to demonstrate this point

6. The combination of penicillin and clindamycin is recommended for treatment of GAS necrotizing fasciitis Clindamycin is included in the therapeutic regimen because in animal models it has been shown to reduce GAS toxin production, especially SpeA Unlike penicillin, it is not prone to an inoculum effect nor does it lose activity against stationary- phase organisms Both are problems with penicillin therapy The number of organisms found in the tissue may be too large for penicillin to kill efficiently In addition, because

of the rapid growth of GAS in tissue, many of the organisms may be at “stationary” phase,

or no longer growing Penicillin only kills actively growing organisms Oddly, there are no good clinical studies that demonstrate the efficacy of clindamycin in the treatment of STSS Given the severity of this disease, its relative rarity, and positive animal model data,

it is unlikely that such trials to demonstrate efficacy will be forthcoming

Detection of clindamycin resistance in Gram-positive cocci including GAS is not

284 Skin and Soft Tissue Infections

form of clindamycin resistance due to the

pres-ence of an erm (erythromycin ribosomal

meth-ylase) gene By standard susceptibility tests,

erm-containing GAS isolates appear

suscepti-ble However, when the inducer, erythromycin,

is placed 12 mm from the clindamycin disk, the

zone of inhibition will flatten on the side of the

disk adjacent to the erythromycin disk This

zone looks like the letter “D” (Fig 39.3); thus

the term “D test.” Isolates that have inducible

resistance may undergo mutation to a

constitu-tive form of the enzyme during clindamycin

therapy, resulting in the organism becoming clindamycin resistant Given the severity of

STSS, it is of value to know if the organism has inducible clindamycin resistance Recent

studies suggest that this resistance mechanism is unusual, being found in 2% of GAS

isolates

REFERENCES

1 Cole JN, Barnett TC, Nizet V, Walker MJ 2011 Molecular insight into invasive group

A streptococcal disease Nat Rev Microbiol 9:724–736.

2 Lynskey NN, Lawrenson RA, Sriskandan S 2011 New understandings in Streptococcus

pyogenes Curr Opin Infect Dis 24:196–202.

3 Minodier P, Bidet P, Rallu F, Tapiero B, Bingen E, Ovetchkine P 2009 Clinical and

microbiologic characteristics of group A streptococcal necrotizing fasciitis in children

Pediatr Infect Dis J 28:541–543.

4 Olsen RJ, Musser JM 2010 Molecular pathogenesis of necrotizing fasciitis Annu Rev

Pathol 5:1–31.

Figure 39.3 D test with erythromycin (E) and mycin (CC)

285

The patient was a 50-year-old male who 7 months ago oped acute swelling, erythema, and synovitis of his right hand

devel-He visited his personal physician, who obtained a radiograph

of the hand, which was negative He was started on prednisone, but his symptoms persisted Three months into his disease course he went to see a rheumatologist, who diagnosed him with seronegative

rheumatoid arthritis and added methotrexate The condition of his hand

wors-ened over the next 3 months Over the 3 weeks prior to being seen at our

insti-tution, he developed ulcerative lesions on his hand draining bloody serous fl uid

He stated that the hand had become much more erythematous On physical

examination he had large, weeping ulcerative lesions across the joints on all four

fi ngers on his right hand The skin over the joints was very red and mildly

ten-der The dorsum of the right hand was swollen, and there was lymphadenopathy

tracking up his arm, but he did not have axillary lymphadenopathy The left

hand was normal and he had no other symptoms His vital signs were normal

His erythrocyte sedimentation rate was 80 mm/hour A biopsy was performed,

which revealed granulomas An acid-fast stain of the tissue is seen in Fig 40.1

Approximately 3 weeks later the organism seen in Fig 40.2 was growing on a

Lowenstein-Jensen slant incubated at 30°C When it was determined that the

patient had granulomas in his hands, further history was elicited for him His

physicians learned that he had gone fi shing on the Chesapeake Bay 3 weeks

prior to his initial presentation

1 What is seronegative rheumatoid arthritis? Did this patient meet the American College of Rheumatology criteria for rheumatoid arthritis?

Besides rheumatoid arthritis, what other possible explanation might account for his symptoms?

2 Why was methotrexate added to his therapeutic regimen? Why do you think that his condition worsened, and why did it take him so long to seek further medical care?

3 Figure 40.1 indicates the group

of organisms with which this patient was infected In what genus is the organism infecting this patient most likely to be?

Figure 40.2 shows the organisms before and after exposure to light What difference do you see? To what group of organisms does this organism belong?

The patient was a 50-year-old male who 7 months ago

devel-He visited his personal physician, who obtained a radiograph

of the hand, which was negative He was started on prednisone, but his symptoms persisted Three months into his disease

CASE

40

Figure 40.1 Kinyoun stain of biopsy of right hand (×1,000 magnifi cation)

286 Skin and Soft Tissue Infections

4 With what organism was he most likely infected? Why do you think the diagnosis was initially missed? How was eliciting further history helpful?

5 Most cultures done for organisms belonging to the genus infecting this patient are cultured at 35 to 37°C However, when culturing for this genus, skin, soft tissue, and joint infection cultures are typically done at 30°C Why?

6 Skin testing for one of the organisms in the genus infecting this patient

is widely done What is the skin test used, and for what organism in this genus is this skin testing done? What would be the likely result of skin testing in this patient? How might this affect management of this patient?

Figure 40.2 Organism prior to (left) and after (right) light exposure

Case 40 287

CASE DISCUSSION

1. Approximately 10 to 20% of patients with rheumatoid arthritis are

seronegative, meaning they do not have rheumatoid factor, i.e.,

autoanti-bodies directed against the Fc portion of immunoglobulin G Rheumatoid

arthritis is an autoimmune disease that causes joint pain and in its most severe tions causes deformity and destruction of the joints, resulting in loss of function By the time the patient saw the rheumatologist, he did meet the American College of Rheumatology’s defi nition of rheumatoid arthritis because he had more than 10 small joints involved (all three small joints on the four fi ngers of his right hand) and had expe-rienced symptoms for more than 6 weeks (see http://www.rheumatology.org/practice/clinical/classifi cation/ra/ra_2010.asp) He did not have an erythrocyte sedimentation rate recorded at the time of his initial visit, and records from his rheumatology visit were not available

manifesta-Other possible explanations for his swollen joints include Lyme disease, for which he did not have an appropriate history; other chronic bacterial or fungal joint infections; rheumatic fever; and a wide variety of autoimmune and infl ammatory diseases

2. Anti-infl ammatory therapies are a standard therapeutic approach for rheumatoid arthritis Methotrexate is recommended as initial therapy for rheumatoid arthritis Methotrexate is a folate antagonist that reduces purine and pyrimidine synthesis and thus cell proliferation, including that of T lymphocytes, which are believed to play a central role

in the infl ammatory process in this disease One of the side effects of any anti-infl ammatory agent is that it can increase the likelihood of infection by reducing the immune-mediated clearance of organisms In this case, the prednisone/methotrexate combination masked the infl ammation that was present as a result of his infection The relatively slow progres-sion that was seen was likely due to the slow growth rate of the organism infecting the patient (see answer 3 for details)

3. The biopsy from this patient’s hand showed an acid-fast bacillus The major group of

organisms that are acid fast is the genus Mycobacterium Nocardia is another higher-order

bacterium that could cause the disease course observed in this patient However, it is tially acid fast, so it would not appear like the organism in Fig 40.1 The difference between an acid-fast and a partially acid-fast organism is that the decolorizing agent in an acid-fast stain contains both alcohol and dilute acid, while the decolorizing agent in a partially acid-fast stain contains only dilute acid Mycobacteria are not decolorized by a

par-solution containing alcohol and acid, while Nocardia species are It should be noted that

both organisms have a beaded, Gram-positive appearance on Gram stain Other isms that cause slowly progressive, indolent skin, soft tissue, joint, and bone infections on

organ-the hand include fungal agents such as Sporothrix schenckii, Histoplasma capsulatum, Blastomyces dermatitidis, and a wide range of environmental dematiaceous fungi Ulcerative

bodies directed against the Fc portion of immunoglobulin G Rheumatoid

CASE

40

288 Skin and Soft Tissue Infections

lesions can be seen with other environmental mycobacteria, the fungi listed above, and

Leishmania However, the patient did not have an appropriate travel history for the

tropi-cal disease leishmaniasis, so it was not considered further

Figure 40.2 shows the organisms growing prior to and after exposure to light

Organisms that produce pigment independent of exposure to light are called

scotochro-mogens Organisms that make pigment only when they are exposed to light, as seen in Fig

40.2, are called photochromogens The pathogenic photochromogenic mycobacteria that

are mostly likely to be encountered clinically are Mycobacterium marinum and Mycobacterium

kansasii.

4. Given that the acid-fast bacillus in this case was a photochromogen, and considering

the location of the infection and the slow rate of disease progression, the organism causing

this infection is most likely M marinum When a photochromogen grew from the patient,

we thought immediately that it was M marinum because this organism most commonly

causes skin, soft tissue, and joint infections on the extremities, with the vast majority on

the hands Sequencing of the 16S rRNA gene confirmed that the organism was M

mari-num It is a common environmental organism that is found in fresh-, brackish, or salt

water M marinum is almost always associated with trauma involving water It may take as

long as 6 weeks to grow from a clinical specimen, although most isolates will be recovered

by 2 to 3 weeks Interestingly, direct acid-fast bacillus stains for clinical specimens are only

positive in ~10% of M marinum infections, so the finding in this case was unusual but may

reflect how long the infection had to progress

The most common form of M marinum infection is called “fish tank granuloma,”

which occurs in people who have breaks in their skin while cleaning fish tanks

contami-nated with this organism However, other sources of infection are well known M

mari-num is a hazard for commercial and recreational fishermen and -women, with trauma

caused by fish fins or teeth or the shells of shellfish

When this patient was originally seen by his personal physician, he had a negative

radiograph and did not have any obvious trauma to the hand, could not remember any

episodes of trauma, and did not own a fish tank or remember any contact with water

beyond everyday bathing As a result, his personal physician had no reason to suspect an

infection, especially one due to an environmental Mycobacterium sp However, once the

identity of the organism was determined, the patient was requestioned and specifically

asked about possible water exposures He remembered that he had gone on a fishing trip

to the Chesapeake Bay 3 weeks prior to developing symptoms, although he did not

remember any traumatic event during the trip

That it took more than 7 months to establish the diagnosis of this infection was not

surprising Several studies suggest that it takes as long as 12 months to diagnose M

mari-num infection This is likely due to the organism’s indolent nature and slow growth rate

and to physicians’ inability to diagnose this infection because of a lack of experience with

infections caused by this organism

species to which humans are exposed Many of these organisms, which include M num, grow better at 30°C In fact, M marinum grows poorly, if at all, at 35 to 37°C

mari-Since environmental mycobacteria are much more likely to cause skin, soft tissue, and joint infections, it is recommended that these specimens be cultured at both 30°C and

35 to 37°C

6. A common strategy for screening patients to detect infection with M tuberculosis is

to do a skin test in which 5 tuberculin units are injected intradermally into the volar

surface of the forearm If the patient is infected with M tuberculosis (tuberculosis [TB]),

an area of induration will appear after 48 to 72 hours This induration is due to a delayed-type hypersensitivity reaction to purified protein derivative present in the skin test material Induration of 5, 10, or 15 mm is considered positive depending on the patient population tested, with 5 mm being used as a cutoff for immunocompromised patients, 10 mm for high-risk individuals such as those with documented exposures, and

15 mm for individuals with a low index of suspicion It should be remembered that 90%

of patients who are infected with M tuberculosis are latently infected and will not have

clinical symptoms

Of patients with M marinum infections, more than half will have a false-positive TB

skin test If these patients are tested, it may result in further testing such as a chest

radio-graph or even the initiation of M tuberculosis therapy M tuberculosis therapy in patients with M marinum infections is problematic because the mainstay of M tuberculosis therapy

is isoniazid, an agent with known liver toxicity and no activity against M marinum Given

the high rate of false-positive TB skin tests in this clinical setting and the low pretest

probability of this being M tuberculosis, TB skin testing really has no role in the

manage-ment of this patient

REFERENCES

1 Aubry A, Chosidow O, Caumes E, Robert J, Cambau E 2002 Sixty-three cases of

Mycobacterium marinum infection: clinical features, treatment, and antibiotic susceptibility

of causative isolates Arch Intern Med 162:1746–1752.

2 Chan ES, Cronstein BN 2010 Methotrexate—how does it really work? Nat Rev Rheumatol 6:175–178.

3 Lewis FM, Marsh BJ, von Reyn CF 2003 Fish tank exposure and cutaneous infections

due to Mycobacterium marinum: tuberculin skin testing, treatment, and prevention Clin

Infect Dis 37:390–397.

290 Skin and Soft Tissue Infections

4 Pandian TK, Deziel PJ, Otley CC, Eid AJ, Razonable RR 2008 Mycobacterium

mari-num infections in transplant recipients: case report and review of the literature Transpl

riding lessons.

1 With what organism was she infected? What disease did she have?

2 What in her history is suggestive of this disease? How is this disease transmitted?

3 How, in the absence of a characteristic rash, is the diagnosis of this ease established?

dis-4 She was appropriately treated with antibiotics and did well What plications can occur in patients with this disease, particularly those in whom there is no treatment or inadequate therapy?

com-5 What efforts can be taken to prevent this illness?

This 12-year-old girl was in her normal state of good health

no localizing symptoms except for the development of a large rash on her back (Fig 41.1) Her history was notable in that she lived in Connecticut near the New York State border and had

CASE

41

Figure 41.1

292 Skin and Soft Tissue Infections

CASE DISCUSSION

1. This patient was infected with the spirochete Borrelia burgdorferi,

which is the etiologic agent of Lyme disease Her symptom of a nonspecifi c fever is consistent with Lyme disease, but it is the presence of the character-istic erythematous annular rash, referred to as erythema migrans, demonstrated in Fig

41.1, that is diagnostic The rash typically has a target-like appearance with expanding

borders Some patients will have these lesions at multiple sites This patient had one

rather prominent lesion

2. The patient lives in Connecticut, a state with a very high incidence of Lyme disease

In fact, the disease was initially described in (and named for) Old Lyme, a town in

Connecticut Other regions in which Lyme disease is endemic include other areas in the

northeastern United States, Minnesota, Wisconsin, northern California, and much of

Europe, particularly between 35° north latitude and 60° north latitude

B burgdorferi is spread to humans by ticks of the genus Ixodes In the northeastern

United States, the white-footed mouse appears to be the primary reservoir of B

burgdor-feri, which is present in the mouse’s bloodstream This mouse is also the preferred host for

the Ixodes scapularis tick, formerly known as Ixodes dammini, the major vector of this

spiro-chete In other geographic locales, other Ixodes species act as major vectors.

Given that the patient was walking through tall grass, the sort of environment where

ticks are likely to be found, she may well have had an ixodid tick attach to her during this

time The tick is frequently found in woody areas, but also can be found in grassy areas

All three stages in the life cycle of the tick, i.e., larva, nymph, and adult, can feed on a

human host, but only the nymph and adult stages can transmit the disease Nymphs and

adults that were infected after feeding on a B burgdorferi-infected mouse (or other small

mammal) pass the organism to humans during the blood meal, probably by regurgitating

the spirochetes into the wound Transfer of the spirochetes from the infected I scapularis

ticks to humans appears to require 36 to 48 hours of attachment The events that occur in

the tick during the attachment are complex, with the spirochetes migrating from the gut

to the salivary glands Additionally, the organism has to express a protein called outer

surface protein C that enhances infectivity of the spirochete for the human host It is

believed that this migration and phenotypic change explain the need for prolonged

attachment prior to transmission Ticks removed before the 36 to 48 hours probably do

not transmit the spirochete However, the nymph stage of the tick is extremely small

(described as the size of a pencil point), so the tick bite may go unnoticed Less than half

of patients with documented Lyme disease are able to recall a tick bite

3. The case defi nition of Lyme disease that is used for surveillance purposes is the

pres-ence of an erythema migrans rash ≥5 cm in diameter or laboratory confi rmation of

infec-tion with objective evidence of musculoskeletal, neurologic, or cardiovascular manifestainfec-tions

fever is consistent with Lyme disease, but it is the presence of the

character-CASE

41

Case 41 293

of Lyme disease Unfortunately, the organism itself is difficult to grow from clinical imens and requires complex media that are not available in most clinical laboratories, making culture a low-yield procedure that is used almost exclusively in research settings Because of this, isolation of this organism from clinical specimens is not routinely attempted Although PCR is used in some settings, such as in cases of arthritis and central nervous system disease, its low sensitivity limits its usefulness The current laboratory recommendation is a two-test approach for the serologic diagnosis of Lyme disease The serum specimen should first be tested using either an enzyme immunoassay or an indirect immunofluorescent assay Positive or equivocal specimens should then be tested with the more specific immunoglobulin G and immunoglobulin M Western blot (immunoblot) The sensitivity and specificity of the serologic tests vary in relation to the time in the course of the illness during which the specimen was obtained, with the tests being more accurate later in the disease course The performance of different laboratories in Lyme serology testing varies greatly, with both false-positive and false-negative results occurring with increased frequency in certain laboratories

spec-4. Approximately 90% of patients with B burgderfori present as this patient did with fever

and skin rash and respond to antimicrobial therapy with no sequelae Involvement of joints with clinical arthritis is seen in ~5% of patients A smaller subset (<5%) may present with a clinical picture of headache and have cerebrospinal fluid (CSF) with a lymphocytic pleocy-tosis Other neurologic symptoms and signs, such as cranial nerve VII palsy, peripheral neuropathy, meningoencephalitis, and subacute encephalopathy, may occur Cardiac involvement with conduction defects and consequent arrhythmias also occurs in ~1% of

patients Coinfection with another tick-borne pathogen, Babesia microti, the major etiologic

agent of babesiosis, has been reported to occur in patients with Lyme disease

One of the most difficult challenges in infectious diseases is the management of patients who present with an entity that has been characterized as “chronic Lyme disease.” Late Lyme neuroborreliosis, a rare complication of this illness, is characterized by increased CSF protein, CSF lymphocyte count, and the production of intrathecal anti-body These patients typically have changes on magnetic resonance imaging and periph-eral neuropathy Antimicrobial therapy may prove helpful in this group

However, many more patients present with chronic Lyme disease without objective evidence of disease Often, these patients have serologic evidence of prior infection and attribute nonspecific symptoms such as fatigue, headache, sleep disturbances, poor con-centration, depression, irritability, and dizziness to chronic infection Alternatively, they may have a specific diagnosis such as multiple sclerosis that they believe is in error A final group is patients with a prior history of erythema migrans who continue to have nonspe-cific symptoms 1 year or more after the initial infection Placebo-controlled studies of antimicrobials have demonstrated that antimicrobial therapy offered little or no benefit over placebo in this group of patients Careful placebo-controlled trials have not been performed in the first two groups of patients

294 Skin and Soft Tissue Infections

Finally, recurrence of Lyme disease may occur when patients are infected with a

B burgdorferi strain that differs from that causing the patient’s initial infection.

5. Prevention of Lyme disease is similar to the prevention of other tick-borne diseases

In areas of endemicity, the use of appropriate clothing, including long pants, long-sleeved

shirts, and closed-toe shoes, is important when exposure to ticks may occur The use of

tick repellents, including the chemical N,N-diethyl-m-toluamide (DEET) on skin and

clothing and permethrin on clothing, is an additional precaution Finally, examination of

the skin after walking in an environment in which tick exposure is a possibility allows for

the removal of ticks before they are able to transmit B burgdorferi.

REFERENCES

1 Feder HM Jr, Johnson BJ, O’Connell S, Shapiro ED, Steere AC, Wormser GP; Ad

Hoc International Lyme Disease Group, Agger WA, Artsob H, Auwaerter P, Dumler

JS, Bakken JS, Bockenstedt LK, Green J, Dattwyler RJ, Munoz J, Nadelman RB,

Schwartz I, Draper T, McSweegan E, Halperin JJ, Klempner MS, Krause PJ, Mead P,

Morshed M, Porwancher R, Radolf JD, Smith RP Jr, Sood S, Weinstein A, Wong SJ,

Zemel L 2007 A critical appraisal of “chronic Lyme disease.” N Engl J Med

357:1422–1430.

2 Halperin JJ, Baker P, Wormser GP 2013 Common misconceptions about Lyme disease

Am J Med 126:264.e1-7 doi:10.1016/j.amjmed.2012.10.008.

3 Nadelman RB, Hanincová K, Mukherjee P, Liveris D, Nowakowski J, McKenna D,

Brisson D, Cooper D, Bittker S, Madison G, Holmgren D, Schwartz I, Wormser GP

2012 Differentiation of reinfection from relapse in recurrent Lyme disease N Engl J Med

367:1883–1890.

4 Rizzoli A, Hauffe HC, Carpi G, Vourc’h GI, Neteler M, Rosà R 2011 Lyme

borreli-osis in Europe Euro Surveill 16:pii=19906 http://www.eurosurveillance.org/ViewArticle.

aspx?ArticleId=19906

5 Stanek G, Wormser GP, Gray J, Strle F 2012 Lyme borreliosis Lancet 379:461–473.