Infectious Diseases Flashcards
1
Q
To what family and genus do the rabies viruses belong?
A
Rabies appears to be caused by a number of different species of neurotropic viruses in the Rhabdoviridae Family, genus Lyssavirus.
2
Q
Which tissue does rabies have a predilection for? How does it cause disease in this tissue?
A
Lyssaviruses have a predilection for neural tissue and spread via peripheral nerves to the central nervous system (CNS). The mechanism by which rabies causes severe CNS disease is unclear. Lyssaviruses may produce neuronal dysfunction, such as autonomic instability, rather than neuronal death. Oxidative stress caused by dysfunction of mitochondria in neurons and other cells of the CNS may also be a pathway leading to the abnormalities observed.
3
Q
How does the rabies virus get to its target system in the body?
A
Viruses amplify near the site of inoculation in muscle cells and subsequently enter local motor and sensory nerves. Viruses then migrate centrally in a retrograde direction within the axoplasm of peripheral nerves at approximately 50 to 100 mm per day until reaching the dorsal root ganglia of the spinal cord. Rabies viruses then ascend rapidly up the spinal cord to the brain, initially infecting the diencephalon, hippocampus, and brainstem.
4
Q
Where does productive viral replication and shedding take place?
A
In highly innervated areas, such as the salivary glands.
5
Q
What is a pathognomonic histological finding in rabies infection?
A
Dense, ovoid, intracytoplasmic inclusions, (ie, Negri bodies).
6
Q
Which factors determine the host’s susceptibility to infection with rabies?
A
Factors that may increase host susceptibility to infection include:
- A bite with prominent salivary contamination
- The virus variant
- The size of the viral inoculum
- The degree of innervation at the site of the bite
- Host immunity and genetics
7
Q
What is the geographical distribution of rabies?
A
Worldwide with some exceptions, including Antarctica, New Zealand, Japan, Sweden, Norway, Spain and some Caribbean Islands.
8
Q
What is the incidence of rabies?
A
Around 30 000 - 70 000 worldwide.
9
Q
How is rabies transmitted?
A
Most rabies is acquired through exposure to saliva from an animal bite. In rare cases, rabies results from a non-bite exposure (eg, aerosolized virus in bat caves or in laboratories handling the virus), or transplantation of tissue or organs from a donor with unrecognized rabies.
10
Q
Which animal reservoirs account for the most rabies infections?
A
In developing countries, rabid dogs account for 90 percent or more of reported cases of rabies transmitted to humans. Rabies surveillance in the United States has identified the four major animal reservoirs as bats, raccoons, skunks, and foxes.
11
Q
What is the typical incubation period for rabies?
A
The average incubation period of rabies is one to three months, but can range from several days to many years after an exposure.
12
Q
Under which conditions can the incubation period be different?
A
The incubation period is shorter in patients with an exposure that occurs in richly innervated areas (eg, the face versus the extremities). Longer incubation periods may also be related to inadequate rabies prophylaxis, or an unknown new exposure.
13
Q
How can the clinical manifestations of rabies be classified?
A
Prodromal phase and then clinical rabies.
14
Q
What are the three main groups of manifestations of clinical rabies?
A
Encephalitic (furious) rabies (80%), paralytic (dumb) rabies (20%) and atypical rabies.
15
Q
What are the features of the rabies prodrome?
A
Rabies is usually unsuspected during the prodromal phase, which starts with non-specific symptoms, such as low-grade fever, chills, malaise, myalgias, weakness, fatigue, anorexia, sore throat, nausea, vomiting, headache, and occasionally photophobia.
Paresthesias radiating proximally from the site of a known wound would be suggestive of rabies infection. The patient may describe a variety of symptoms including pain, tenderness, tingling, itching, burning, abnormal localized temperature sensation, or numbness at the site. In addition, percussion myoedema (mounding of the muscle at the percussion site) may be present during the prodrome and throughout the illness.
16
Q
How long does the rabies prodrome last?
A
This stage lasts from a few days to approximately one week.
17
Q
Outline the classic features of encephalitic rabies.
A
The classic presentation of encephalitic rabies includes fever, hydrophobia, pharyngeal spasms, and hyperactivity subsiding to paralysis, coma and death.
18
Q
Describe the features of encephalitic rabies.
A
●Hydrophobia is the most characteristic clinical feature of rabies, occurring in 33 to 50 percent of patients. After some preliminary feeling of discomfort in the throat or dysphagia, the patient suddenly develops an overwhelming terror of water based on involuntary pharyngeal muscle spasms during attempts to drink. Later in the disease, even the sight or mention of water may trigger these involuntary spasms.
●Aerophobia is also pathognomonic of rabies although it occurs less often than hydrophobia (approximately 9 percent in one series). Pharyngeal spasms are triggered upon feeling a draft of air and can last approximately 5 to 15 seconds. Painful inspiratory spasms of the diaphragm and accessory inspiratory muscles can lead to aspiration, coughing, choking, vomiting and hiccups; when severe, these spasms can lead to asphyxiation and respiratory arrest.
●The facial muscles may contract leading to a grimace and the neck and back can become hyperextended with muscle spasticity (referred to as opisthotonos).
●Autonomic instability is observed in approximately 25 percent of patients.
●Patients may exhibit dysarthria, dysphagia or may complain of diplopia or vertigo. Dysphagia was reported in approximately half of all cases in one retrospective series.
●Agitation and combativeness are also commonly seen (approximately 50 percent of patients), along with auditory and visual hallucinations.
19
Q
What additional features of clinical rabies may be found on examination?
A
The physical examination is notable for mental status changes, increased muscular tone and tendon reflexes with extensor plantar responses and fasciculations. Nuchal rigidity may be present. Once the patient develops coma, flaccid paralysis with generalized areflexia is usually noted.
20
Q
Describe the clinical features of paralytic rabies.
A
Fewer than 20 percent of rabies patients present with an ascending paralysis, which can mimic Guillain-Barré syndrome. These patients have little evidence of cerebral involvement until late in their course of disease.
After the prodromal symptoms described above, the patient develops a flaccid paralysis. Paralysis is usually most prominent in the bitten limb, and then spreads symmetrically or asymmetrically. The physical examination is notable for fasciculations; deep tendon and plantar reflexes are lost.
The patient may complain of headache and pain in the affected muscles with mild sensory disturbance. Nuchal rigidity and cranial nerve palsies are occasionally seen, while hydrophobia is unusual.
As the paralysis ascends, there is onset of dense paraplegia with loss of sphincter tone and subsequent paralysis of the muscles of deglutition and respiration, leading to death.
21
Q
How soon after the onset of coma do most patients die? What do they die from?
A
Most patients with rabies die within two weeks after the onset of coma, although longer courses have been described with intensive care support.
Patients often die of complications, such as asphyxiation and respiratory arrest secondary to muscular spasms or uncontrolled generalized seizures in encephalitic rabies or respiratory paralysis in paralytic rabies.
22
Q
Besides the CNS, which other organ is affected by rabies and how does this manifest clinically?
A
The heart.
Supraventricular arrhythmias, atrioventricular block, sinus bradycardia and sinus arrest with non-specific ST segment and T-wave changes have all been reported. Myocarditis has been found at necropsy with evidence of viral invasion and lymphocytic infiltration.
23
Q
What lab findings are associated with rabies?
A
Routine laboratory tests are non-specific. A peripheral leukocytosis is often noted. When a constellation of clinical features suggestive of meningitis or encephalitis is present, a lumbar puncture may demonstrate a lymphocytic pleocytosis (mean 60 cells/uL). CSF protein is characteristically elevated, but typically less than 100 mg/dL, with a normal glucose concentration. A hemorrhagic CSF is not characteristically seen with rabies.
24
Q
What radiographic findings are associated with rabies?
A
CT scans are usually normal in the early phase of the illness. In later stages, cerebral edema may be seen. MR imaging may show areas of increased T2 signaling in the hippocampus, hypothalamus and brainstem.
25
How can an antemortem diagnosis of rabies be made?
Before death, the diagnosis can be made by virus-specific immunofluorescent staining of skin biopsy specimens, isolation of virus from the saliva, or detection of anti-rabies antibodies in serum or cerebrospinal fluid (CSF). Important to utilize all modalities.
26
How do you interpret the presence of rabies antibodies in the serum?
If no vaccine or rabies immune globulin has been given, the presence of antibody to rabies virus in serum is diagnostic of infection. A patient who has been immunized will have rabies antibodies in serum. Thus, in the immunized patient, a second specimen should be obtained a few days later to see if antibody titers are rising, which would be indicative of infection.
27
How do you interpret the presence of rabies antibodies in the CSF?
Antibody to virus in a CSF specimen, regardless of immunization history, suggests infection.
28
What is the differential diagnosis of encephalitic rabies?
In patients with a constellation of symptoms and signs of encephalitis, other more common infections (eg, herpes simplex virus, West Nile virus) and other noninfectious disorders (eg, central nervous system vasculitis, toxic or metabolic encephalopathy ) should be ruled out. Other causes of muscular rigidity that can be seen with rabies include tetanus, phenothiazine dystonia, and strychnine poisoning.
29
What is the differential diagnosis of paralytic rabies?
Paralytic rabies may be confused with Guillain-Barré syndrome, poliomyelitis, West Nile virus and acute transverse myelitis.
30
What is the approach to the treatment of rabies?
There is no proven effective therapy for rabies. Thus, preventing human rabies infection through the use of either pre-exposure prophylaxis (for high-risk groups) or post-exposure prophylaxis remains the cornerstone of management.
For patients with symptomatic rabies, treatment is mostly supportive. However, in rare situations, the use of an aggressive treatment protocol may provide some benefit.
31
What supportive care should be given to patients infected with rabies?
For most patients, the management of symptomatic rabies is palliative. Palliative therapy should focus on comfort care, pain control, and sedation.
32
Are glucocorticoids indicated as adjunctive therapy in rabies?
Corticosteroid therapy is not recommended for rabies since glucocorticoids have been found to increase mortality and decrease the incubation period in experimental rodent models.
33
What are the roles of rabies immune globulin and vaccine in the treatment of patients with clinical rabies?
There is no role for rabies vaccine or immune globulin in patients with symptomatic infection.
34
What is the Milwaukee protocol?
An aggressive treatment approach designed to protect the brain from injury while waiting for the host immune response to clear the virus.
35
For which patients is the Milwaukee protocol indicated?
In light of experience thus far, we agree with most experts and do not use this protocol for the routine treatment of patients with rabies.
However, this protocol may be reasonable for patients who present at an early stage of disease, had the rabies vaccine administered before the onset of clinical rabies, and/or are otherwise healthy. Another favorable prognostic factor is the presence of rabies antibodies at presentation in the absence of viral antigen or viral RNA.
36
What are the components of therapy of the Milwaukee protocol?
●Induction of therapeutic coma to reduce putative excitotoxicity (the proposed pathologic actions of viral-induced excessive excitatory amino acids or neurotransmitters upon neural cells), brain metabolism, and autonomic reactivity, which can be severe and life-threatening. One suggested therapeutic agent is ketamine, a dissociative anesthetic agent and a noncompetitive antagonist of the N-methyl-D-aspartate receptor; at high concentrations, ketamine may also inhibit rabies virus replication in vitro or in animal models. Benzodiazepines and barbiturates have also been used in this protocol.
●Intensive supportive care
●Use of drugs with potential antiviral activity (eg, ribavirin, amantadine)
●Therapeutic blockade of cerebral artery spasm
●Avoidance of passive or active immunization with rabies vaccine or rabies immunoglobulin because of theoretical concerns regarding interference with the native immune response and uncertainty about penetration into the central nervous system
37
What are the outcomes when using the Milwaukee protocol?
Dismal.
38
Which antiviral medication has been proven useful in the management of clinical rabies?
None.
39
Which infection control measures should be applied in the care of rabies patients?
●Consistent standard precautions should be utilized by HCP and family members (for example, HCP should wear gowns, masks, gloves, and eye/face protection).
●Individuals who have a percutaneous, mucous membrane, or nonintact skin exposure to the body fluids or tissues of a patient with rabies should receive proper wound care and post-exposure prophylaxis as soon as possible. Saliva, respiratory secretions, spinal fluid, and nervous tissue are most likely to transmit infection; however, all specimens collected from patients with rabies should be considered infectious.
40
Comment on the appropriate timing of rabies PEP.
Rabies postexposure prophylaxis is an urgent medical intervention and should begin as soon as possible after the presumed exposure.
41
When should each of either rabies vaccine or immune globulin be given? When should they both be given?
Rabies immunoglobulin is referred to as "passive immunization"; rabies vaccine is referred to as "active immunization".
●Vaccine alone is given for preexposure prophylaxis
●Postexposure rabies prophylaxis, in previously unimmunized persons, should always include both passive and active immunization.
●Vaccine alone is indicated in exposed persons who have had preexposure prophylaxis with a cell culture vaccine series or who had been vaccinated with other types of rabies vaccine with a documented neutralizing antibody response.
42
How should a potential rabies wound be treated?
One of the most important initial steps to prevent rabies is wound care. Thorough washing of bite wounds, scratches, and non-bite exposures with soap and water is recommended, if feasible. When available, a virucidal agent such as povidone-iodine should also be used. In animal studies of rabies, wound cleansing alone reduced the likelihood of rabies up to 90 percent. Tetanus prophylaxis, as well as antibiotics, should also be considered depending on the type of wound.
43
How does rabies immune globulin work?
The administration of RIG provides immediate virus-neutralizing antibodies until protective antibodies are generated in response to vaccine. HRIG has a half-life of approximately three weeks.
44
How does the rabies vaccine work?
Rabies vaccine induces the production of protective virus-neutralizing antibodies within approximately 7 to 10 days that persist for several years.
45
Is post-exposure prophylaxis with RIG and rabies vaccine effective?
The effectiveness of cell culture rabies vaccine plus RIG in preventing death and eliciting neutralizing antibodies after rabies exposure has been demonstrated in several studies.
46
Is the rabies vaccine effective for pre-exposure prophylaxis?
Multiple studies in humans demonstrate that vaccination with HDCV or PCECV results in significant titers of neutralizing antibodies by day 14.
47
What are the side-effects of RIG?
HRIG is associated with local reactions including pain and tenderness, erythema, and induration. Headache is the most commonly reported systemic side effect.Only one patient developed anaphylaxis associated with ERIG administration.
48
What are the side-effects of the rabies vaccine?
Local reactions, including pain at the injection site, redness, swelling, and induration. Systemic reactions are less common and include mild fever, headache, dizziness, and gastrointestinal symptoms. Systemic hypersensitivity reactions have been reported in up to 6 percent of persons receiving a booster vaccination with HDCV following primary rabies prophylaxis.
49
What is the dose of RIG and how is it given?
The recommended dose of HRIG in all age groups is 20 IU/kg while the recommended dose of ERIG (including F(ab")2 products) is 40 IU/kg body weight. RIG can partially suppress antibody production, so no more than the single recommended dose should be administered.
RIG should always be given in a different syringe from the vaccine, and at a different intramuscular site, such as the deltoid muscle opposite the vaccine dose or the anterior thigh.
As much of the RIG dose as is anatomically feasible should be infiltrated in the area around and in the wounds. Any remaining dose should be given intramuscularly. If there is no obvious wound (eg, suspected bat exposure), the large volume of RIG is best administered into the gluteal muscle. When this area is used for injection, RIG should be administered carefully in the upper outer quadrant of the gluteus to avoid possible damage to the sciatic nerve.
50
How should the rabies vaccine be given in previously unimmunized persons?
1mL IM according to the relevant schedule. Check the package insert/ local guidelines (there are 5-dose schedules and 4-dose schedules; immunocompromised patients should receive the 5-dose one).
51
How should the rabies vaccine be given in immunized persons?
A previously vaccinated person who has had a potential rabies exposure should receive two intramuscular doses of vaccine; the first dose should be given on day 0, as soon after exposure as possible, and the other three days later.
52
Where should the rabies vaccine never be given?
Vaccine should never be administered in the gluteal area, because this may result in lower antibody titers. The deltoid is the only acceptable site of administration in adults.
53
Is post-vaccination serological testing required?
Rabies vaccine induces protective neutralizing antibodies in the vast majority of patients; thus, no postvaccination serologic testing is necessary. However, serologic testing may be considered in the immunosuppressed host or in any patient who has had significant deviations from the recommended vaccine schedule.
54
What does one do if rabies PEP cannot be given immediately and is delayed?
However, no vaccine failures have been reported in the United States, despite an average delay to vaccination of approximately five days. Furthermore, since latency periods between exposure and onset of disease as long as one to eight years have been reported, postexposure prophylaxis should be given following a rabies exposure, regardless of the length of the delay. Postexposure prophylaxis is never too early and is only too late when signs of clinical rabies are developing.
55
What if a patient misses a rabies injection after having started a schedule?
Most deviations from the immunization schedule do not require complete reinitiation of vaccination. If a patient misses an injection, the immunization series should be continued until all doses have been administered. Vaccine should be administered according to the regular intervals (eg, if day 7 vaccine is given on day 10, the next dose should be on day 17, 7 days later, etc.). If there is any concern regarding efficacy, antibody testing can be conducted at or after 14 days and 7 to 14 days after the final dose is given.
Although the vaccine formulations are essentially equivalent in immunogenicity, and theoretically can be substituted for one another, there are scant data on this approach. Thus, when feasible, use of the same vaccine formulation is recommended during the entire immunization series.
56
Is the rabies vaccine safe in pregnancy?
Yes.
57
Should the general population receive pre-exposure prophylaxis?
Nope.
58
What is brucellosis?
Brucellosis is a zoonotic infection transmitted to humans by contact with fluids from infected animals (sheep, cattle, goats, pigs, or other animals) or derived food products such as unpasteurized milk and cheese.
59
Whch Brucella species cause disease in humans and which one is the major cause worldwide?
B. melitensis (small ruminants), B. abortus (cattle), B. suis (swine), and B. canis (dogs) are known to cause human disease. The majority of human cases worldwide are attributed to B. melitensis.
60
What does Brucella look like under the microscope?
Brucellae are small, nonmotile, facultative intracellular aerobic rods. Gram staining demonstrates single tiny, gram-negative coccobacilli.
61
What is the incidence of Brucella infection and what is its geographical distribution?
It is estimated that the number of Brucella-infected individuals may be up to 26 times higher than the 500,000 cases reported annually. (Most common zoonosis worldwide) Major endemic areas include countries of the Mediterranean basin, Persian Gulf, the Indian subcontinent, and parts of Mexico and Central and South America.
62
What does the prevalence of Brucellosis depend on?
The prevalence of Brucella infection in humans depends upon several factors, including geography, husbandry practices, slaughtering, food preparation techniques, and trade.
63
How do humans become infected with Brucellosis?
Humans acquire the infection through the consumption of products from infected animals, such as unpasteurized milk, cheese, and insufficiently cooked or raw meat. Infection may also result from the entry of the bacteria from infected animals or their secretions through skin lesions, conjunctiva, or from inhalation of contaminated dust or aerosols.
Human-to-human transmission is unusual. Rare cases due to blood transfusion, tissue transplantation, breastfeeding, sexual contact, congenital, laboratory, and nosocomial infection have been reported.
Laboratory workers handling Brucella cultures are at a high risk of acquiring brucellosis through accidents, aerosolization, and/or inadequate laboratory precautions (table 1). Laboratory-associated infections represent 2 percent of reported cases.
64
Should contacts of Brucellosis sufferers be traced?
screening household members of an index case detects additional unrecognized cases, allowing early diagnosis and prevention of complications.
65
What is the pathogenesis of Brucellosis?
Brucellae are readily ingested by polymorphonuclear cells and macrophages, which then pass to local lymph nodes. Organisms replicate intracellularly, and bacteria from lysed cells can infect other cells or disseminate systemically. Some Brucellae are destroyed within the lysosomes of phagocytic cells, while others are capable of preventing phagosome-lysosome fusion and avoiding intracellular killing in lysosomes to reach an endoplasmic reticulum-derived vacuole.Once inside the endoplasmic reticulum, Brucella replicates extensively without restricting basic cellular functions or generating obvious cell damage. Brucella establish long-lasting infection within host cells.
66
How does Brucella evade the host immune response once inside a host cell?
During the intracellular stage, Brucellae display a range of survival strategies to suppress host immune response and avoid immediate destruction; they circumvent strong activation of the innate immune system, withstand the direct action of complement and other bactericidal substances, and evade the action of polymorphonuclear cells and macrophages.
67
Does Brucella exhibit classic virulence factors? If yes, which ones; if no, then how does it go about virulence?
No classical virulence factors.
The smooth LPS and proteins involved in signaling, gene regulation, and transmembrane transportation are suspected to be involved in virulence. The LPS does not trigger a strong innate immune response, and, thus, the synthesis of inflammatory cytokines is low during the early stages of infection, which prevents a timely triggering of Th1 responses. Moreover, LPS has a role in cell entry and immune evasion of the infected cell and is essential for intracellular survival.
68
Comment on the immune response to Brucellosis. Mention whether it is predominantly humoral- or cell-mediated.
Cell-mediated immunity appears to be the principal mechanism of recovery as well as the mechanism for partial resistance to subsequent reinfection. Antibody response in brucellosis plays a limited part in the overall host response.
the immune response in brucellosis can be classified into three mechanisms. First, IFN-gamma activates the bactericidal function in macrophages to hamper the intracellular survival of Brucella. Then, cytotoxicity of CD8+ and gamma delta T cells destroys the infected macrophages. Finally, Th1-type antibodies opsonize the pathogen to facilitate phagocytosis.
69
What is the typical histology in Brucellosis?
In humans, Brucella spp infection results in the formation of noncaseating sarcoidosis-like granulomas, consisting of epithelioid cells, polymorphonuclear leukocytes, lymphocytes, and some giant cell.
70
What is the incubation period of Brucellosis?
The incubation period is usually one to four weeks; occasionally, it may be as long as several months
71
What is the clinical spectrum of Brucellosis infection?
Brucellosis is a systemic infection with a broad clinical spectrum, ranging from asymptomatic disease to severe and/or fatal illness.
72
What are the two main presentations of Brucellosis?
The main presentations are acute febrile illness, with or without signs of localization, and chronic infection.
73
What symptoms can patients with acute brucellosis present with?
Acute illness usually consists of the insidious onset of fever, night sweats (with a strong, peculiar, moldy odor), arthralgias, myalgias, low back pain, and weight loss as well as weakness, fatigue, malaise, headache, dizziness, depression, and anorexia. A significant percentage of patients may have dyspepsia, abdominal pain, and cough.
74
What signs can patients with acute brucellosis present with?
Physical findings are variable and nonspecific. Hepatomegaly, splenomegaly, and/or lymphadenopathy may be observed. The fever in untreated acute brucellosis can be high or slightly elevated and usually lasts for days to weeks. Irregular undulation has been described. Brucellosis can be a cause of fever of unknown origin.
75
How common is localized infection in brucellosis?
Focal infection occurs in about 30 percent of cases.
76
Which organ systems can be affected by brucellosis?
Any organ system.
77
Which is the organ system most commonly affected by focal brucellosis and how disease manifest there?
Osteoarticular involvement is the most common presentation. The sacroiliac joints and large joints of the lower limbs are most frequently involved. Spondylitis is a serious complication of brucellosis. The lumbar vertebrae are involved more frequently than the thoracic and cervical vertebrae. Paravertebral, epidural, and psoas abscess can occur in the setting of brucellar spondylitis.
78
Which is the second most commonly affected organ system by focal brucellosis and how does disease manifest there?
Genitourinary involvement occurs in 2 to 20 percent of cases; orchitis and/or epididymitis are the most common manifestations. Less common manifestations include prostatitis, cystitis, interstitial nephritis, glomerulonephritis, and renal, testicular, or tuboovarian abscess.
79
Briefly outline pulmonary brucellosis.
Pulmonary involvement occurs in up to 7 percent of patients with brucellosis. Bronchitis, interstitial pneumonitis, lobar pneumonia, lung nodules, pleural effusion, hilar lymphadenopathy, empyema, or abscesses may be observed.
80
Briefly outline GI brucellosis.
Gastrointestinal involvement can present with clinical hepatitis (3 to 6 percent of cases). Rarely, other manifestations include hepatic or splenic abscess, cholecystitis, pancreatitis, ileitis, colitis, and spontaneous peritonitis.
81
Briefly outline haematological abnormalities in brucellosis.
Hematological abnormalities, including anemia, leukopenia, thrombocytopenia, pancytopenia, and/or disseminated intravascular coagulation, are relatively common.
82
Briefly outline neurological brucellosis.
Neurological involvement occurs in 2 to 7 percent of cases. Manifestations include meningitis (acute or chronic), encephalitis, myelitis, radiculitis, and/or neuritis (with involvement of cranial or peripheral nerves).
83
Briefly outline cardiac brucellosis.
Cardiac involvement is relatively rare but may include endocarditis, myocarditis, pericarditis, endarteritis, thrombophlebitis, and/or mycotic aneurysm of the aorta or ventricles. Of these, endocarditis occurs most frequently (1 to 2 percent of cases) and is the main cause of death attributable to brucellosis.
84
Briefly outline ophthalmological brucellosis.
Ocular involvement most commonly presents with uveitis. Other manifestations include keratoconjunctivitis, corneal ulcers, iridocyclitis, nummular keratitis, choroiditis, optic neuritis, papilledema, and endophthalmitis.
85
Briefly outline dermatological brucellosis.
Dermatologic manifestations occur in up to 10 percent of patients. Findings may include macular, maculopapular, scarlatiniform, papulonodular, and erythema nodosum-like eruptions, ulcerations, petechiae, purpura, granulomatous vasculitis, and abscesses.
86
Comment on relapses of infection on brucellosis.
The rate of relapse following treatment is about 5 to 15 percent. Relapse usually occurs within the first six months following completion of treatment, although it may occur up to 12 months following completion of treatment. Relapse due to antibiotic resistance is rare.
87
What is the definition of chronic brucellosis?
Chronic brucellosis refers to patients with clinical manifestations for more than one year after the diagnosis of brucellosis is established.
88
What are the clinical features of chronic brucellosis?
Chronic brucellosis is characterized by localized infection (generally spondylitis, osteomyelitis, tissue abscesses, or uveitis) and/or relapse in patients with objective evidence of infection (elevated antibody titers and/or recovery of brucellae from blood or tissues).
In some cases, patients attribute symptoms to chronic brucellosis in the absence of objective evidence for infection (low antibody titers, sterile cultures). Such patients typically have a cyclic course with intermittent back pain, arthralgias, sweats, and signs of psychoneurosis.
89
Give an overview on the diagnosis of brucellosis.
The laboratory findings should be interpreted together with clinical manifestations, exposure history, occupation, and history of past infection.Laboratory tools for diagnosis of brucellosis include culture, serology, and polymerase chain reaction (PCR). Ideally, the diagnosis is made by culture of the organism from blood or other sites such as bone marrow or liver biopsy specimens.
90
What do routine lab tests usually show in brucellosis?
Results of routine laboratory studies are usually nonspecific. White blood cell counts are usually normal to low; pancytopenia can occur. Minor abnormalities in hepatic enzymes are relatively common.
91
What does the CSF look like in neurobrucellosis?
In neurobrucellosis, abnormalities of the cerebrospinal fluid typically include a pleocytosis of 10 to 200 white blood cells (predominantly mononuclear cells), elevated protein levels, and hypoglycorrhachia. In the setting of findings consistent with aseptic meningitis, elevated levels of adenosine deaminase in cerebrospinal fluid suggest brucella meningitis (or tuberculous meningitis).
92
What is the role of imaging in brucellosis?
Radiographs, bone scans, computerized tomography (CT), magnetic resonance imaging (MRI), and echocardiography may be helpful in evaluating focal disease but do not provide a definitive diagnosis.
93
Comment on the use of blood cultures in the diagnosis of brucellosis.
The sensitivity of culture is limited; if standard blood cultures are negative and brucellosis remains a consideration, the lab should be alerted regarding suspicion for brucellosis so that additional blood culture techniques can be performed.
The percentage of cases with positive blood cultures ranges from 15 to 70. The majority of blood cultures are positive between the 7th and 21st day.
94
What is the gold-standard culture in suspected brucellosis? Comment.
Bone marrow culture is considered the gold standard for the diagnosis of brucellosis. It is significantly more sensitive than blood culture, especially in chronic cases. However, because harvesting bone marrow for culture is an invasive procedure, bone marrow culture is reserved for patients with abnormal hematologic findings, fever of unknown origin, and negative brucellosis serology.
95
Give an overview of the use of serological tests in brucellosis.
A presumptive diagnosis of brucellosis can be made by demonstrating elevated or rising titers of specific serum antibodies.
The interpretation of serological tests can be difficult, particularly in the setting of chronic infection, reinfection, relapse, and in endemic areas where a high proportion of the population has antibodies against brucellosis.
Positive serological test results can persist long after recovery in treated individuals, so it is not always possible to distinguish serologically between active and past infection.
96
Give the names of the common serological tests available for the diagnosis of brucellosis
●Serum agglutination (standard tube agglutination)
●Enzyme-linked immunosorbent assay
●Rose Bengal agglutination
●Coombs test
●Immunocapture agglutination (Brucellacapt)
●2-mercaptoethanol agglutination
97
Which is the gold-standard serological test for brucellosis? Comment briefly on its use.
Serum agglutination testing (SAT) is the modality for which there is the greatest published experience and remains the reference to which other tests are compared. The best serological definition of brucellosis is confirmation by a fourfold or greater rise in Brucella agglutination titer between acute- and convalescent-phase serum specimens obtained ≥2 weeks apart and studied at the same laboratory. In general, positive titers consist of 1:80 in nonendemic regions and 1:160 in endemic areas. It is important to note that infection with B. canis does not produce antibodies that cross-react with standard Brucella antigens (so a separate serological test needs to be requested).
98
What is the second most common serologic method utilized in evaluating patients with suspected brucellosis?
ELISA is the second most common serologic method utilized in evaluating patients with suspected Brucella infections. ELISA is rapid, objective, and highly sensitive and specific; it measures immunoglobulin (Ig)M, IgG, and IgA.
99
What is the role of the Rose Bengal plate agglutination test in the diagnosis of brucellosis?
Rose Bengal plate agglutination test is often used as a rapid screening test, with very high sensitivity (>99 percent) and fairly high specificity.
100
What is the role of Coombs and brucellacapt testing in the diagnosis of brucellosis?
The Coombs and immunocapture agglutination (Brucellacapt) tests may be more suitable in relapsing brucellosis and patients with persistent active infection
101
Comment on the use of molecular testing in the diagnosis of brucellosis.
Polymerase chain reaction is a promising tool for rapid and accurate diagnosis of human brucellosis. PCR can be performed on blood or on any body tissue and can yield positive results as early as 10 days after inoculation. PCR-based laboratory tests cannot yet be considered a routine diagnostic method, however, given the need for standardization of methods, infrastructure, equipment, expertise, and a better understanding of the clinical significance of the results
102
Is there any radiographical sign that distinguishes brucellosis from other infections?
Yes. Localized snowflake calcification in chronic hepatosplenic brucellosis is the only specific radiographic finding that may be used to distinguish brucellosis from other diseases.
103
What are the treatment goals in brucellosis?
The goal of brucellosis therapy is to control the illness and prevent complications, relapses, and sequelae.
104
What are important therapeutic principles in the management of brucellosis?
Important principles of brucellosis treatment include use of antibiotics with activity in the acidic intracellular environment (doxycycline, rifampin), use of combination regimens, and prolonged duration of treatment.
105
What are the 2 major antibiotic regimens in the treatment of uncomplicated brucellosis (no spondylitis, endocarditis or neurobrucellosis)? Which is the better of the two?
●Doxycycline 100 mg orally twice daily for six weeks, plus streptomycin 1 g intramuscularly once daily for the first 14 to 21 days. It has been suggested that gentamicin (5 mg/kg) may be substituted for streptomycin; equal efficacy has been demonstrated. The optimal duration of gentamicin is uncertain; 5 days to 14 days is acceptable.
●Doxycycline 100 mg orally twice daily plus rifampin 600 to 900 mg (15 mg/kg) orally once daily. Both drugs are administered for six weeks.
The doxycycline-streptomycin regimen is considered the "gold standard" and has been proven to be more effective than doxycycline-rifampin in some studies. However, many favor doxycycline-rifampin since it is relatively inexpensive and convenient.
106
Which other antibiotics may be used in the treatment of brucellosis and when are they appropriate?
Fluoroquinolones (ciprofloxacin 500 mg twice daily or ofloxacin 200 mg twice daily) have good in vitro activity against Brucella spp and can be used in combination with doxycycline or rifampin but are not appropriate first-line agents. They may be useful in the setting of drug resistance, antimicrobial toxicity, and some cases of relapse.
There are some reports demonstrating more favorable cure rates with three-drug therapy than two-drug therapy. Trimethoprim-sulfamethoxazole (TMP-SMX; one double-strength tablet twice a day) may be used as an additional (third) agent in complex cases of focal brucellosis, relapse, or refractory disease.
107
How does the treatment of focal brucellosis differ from that of uncomplicated brucellosis?
In general, longer courses of therapy (at least 12 weeks) are warranted for treatment of spondylitis, neurobrucellosis, endocarditis, or localized suppurative lesions. At least three drugs are generally warranted in the setting of neurobrucellosis, endocarditis, and localized suppurative lesions. In general, other forms of localized infection are treated in the same way as uncomplicated brucellosis.
108
How is brucella spondylitis treated?
Treatment for Brucella spondylitis should consist of two antibiotic agents for at least 12 weeks. Patients with Brucella spondylitis appear to respond better to doxycycline (100 mg orally twice daily for 12 weeks) plus streptomycin (1 g intramuscularly once daily for the first 14 to 21 days) than to doxycycline-rifampin.
Surgery may be warranted in the setting of spinal instability, persistence or progression of neurological deficit, vertebral collapse, or localized abscess (epidural or paravertebral).
109
How is neurobrucellosis treated?
Most experts favor administration of two or three drugs that cross the blood-brain–cerebrospinal fluid (CSF) barrier for treatment of neurobrucellosis. Reasonable regimens include doxycycline, rifampin, and either ceftriaxone or trimethoprim-sulfamethoxazole. Ceftriaxone-based regimens may be more successful and allow shorter duration of therapy. The duration of therapy is generally prolonged (months) and needs to be individualized according to clinical signs and symptoms; in general, it should be continued until CSF parameters have returned to normal.
The role of corticosteroids is uncertain and they are not part of routine therapy. Use of steroids may be appropriate in the setting of neurobrucellosis complicated by iritis, papilledema, myelopathy, polyneuropathy, and/or cranial nerve palsies.
110
How is brucella endocarditis treated?
Endocarditis is a rare but life-threatening complication of brucellosis. Most patients with endocarditis due to brucellosis require a combination of surgery and antimicrobial agents for the best chance of cure.
Antimicrobial therapy alone may be attempted in the absence of heart failure, valvular destruction, abscess, or a prosthetic valve.
In general, thus far, clinical experience has been best using combination therapy with an aminoglycoside, doxycycline, and rifampin; further study is needed.
The optimal duration of therapy is uncertain; therapy is usually given for six weeks to six months (mean duration three months). Following valve replacement, the duration of antimicrobial therapy is also uncertain; the decision to stop treatment must be determined on an individual basis after thorough clinical observation.
111
How should disease activity in brucellosis be assessed?
Assessing disease activity following completion of treatment can be difficult; it is not always possible to distinguish serologically between persistent (active) and past (inactive) infection
.
Brucella-specific immunoglobulin (Ig)G antibodies may decline with treatment, although negative serology does not definitively exclude persistence of active Brucella infection. Some patients may have persistent symptoms (which are attributable to persistent infection or another cause) after completing treatment, even in the setting of declining or negative serology. Conversely, elevated levels of IgG antibodies may persist for years in fully treated individuals with no clinical signs of infection.
Therefore, interpretation of serologic and molecular tests requires correlation with clinical history including exposure, clinical manifestations, and treatment history.
112
How should brucellosis relapses be treated?
Relapse of symptoms should prompt assessment for a focal lesion. While antimicrobial susceptibility should be performed on any culture isolate, development of resistance is rare. Most relapses can be treated successfully with a repeat course of a standard regimen
.
Occurrence of second or third relapse should prompt selection of an alternative regimen.
113
What are the risks of brucellosis in pregnancy?
Brucellosis in pregnancy is associated with risk of spontaneous abortion, premature delivery, miscarriage, and intrauterine infection with fetal death.
114
How should brucellosis in pregnancy be managed?
Management of brucellosis in pregnant women is a challenging problem with limited data. Regimens include rifampin (900 mg once daily), with or without TMP-SMX (one double-strength tablet twice a day) for six weeks. Use of TMP-SMX during the last week prior to delivery is associated with kernicterus and should be avoided if possible.
115
Outline the procedure for brucellosis PEP.
High-risk exposure in a microbiology laboratory warrants baseline serologic testing and postexposure prophylaxis (doxy 100mg bd + rifampin 600mg dly for 3wks).
Management of Brucella vaccine accidents warrants baseline serologic testing and a full treatment course of antibiotics.
116
How often does brucella therapy fail?
Therapeutic failures are usually associated with brucellar spondylitis and have been reported in up to 15 percent of cases.
117
What is the mortality rate of brucellosis?
With appropriate antimicrobial treatment, the mortality rate of brucellosis is <1 percent.
118
How may brucellosis be prevented?
Brucellosis may be prevented via vaccination of domestic livestock, serologic testing, quarantine of herds, and slaughter of infected animals. Pasteurization of milk is also very important for the prevention of transmission to humans. Vaccination for the prevention of human brucellosis is not available.
119
What are the 3 broad categories of staph aureus bacteraemia?
●Healthcare associated, hospital onset (ie, nosocomial)
●Healthcare associated, community onset
●Community acquired
120
How common is nosocomial SAB?
S. aureus is a leading cause of nosocomial bloodstream infection in the United States. Among 24,000 nosocomial bloodstream infections between 1995 and 2002, S. aureus was the second most common cause (after coagulase-negative staphylococci), accounting for 20 percent of cases.
121
What is the single greatest risk factor for SAB?
Central venous catheter.
122
Besides a CVC, what are other risk factors for nosocomial staph aureus bacteraemia?
Predisposing conditions were observed in 91 percent of cases; these included diabetes, immunosuppressive therapy, and malignancy. Most bacteremic patients also had some breach in normal host protective barriers, such as an intravascular device or a wound.
123
Is nosocomially-acquired SAB more likely to be MRSA?
Yes (57% of isolates in the US!).
124
What percentage of patients with nosocomially-acquired SAB develop metastatic complications?
Among patients who acquire healthcare-associated, hospital-onset S. aureus bacteremia, approximately 20 percent develop metastatic complications, including endocarditis.
125
What is the mortality-rate of nosocomial SAB?
The mortality rate is 20 to 30 percent.
126
Briefly explain what is meant by hospital-acquired, community-onset SAB.
Healthcare-associated, community-onset infection refers to infection in an outpatient who has had recent, extensive contact with the healthcare system. The infection must be diagnosed as an outpatient or within 48 hours of hospital admission. Examples of healthcare contact include:
●Hospitalization in an acute care hospital for ≥2 days within the prior 90 days
●Receipt of dialysis or intravenous therapy (including chemotherapy) within the prior 30 days
●Receipt of intravenous therapy, wound care, or specialized nursing care at home
●Residence in a nursing home or other long-term care facility.
127
What is an important risk-factor for hospital-acquired, community-onset SAB?
Intravascular catheter.
128
Briefly explain what is meant by community-acquired SAB and outline who it affects.
Community-acquired infection refers to infection in a patient who has had no recent contact with the healthcare system. Patients with community-acquired S. aureus bacteremia include injection drug users and patients with a clinically inapparent source of bacteremia (such as vertebral osteomyelitis or epidural abscess).
129
What is worrying about patients who present with community-acquired SAB?
Patients with onset of S. aureus bacteremia acquired in the community are likely to present with complicated infection. In one study, more than 40 percent of patients with community-acquired SAB had metastatic infection, including infective endocarditis (IE). Other studies have shown greater rates of complications.
130
How common is daptomycin resistance in SAB?
Daptomycin resistance is uncommon. Resistance to daptomycin may appear in patients who receive prolonged courses of therapy, particularly if their underlying infection is not amenable to surgical drainage or if it involves a prosthetic device such as a vascular graft. Other risk factors for the emergence of resistance include previous exposure to vancomycin, infection with a methicillin-resistant S. aureus strain with a minimum inhibitory concentration to vancomycin of 2 mcg/mL or greater, and treatment with insufficient doses of vancomycin.
131
Outline the risk factors for the development of SAB.
Risk factors for development of S. aureus bacteremia (SAB) include presence of a prosthetic device such as an intravascular catheter, injection drug use, and underlying medical comorbidities.
132
Elaborate on 'underlying medical comorbidities' as a risk factor for SAB.
In addition to the usual causes of immunosuppression:
Host genetics may contribute to human susceptibility to S. aureus infection. In addition, hereditary defects in white blood cell function or immune response such as Job's syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome predispose patients to recurrent staphylococcal infections.
Patients with conditions conferring increased risk for nasal colonization (such as patients with diabetes and patients who are hemodialysis dependent) are also more prone to S. aureus bacteremia.
133
Comment on nasal carriage of S. aureus and SAB.
Patients with S. aureus nasal colonization are at increased risk for S. aureus bacteremia (3x more likely to develop it in one study). However, nasal carriers had significantly lower rates of SAB-related mortality (8 versus 32 percent).
134
What is an important risk-factor for hospital-acquired, community-onset SAB?
Intravascular catheter.
135
Briefly explain what is meant by community-acquired SAB and outline who it affects.
Community-acquired infection refers to infection in a patient who has had no recent contact with the healthcare system. Patients with community-acquired S. aureus bacteremia include injection drug users and patients with a clinically inapparent source of bacteremia (such as vertebral osteomyelitis or epidural abscess).
136
What is worrying about patients who present with community-acquired SAB?
Patients with onset of S. aureus bacteremia acquired in the community are likely to present with complicated infection. In one study, more than 40 percent of patients with community-acquired SAB had metastatic infection, including infective endocarditis (IE). Other studies have shown greater rates of complications.
137
How common is daptomycin resistance in SAB?
Daptomycin resistance is uncommon. Resistance to daptomycin may appear in patients who receive prolonged courses of therapy, particularly if their underlying infection is not amenable to surgical drainage or if it involves a prosthetic device such as a vascular graft. Other risk factors for the emergence of resistance include previous exposure to vancomycin, infection with a methicillin-resistant S. aureus strain with a minimum inhibitory concentration to vancomycin of 2 mcg/mL or greater, and treatment with insufficient doses of vancomycin.
138
Outline the risk factors for the development of SAB.
Risk factors for development of S. aureus bacteremia (SAB) include presence of a prosthetic device such as an intravascular catheter, injection drug use, and underlying medical comorbidities.
139
Elaborate on 'underlying medical comorbidities' as a risk factor for SAB.
In addition to the usual causes of immunosuppression:
Host genetics may contribute to human susceptibility to S. aureus infection. In addition, hereditary defects in white blood cell function or immune response such as Job's syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome predispose patients to recurrent staphylococcal infections.
Patients with conditions conferring increased risk for nasal colonization (such as patients with diabetes and patients who are hemodialysis dependent) are also more prone to S. aureus bacteremia.
140
Comment on nasal carriage of S. aureus and SAB.
Patients with S. aureus nasal colonization are at increased risk for S. aureus bacteremia (3x more likely to develop it in one study). However, nasal carriers had significantly lower rates of SAB-related mortality (8 versus 32 percent).
141
How common is repeat SAB?
Repeat infection with S. aureus bacteremia (SAB) is common. In one cohort including more than 10,000 patients, approximately 7 percent of patients with SAB developed recurrent SAB; the risk of reinfection was defined as an episode of SAB >90 days after an initial episode of SAB.
142
What is the median time to relapsed SAB and what are the risk factors for it?
The median time to recurrent infection was 15 months. Risk of recurrent SAB was associated with comorbidities including renal disease, diabetes with associated complications, severe liver disease, and paraplegia.
143
S. aureus is a skin commensal; approximately how much of the population does it colonize?
Approximately 30 percent of the human population.
144
What are the common clinical manifestations of S. aureus?
- Skin and soft tissue infection;
- Bacteraemia
- IE
- Cardiac device infection
- Intravascular catheter infection
- Sepsis and toxic shock syndrome
- Splenic abscess
- Bone and joint infection, incl. osteomyelitis, prosthetic joint infection and septic arthritis/bursitis
- Pulmonary infection
- Meningitis
- Bacteriuria
- Food-borne illness
- Waterhouse-Friedrichson syndrome
- Henoch-Schonlein purpura
145
List the skin and soft tissue infections that may be caused by S. aureus.
●Impetigo (infection of the epidermis)
●Folliculitis (infection of the superficial dermis)
●Furuncles, carbuncles, and abscess (infection of the deep dermis)
●Hydradenitis suppurativa (follicular infection of intertriginous areas)
●Cellulitis, erysipelas, and fasciitis (infection of the subcutaneous tissues)
●Pyomyositis (infection of skeletal muscle)
●Mastitis
●Surgical site infections
146
What is an important risk-factor for hospital-acquired, community-onset SAB?
Intravascular catheter.
147
Briefly explain what is meant by community-acquired SAB and outline who it affects.
Community-acquired infection refers to infection in a patient who has had no recent contact with the healthcare system. Patients with community-acquired S. aureus bacteremia include injection drug users and patients with a clinically inapparent source of bacteremia (such as vertebral osteomyelitis or epidural abscess).
148
What is worrying about patients who present with community-acquired SAB?
Patients with onset of S. aureus bacteremia acquired in the community are likely to present with complicated infection. In one study, more than 40 percent of patients with community-acquired SAB had metastatic infection, including infective endocarditis (IE). Other studies have shown greater rates of complications.
149
How common is daptomycin resistance in SAB?
Daptomycin resistance is uncommon. Resistance to daptomycin may appear in patients who receive prolonged courses of therapy, particularly if their underlying infection is not amenable to surgical drainage or if it involves a prosthetic device such as a vascular graft. Other risk factors for the emergence of resistance include previous exposure to vancomycin, infection with a methicillin-resistant S. aureus strain with a minimum inhibitory concentration to vancomycin of 2 mcg/mL or greater, and treatment with insufficient doses of vancomycin.
150
Outline the risk factors for the development of SAB.
Risk factors for development of S. aureus bacteremia (SAB) include presence of a prosthetic device such as an intravascular catheter, injection drug use, and underlying medical comorbidities.
151
Elaborate on 'underlying medical comorbidities' as a risk factor for SAB.
In addition to the usual causes of immunosuppression:
Host genetics may contribute to human susceptibility to S. aureus infection. In addition, hereditary defects in white blood cell function or immune response such as Job's syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome predispose patients to recurrent staphylococcal infections.
Patients with conditions conferring increased risk for nasal colonization (such as patients with diabetes and patients who are hemodialysis dependent) are also more prone to S. aureus bacteremia.
152
Comment on nasal carriage of S. aureus and SAB.
Patients with S. aureus nasal colonization are at increased risk for S. aureus bacteremia (3x more likely to develop it in one study). However, nasal carriers had significantly lower rates of SAB-related mortality (8 versus 32 percent).
153
How common is repeat SAB?
Repeat infection with S. aureus bacteremia (SAB) is common. In one cohort including more than 10,000 patients, approximately 7 percent of patients with SAB developed recurrent SAB; the risk of reinfection was defined as an episode of SAB >90 days after an initial episode of SAB.
154
What is the median time to relapsed SAB and what are the risk factors for it?
The median time to recurrent infection was 15 months. Risk of recurrent SAB was associated with comorbidities including renal disease, diabetes with associated complications, severe liver disease, and paraplegia.
155
S. aureus is a skin commensal; approximately how much of the population does it colonize?
Approximately 30 percent of the human population.
156
What are the common clinical manifestations of S. aureus?
- Skin and soft tissue infection;
- Bacteraemia
- IE
- Cardiac device infection
- Intravascular catheter infection
- Sepsis and toxic shock syndrome
- Splenic abscess
- Bone and joint infection, incl. osteomyelitis, prosthetic joint infection and septic arthritis/bursitis
- Pulmonary infection
- Meningitis
- Bacteriuria
- Food-borne illness
- Waterhouse-Friedrichson syndrome
- Henoch-Schonlein purpura
157
List the skin and soft tissue infections that may be caused by S. aureus.
●Impetigo (infection of the epidermis)
●Folliculitis (infection of the superficial dermis)
●Furuncles, carbuncles, and abscess (infection of the deep dermis)
●Hydradenitis suppurativa (follicular infection of intertriginous areas)
●Cellulitis, erysipelas, and fasciitis (infection of the subcutaneous tissues)
●Pyomyositis (infection of skeletal muscle)
●Mastitis
●Surgical site infections
158
Is S. aureus the most common pathogen isolated from purulent cellulitis, cutaneous abscesses, and surgical site infections?
Yes.
159
How does SAB develop?
Bacteremia may develop as a complication of a primary S. aureus infection such as skin and soft tissue infection, bone and joint infection, or pneumonia. Vascular catheters are a common source of bacteremi.
160
What is the commonest cause of IE in resource-rich settings?
SAB
161
What are the risk factors for the development of IE in patients with SAB?
```
●Prosthetic heart valve (incidence up to 50 percent)
●Predisposing cardiac abnormalities
●Injection drug use
●Intravascular catheter infection
●Bacteremia of unclear origin
●Persistent bacteremia
```
162
What is the concern when patients with cardiac devices get SAB?
IE and device infection.
163
Which MSS infections is S. aureus the most common infecting organism in? Which symptoms should raise concern for these in patients with SAB?
S. aureus is the most common pathogen causing osteomyelitis, septic arthritis, and prosthetic joint infection. Development of back or joint pain should raise the suspicion of an occult site of infection in patients with current or recent S. aureus bacteremia.
164
In which settings does S. aureus most commonly cause meningitis/CNS disease?
S. aureus meningitis most commonly occurs in the setting of head trauma or neurosurgery; less commonly, it can also occur as a complication of S. aureus bacteremia.
165
Comment on the finding of S. aureus on urine culture.
Bacteriuria due to S. aureus can occur via ascending infection in the presence of a urinary catheter or in the setting of S. aureus bacteremia. In the absence of systemic signs of infection, S. aureus bacteriuria associated with the presence of a urinary catheter does not warrant routine investigation for bacteremia.
166
Outline the clinical approach to SAB.
The clinical approach to S. aureus bacteremia consists of careful history and physical examination, infectious disease consultation, and diagnostic evaluation including echocardiography and additional imaging as needed.
167
What are two important questions to ask patients with (suspected) SAB?
1. Portals of entry, including recent skin or soft tissue infection and presence of indwelling prosthetic devices (including intravascular catheters, orthopedic hardware, and cardiac devices).
2. Patients should also be questioned regarding symptoms that may reflect metastatic infection, which can occur in up to 30 percent of cases.
168
Give examples of some questions about metastatic infection in SAB.
These include bone or joint pain (particularly back pain, suggesting vertebral osteomyelitis, discitis, and/or epidural abscess), protracted fever and/or sweats (suggestive of endocarditis), abdominal pain (particularly left upper quadrant pain, which may reflect splenic infarction), costovertebral angle tenderness (which may reflect renal infarction or psoas abscess), and headache (which may reflect septic emboli).
169
Which features should be sought on examination of a patient with SAB?
The physical examination should include careful cardiac examination for signs of new regurgitant murmurs or heart failure. A vigorous search should be undertaken for the clinical stigmata of endocarditis, including evidence of small and large emboli with special attention to the fundi, conjunctivae, skin, and digits. A neurologic evaluation should be undertaken for evidence of focal neurologic impairment; it is also important as a baseline examination should neurologic deficits develop later.
170
What is the most important examination in SAB and why?
The re-examination.
Serial bedside examinations are critical for detection of complications that may develop after initial evaluation and during the course of treatment. In several case series, only 39 percent of 133 patients with bacteremic S. aureus vertebral osteomyelitis and 57 percent of 35 patients with epidural abscess had a diagnosis on admission related to the spine.
171
Should a growth of S. aureus on B/C ever be treated as a commensal?
In general, blood cultures positive for S. aureus should be respected as a clinically significant finding that should prompt clinical evaluation and initiation of empiric therapy.
172
Should all patients with SAB receive an echo?
All patients with S. aureus bacteremia should undergo echocardiography to evaluate for presence of endocarditis.
173
Which modality of echo is favoured in SAB?
Transthoracic echocardiography (TTE) should be performed first.
The indications for TEE in patients with S. aureus bacteremia and no evidence of vegetation on TTE are controversial. TEE is substantially more sensitive than TTE for identification of valvular vegetation; it is most sensitive when performed five to seven days after the onset of bacteremia. In the setting of high clinical suspicion for IE and a negative echocardiogram, a repeat study is warranted.
174
Under what conditions is a TOE probably not required in SAB?
It may be reasonable to forgo TEE for circumstances in which all of the following conditions are met:
●Nosocomial acquisition of bacteremia
●Sterile follow-up blood cultures within four days after the initial positive culture
●No permanent intracardiac device
●No hemodialysis dependence
●No clinical signs of endocarditis or secondary foci of infection
●Removable focus of infection removed promptly, if present
●Defervescence within 72 hours of initial positive blood culture
175
Besides an echo, how does one go about imaging a patient with SAB?
Imaging should be tailored to findings on history and physical examination.
Patients with back pain should be evaluated for vertebral osteomyelitis and discitis. Imaging of the torso (computed tomography) should be pursued for patients with abdominal pain or costovertebral angle tenderness to evaluate for presence of splenic infarct, renal infarct, psoas abscess, or other intraabdominal sites of infection. Such imaging is also appropriate for patients with documented endocarditis even in the absence of focal symptoms to evaluate for subclinical sites of metastatic infection.
Patients with headache and known or suspected IE should undergo magnetic resonance imaging of the head.
176
What is the approach to treatment of SAB?
Treatment of S. aureus bacteremia includes prompt source control (such as removal of implicated vascular catheters and/or surgical drainage of abscess if present) and antimicrobial therapy.
177
Outline the empiric treatment for SAB.
Empiric treatment should consist of antimicrobial therapy with activity against methicillin-resistant S. aureus (MRSA) when positive blood cultures with gram-positive cocci are observed and should be continued until culture and susceptibility become available. Empiric treatment consists of vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose); daptomycin (6 mg/kg intravenously once daily) is an acceptable alternative agent. Once susceptibility results are available, if the isolate is methicillin-susceptible S. aureus (MSSA), antibiotic treatment should be deescalated to a beta-lactam agent (such as nafcillin, oxacillin, or cefazolin).
178
Describe the treatment of MSSA SAB.
Penicillin (4 million units intravenously [IV] every four hours) is the drug of choice for S. aureus bacteremia if the isolate is penicillin sensitive; however, virtually all isolates are penicillin resistant. Therefore, treatment of MSSA bacteremia generally consists of a beta-lactam agent such as nafcillin (2 g IV every four hours), oxacillin (2 g IV every four hours), or flucloxacillin (2 g IV every six hours).
A first-generation cephalosporin such as cefazolin (2 g IV every eight hours) is an acceptable alternative in patients with hypersensitivity to the preceding agents.
179
Comment on the use of vancomycin in patients with MSSA SAB.
Vancomycin is less effective for treatment of S. aureus bacteremia than beta-lactam agents and should not be administered as primary therapy for methicillin-sensitive strains unless the use of a beta-lactam agent is precluded by drug intolerance.
180
How do you treat MSSA SAB if the patient has a penicillin allergy?
Patients with MSSA bacteremia and a reported penicillin allergy should have treatment guided by allergy history (cefazolin may be given if history excludes anaphylactic features) or, if available, full allergy evaluation with skin testing.
181
Comment on the use of aminoglycosides in the treatment of SAB.
Routine combination of aminoglycosides with antistaphylococcal penicillins or vancomycin for treatment of S. aureus bacteremia is not warranted because the evidence for clinically significant benefit is minimal.
182
When should blood cultures be repeated following the initial positive culture for SAB? What are the implications of a second positive result?
Blood cultures should be repeated to document clearance of bacteremia. Failure to clear bacteremia within 48 hours after initiation of therapy should prompt further evaluation, including evaluation of susceptibility data to ensure appropriate antibiotic selection and dosing, as well as clinical evaluation for occult focus of infection that may require drainage or other intervention beyond antimicrobial therapy alone.
183
How long should patients with SAB be treated for?
Depends on whether the infection is uncomplicated or not.
Determination of treatment duration requires differentiation of patients with uncomplicated S aureus bacteremia (who may be cured with 14 days of intravenous therapy from the first negative blood culture) from patients with complicated S. aureus bacteremia (who require longer duration of intravenous treatment, dependent on the site of infection).
184
How do you define 'uncomplicated SAB'?
In general, a patient may be presumed to have uncomplicated S. aureus bacteremia if all of the following criteria are met:
●Infective endocarditis has been excluded via echocardiography.
●No indwelling devices (such as prosthetic heart valves or vascular grafts) are present.
●Follow-up blood cultures drawn two to four days after initiating intravenous antistaphylococcal therapy and removing the presumed focus of infection (if present) are negative.
●The patient defervesced within 48 to 72 hours after initiating intravenous antistaphylococcal therapy and removal of the presumed focus of infection (such as debridement of soft tissue infection or intravascular catheter removal).
●There is no evidence of metastatic staphylococcal infection on physical examination.
185
How do you manage a patient with SAB and valvular abnormalities but with no vegetations on TOE?
Patients with S. aureus bacteremia and cardiac valvular abnormalities with no vegetation on transesophageal echocardiography (TEE) may be treated with 14 days of antimicrobial therapy. These patients should have negative surveillance blood cultures within 72 hours after initiation of appropriate antimicrobial therapy and no signs of systemic staphylococcal infection.
186
What is the mortality rate of SAB?
— Mortality rates of 20 to 40 percent have been reported in most case series of patients with S. aureus bacteremia.
187
Which clinical features predict a worse outcome for patients with SAB?
Mortality is higher among patients with underlying comorbidities, methicillin-resistant S. aureus (MRSA) infection (odds ratio [OR] 9.3; 95% CI 1.5-59.2), and/or time to positivity of blood cultures ≤12 hours (OR 6.9; 95% CI 1.1-44.7).
188
What is the definition of methicillin resistance in S. aureus?
Methicillin resistance in S. aureus is defined as an oxacillin minimum inhibitory concentration (MIC) of ≥4 mcg/mL.
189
Outline the approach to the management of patients with MRSA SAB.
Treatment of MRSA bacteremia consists of prompt source control (such as removal of implicated vascular catheters and/or drainage of purulent collection if present) and prompt initiation of appropriate antimicrobial therapy.
190
What are the antibiotics of choice in patients with MRSA SAB?
Vancomycin or daptomycin are the agents of choice for treatment of invasive MRSA infections.
191
When do you use vancomycin and when do you use daptomycin in the treatment of MRSA SAB?
Patients with S. aureus infection due to an isolate with vancomycin MIC ≥2 mcg/mL may not respond to therapy as well as those with infection due to an isolate with a lower MIC. In such cases, poor clinical response to vancomycin therapy should prompt use of daptomycin or another agent.
192
What is the role of combination therapy in the management of MRSA SAB?
There is no role for routine use of combination therapy (such as vancomycin plus gentamicin or rifampin) for treatment of MRSA bacteremia; combination therapy may be useful in the presence of a prosthetic device or for salvage therapy.
193
What are the vancomycin MIC breakpoints for S. aureus?
●Susceptible: MIC ≤2 mcg/mL
●Intermediate: MIC 4 to 8 mcg/mL
●Resistant: MIC ≥16 mcg/mL
194
Can vancomycin fail as a therapy despite the organism being sensitive to it?
Clinical failures have been reported in patients without evidence of vancomycin resistance; some of these failures have occurred in patients with heteroresistant infection (in which subpopulations of organisms have higher vancomycin MICs, although it is uncertain whether heteroresistance is a cause of vancomycin treatment failure).
195
When is salvage therapy indicated?.
Suspected antibiotic failure as a contributing factor to inadequate clinical response should prompt antibiotic adjustment (increasing the drug dose or switching to an alternative regimen) at or after three to four days of persistent bacteremia. For patients with persistent bacteremia in the setting of vancomycin therapy, the MIC should be reviewed carefully, with antibiotic adjustment if needed.
For patients who are not responsive to or are intolerant of vancomycin and daptomycin, there are several potential alternative agents. The optimal salvage regimen for persistent MRSA bacteremia is uncertain, and it is unknown whether combination therapy or monotherapy is warranted.
196
What are some possible salvage regimens and which is the preferred one?
Possible combination salvage regimens include:
●Daptomycin plus ceftaroline or other beta-lactam
●Vancomycin plus ceftaroline or other beta-lactam
●Daptomycin plus trimethoprim-sulfamethoxazole
●Ceftaroline plus trimethoprim-sulfamethoxazole
Based on the available data, we favor combination therapy with daptomycin (dosed at 8 to 10 mg/kg rather than 6 mg/kg intravenously [IV] daily) with ceftaroline.
(Based on a small case study [26pats])
197
For which condition associated with MRSA SAB should daptomycin not be used?
Daptomycin should not be used for treatment of MRSA bacteremia associated with pneumonia.
198
What are some issues related to daptomycin use?
The daptomycin minimum inhibitory concentration may increase during therapy and may be influenced by prior exposure to vancomycin. Therefore, daptomycin susceptibility testing must be performed prior to therapy and repeated in the event of positive cultures obtained during therapy, particularly if prolonged therapy is administered and/or there is microbiological evidence of persistent infection during therapy.
Adverse effects associated with daptomycin include myopathy, peripheral neuropathy, and eosinophilic pneumonia. Serial measurements of serum creatine kinase should be monitored at least weekly, and daptomycin should be discontinued in patients with symptomatic myopathy and creatine phosphokinase (CPK) ≥5 times the upper limit of normal (ULN) or in asymptomatic patients with CPK ≥10 times the ULN.
