1DiseasesSECTIONInfectious •
cated as the most responsible organism for endophthalmitis. Recent reports indicate that S. epidermidis that the most commonly cultured intraocular pathogen, accounting for 70% of postoperative endophthalmitis. This is consistent with the finding of S. epidermidis as the most common isolate from conjunctival cultures. Also, molecular techniques have established that in most cases of postoperative endophthalmitis, the coagulase-negative staphylococci arise from the patient’s eyelid flora. In a recent study regarding antibiotic susceptibility of bacterial isolates from endophthalmitis, about 63% of isolated coagulase-negative staph were methicillin sensitive and 75% of the isolated S. aureus were methicillin sensitive. Both staph isolates were 100% sensitive to vancomycin. Because these organisms can be resistant to penicillinase-resistant penicillins, treatment should be guided by culture and sensitivity results.
REFERENCES
Archer GL: Staphylococcus epidermidis and other coagulase-negative staphylococci. In: Mandell GL, Bennett JE, Dolin R, eds: Principles and practice of infectious diseases. 5th edn. New York, Churchill Livingstone, 2000:2092–2100.
Bannerman TL, Rhoden DL, McAllisster SK, et al: The source of coagulasenegative staphylococci in the Endophthalmitis Vitrectomy Study. Arch Ophthalmo 115:357–361, 1997.
Ha DP, Wisniewski SR, Wilson LA, et al: Spectrum and susceptibilities of microbiological isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol 122:1–17, 1996.
Kowalski RP, Karenchak LM, Romanowski EG: Infectious disease: changing antibiotic susceptibility. Ophthalmology Clinics of North America 16(1):1–11, 2003.
Mather R, Karenchak LM, Romanowski EG, Kowalski RP: Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 133(4):L463–L466, 2002.
Sotonzo C, Inagaki K, Fujita A, et al: Methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis infections in the cornea. Cornea 21(7 suppl):S94–S101, 2002.
Tungsiripat T, Sarayba MA, Kaufman MB, et al: Fluoroquinolone therapy in multi-drug resistant staphylococcal keratitis after lamellar keratectomy in a rabbit model. Am J Ophthalmol 136(1):76–81, 2003.
Waldvogel FA: Staphylococcus aureus (including toxic shock syndrome). In: Mandell GL, Bennett JE, Dolin R, eds: Principles and practice of infectious diseases. 5th edn. New York, Churchill Livingston, 2000:2069–2092.
48 STREPTOCOCCUS 041.0
Rookaya Mather, MD, MBBCh, FRCS(C), DABO
London, Ontario
Another useful classification scheme is based on the ability of the organism to produce zones of hemolysis around the colony when cultured on blood agar. α-Hemolysis is characterized by a zone of partial hemolysis, which often appears as a greenish hue on the agar. A clear zone of complete hemolysis characterizes β-hemolysis. γ-Hemolysis indicates the absence of hemolysis.
The most important pathogen in the a-hemolytic group is Streptococcus pneumoniae, commonly referred to as pneumococcus. It is a common cause of pneumonia, meningitis, endocarditis, and otitis media. The S. viridans group consists of several a-hemolytic species (S. mitis, S. sanguis, S. salivarius, S. mutans, and S. anginosus). These bacteria can cause acute and subacute endocarditis and dental and brain abscess.
Among the streptococci, the β-hemolytic groups are the most common pathogens. S. pyogenes (group A) can give rise to pharyngitis, impetigo, necrotizing fasciitis, cellulitis, toxic streptococcal syndrome, and scarlet fever. In addition, this organism is known to trigger the postinfectious syndromes of acute rheumatic fever and poststreptococcal glomerulonephritis. S. agalactiae (group B) is a frequent cause of neonatal sepsis and meningitis. S. equi (group C) has been identified as a cause of cellulitis and endocarditis.
Enterococci, formerly designated as group D streptococci, exhibit variable hemolysis. These bacteria cause urinary tract infections, wound infections, peritonitis, and endocarditis.
Streptococcal infections of the eye and its adnexa are relatively common. The orbit, eyelids, lacrimal sac, conjunctiva, cornea, uvea, and globe may be involved.
COURSE/PROGNOSIS
●S. pyogenes causes membranous or pseudomembranous conjunctivitis, which can lead to corneal infiltration, ulceration, and eventual perforation.
●S. pneumoniae conjunctivitis is usually self-limited. Topical antibiotics are typically prescribed to shorten the duration of the infection, reduce the risk of developing complications and possibly reduce epidemic spread of the pathogen.
●Endophthalmitis caused by streptococci has a poor prognosis for vision. S. pyogenes and S. pneumoniae infections tend to have the worst outcomes, whereas S. viridans have the best. Streptococcus species account for the majority of post-penetrating keratoplasty endophthalmitis.
●S. pneumoniae and S. viridans can cause keratitis following refractive surgery. Management of these infections may require LASIK flap amputation and/or subsequent penetrating keratoplasty.
ETIOLOGY/INCIDENCE
Streptococci are gram-positive cocci that grow in pairs or chains. Most pathogenic streptococci are facultative anaerobes. Many species of streptococci constitute the normal flora of the respiratory, gastrointestinal, and genitourinary tracts. These organisms cause disease either directly by invasion of tissues or indirectly through the elaboration of toxins.
Streptococci may be classified based on the antigenic composition of cell wall carbohydrates. To date, Lancefield serogroups A to H and K to V have been identified.
DIAGNOSIS
Clinical signs and symptoms
●S. pyogenes can cause preseptal and orbital cellulitis, conjunctivitis, suppurative keratitis, postinfectious uveitis, and endophthalmitis.
●Preseptal cellulitis usually occurs in children in the form of erysipelas, impetigo, or nonsuppurative cellulitis.
●Severe and at times life-threatening group A streptococcal infections occur, including toxic shock-like syndrome and necrotizing fasciitis.
82
●S. pneumoniae can cause preseptal and orbital cellulitis, dacryocystitis, conjunctivitis, suppurative keratitis, crystalline keratopathy and endophthalmitis.
●Group B streptococci causes conjunctivitis in neonates, keratitis, and endophthalmitis.
●They are a common cause of bleb-associated endophthalmitis.
●They are a major cause of sepsis and meningitis in neonates.
●S. viridans can cause keratitis, crystalline keratopathy and endophthalmitis.
●Enterococci can cause conjunctivitis in neonates, keratitis, crystalline keratopathy and endophthalmitis.
●Group C streptococci can cause conjunctivitis and endophthalmitis.
Laboratory findings
Infected tissues should be examined microbiologically with culture and serologic typing. Most streptococci are fastidious organisms. Sheep blood agar is especially useful, and growth is enhanced at reduced oxygen levels.
resistance is rare in the United States, viridans streptococci resistance to antibiotics is increasing. Possible resistance to penicillin should be considered when selecting empiric therapy. Vancomycin is the drug-of-choice for serious viridans streptococcal infection until susceptibility data are available. Imipenem has been shown to be highly active against viridans streptococci in vitro.
●Enterococci: penicillin alone is usually ineffective. Penicillin or vancomycin, in combination with an aminoglycoside, is the treatment of choice. Enterococci are resistant to cephalosporins. Emergence of high-level resistance to vancomycin in the US and some other parts of the world during the 1990s has severely constrained therapeutic options for management of serious infection because enterococci already possess intrinsic and acquired resistance to most other antimicrobials.
●Group C streptococci: penicillin is the drug of choice. Aminoglycosides may be synergistic in some infections. The majority of GCS and GGS strains demonstrate in vitro susceptibility to penicillins, vancomycin, erythromycin and cephalosporins.
PROPHYLAXIS
●Group B streptococcus: Identification and treatment of high-risk carrier mothers may have a role in preventing group B streptococcal infections. GBS has shown continued sensitivity to ampicillin and penicillin but increased resistance to erythromycin and clindamycin. Intravenous antibiotics should be administered during labor and until delivery for at least 4 hours. Vancomycin is reserved for GBS resistant to clindamycin and erythromycin.
●Streptococcus pneumoniae is a major cause of morbidity and mortality in infants, children and the elderly. Although, the 23-valent polysaccharide vaccine is protective in most adults and children over 5 years of age, it fails to protect children under 2 years of age. Conjugate vaccines are efficacious in preventing invasive diseases in this risk group. Unfortunately, protection is confined to a limited number of pneumococcal serotypes.
●Streptococcus pneumoniae has gradually become resistant to penicillins, macrolides and older generation fluoroquinolones. The selection of antibacterials used for treatment and prophylaxis should be based upon local resistance patterns. Penicillin resistance has risen to 80% of isolates in some parts of Asia. In the US, intermediate-level resistance of pneumococcus to penicillin was found to be 27.8% and high-level resistance was 16%. There is considerable
regional variability. In addition, high-level penicillin resistance predicts resistance to other (β)-lactams, macrolides and cotrimoxazole. Telithromycin and linezolid may prove to be potent new drugs for treating pneumococcal disease.
●S. pyogenes: penicillin has been the drug of choice. Alternative drugs include 2nd generation cephalosporins, tetracyclines, chloramphenicol, erythromycin, clindamycin, vancomycin and bacitracin. Erythromycin is the preferred agent in patients who are hypersensitive to penicillin.
●S. viridans: penicillin is the drug of choice. Alternative drugs include cephalosporins, tetracyclines, chloramphenicol, erythromycin, clindamycin, vancomycin and bacitracin. Erythromycin is the preferred agent in patients who are hypersensitive to penicillin. Although, high-level penicillin
Ocular
●Impetigo: oral penicillin or cephalexin for 10 days with topical antibiotic ointment, hot compresses and gentle debridement of skin crusts are recommended. There is no standard therapy and treatment guidelines differ widely. There is good evidence that the topical antibiotics mupirocin and fusidic acid are equal to or possibly more effective
than oral treatment. Based on the available evidence, there is no clear preference for β-lactamase resistant narrow-spec- trum penicillins such as cloxacillin, dicloxacillin and flucloxacillin, versus broad spectrum penicillins such ampicillin and amoxicillin plus clavulanic acid, cephalosporins and macrolides. Although, there is no evidence to support oral antibiotics over topical for serious and extensive forms of impetigo, oral antibiotics may be an easier option for people with very extensive impetigo.
●Preseptal cellulitis: Streptococci are now the most common organisms causing bacteremia in patients with periorbital cellulitis. In young children, S. pneumoniae is the most common organism; in older children, group A streptococcus is more likely. Adults and older children can be managed conservatively with oral antibiotics, such as penicillin or moxifloxacin for a total of 7 to 10 days. Children younger than 5 years should receive parenteral therapy regardless of the severity of infection. If the orbit or optic nerve are involved orbital imaging and aggressive intervention are required. Patients who have had recent surgery are at risk for developing endophthalmitis. Complaints of pain or a red eye indicate intraocular infection until ruled out.
●Orbital cellulitis: management requires a multispecialty team including infectious diseases, otolaryngology and ophthalmology. Patients should be examined at least daily by an ophthalmologist to assess vision and extraocular muscle function. Repeat CT scan should be obtained in 24 to 48 hours if there has been no clinical improvement. Parenteral treatment with penicillin is recommended. Patients with a large, well-defined abscess, complete ophthalmoplegia and/ or significant visual impairment should undergo surgical drainage of the abscess and sinus(es). Antimicrobial therapy for empiric treatment should to cover S. pneumoniae, Staphylococcus aureus and other Streptococcus spp. Orbital cellulitis caused by H. influenzae type b is now rare.
Streptococcus • 48 CHAPTER
83
1DiseasesSECTIONInfectious •
●Dacryocystitis: oral penicillin (or alternative) and topical antibiotics are recommended for 7 to 10 days. Dacryocystorhinostomy may be necessary to prevent recurrence.
●Conjunctivitis: treatment of bacterial conjunctivitis is often empirical and initiated before bacteriological culture. Empiric antibiotic therapy should have broad spectrum of antimicrobial activity. Topical fluoroquinolone antibiotics are widely used for the treatment of acute bacterial conjunctivitis. The newer 4th generation fluoroquinolones (moxifloxacin and gatifloxacin) exhibit improved bactericidal activity by inhibiting two essential bacterial topoisomerase enzymes, DNA gyrase (topoisomerase II) and topoisomerase IV. Topical polymyxin-trimethoprim, or neomycinpolymixin drops are alternatives. If S. pyogenes is the cause of conjunctivitis, 250 mg penicillin VK q.i.d. PO for 10 days should be considered for prophylaxis against poststreptococcal sequelae.
●Keratitis: streptococcal corneal ulceration must be treated aggressively to maintain corneal integrity. Topical cefazolin 50 mg/mL, or vancomycin 50 mg/mL should be administered at least hourly for the first 24 or 48 hours and then tapered to four times daily, based on the therapeutic response. Topical erythromycin, ciprofloxacin or bacitracin ointments may be applied nightly as the fortified antibiotic is tapered. Supplementation with subconjunctival antibiotic injections may be considered in some cases. Moxifloxacin and gatifloxacin have shown improved potency against previously fluoroquinolone-resistant strep isolates. These agents provide improved penetration into ocular tissues. Systemic therapy in keratitis is generally unnecessary unless the threat of intraocular spread, scleritis or sepsis is present. Corneal perforation or scarring may require penetrating keratoplasty.
●Post-laser refractive surgery keratitis: laser refractive surgery procedures involve breakdown of the epithelial barrier of the cornea with an inherent risk of infectious complication. Since laser in situ keratomileusis (LASIK) has become widely available, numerous cases of LASIK-associated infectious keratitis have been reported. In such cases, the corneal flap must sometimes be lifted and stromal bed cultured, irrigated or amputated in addition to aggressive topical antibiotic therapy.
●Uveitis: streptococcus-associated uveitis should be treated with topical corticosteroids and cycloplegics. Corticosteroids may be used hourly, depending on the degree of inflammation. Poststreptococcal reactive arthritis (PSRA) can occur concomitantly with uveitis.
●Endophthalmitis: streptococci are currently the second most frequent group of bacteria recovered from patients with post-cataract endophthalmitis. Streptococcal endophthalmitis is a visually devastating infection that requires prompt and aggressive therapy with topical, intravitreal, and sometimes systemic antibiotics and pars plana vitrectomy, depending on severity. At the time of vitreous tap or vitrectomy, a broad-spectrum cocktail consisting of 1 mg of vancomycin and 2.25 mg of ceftazadime is injected into the vitreous cavity. Additionally, dexamethasone may be injected. Once an organism is identified, the choice of antibiotic must be tailored to the in vitro susceptibility results. Topical cefazolin 50 mg/mL, vancomycin 50 mg/mL, or penicillin 100,000 units/mL may be applied. Systemic antibiotics such as the 4th generation fluoroquinolones, cefazolin, penicillin G and vancomycin have been used. Filtering blebs infected with streptococci usually require revision or excision.
COMMENTS
Streptococci are common causes of bacterial infection of the eye and its adnexa. Most streptococci are sensitive to the β- lactam family of antibiotics. Emerging strains of penicillinresistant organisms pose a threat to the treatment of streptococcal infections on an empiric basis. A specimen for culture and in vitro antimicrobial susceptibility testing should be obtained whenever possible. Because resistance patterns of streptococci causing ocular infections change over time, outcomes of studies dating back more than 10 years, may not be applicable to the current prevalence of infecting agents. Also, resistance between regions and countries may vary considerably. Up-to-date, local characteristics and resistance patterns of the causative bacteria should always be taken into account when choosing antibiotic treatment. Local health authorities and other relevant bodies may advise against prescribing certain antibiotics in order to restrict the development of bacterial resistance and reserve these drugs for more serious infections.
REFERENCES
Bisno AL: Group A streptococcal infections and acute rheumatic fever. N Engl J Med 325:783–793, 1991.
Bogaert D, Hermans PWM, Adrian PV, et al: Pneumococcal vaccines: an update on current strategies. Vaccine 22(17–18):2209–2220, 2004.
Givner LB: Periorbital versus orbital cellulitis. Pediatric Infect Disease J 21(12):1157–1158, 2002.
Koning S, Verhagen AP, van Suijlekom-Smit LW, et al: Interventions for impetigo. Cochrane Database of Systematic Reviews. (2):CD003261, 2004.
Kunimoto DY, Tasman W, Rapuano C, et al: Endophthalmitis after penetrating keratoplasty: microbiologic spectrum and susceptibility of isolates. Am J Ophthalmol 137(2):343–345, 2004.
Meisler DM, Langston RH, Naab TJ, et al: Infectious crystalline keratopathy. Am J Ophthalmol 97:337–343, 1984.
Neralla S, Meyer KC: Drug treatment of pneumococcal pneumonia in the elderly. Drugs & Aging 21(13):851–864, 2004.
Platt JS, O’Brien WF: Group B streptococcus: prevention of early-onset neonatal sepsis. Obstetrical & Gynecological Survey 58(3):191–196, 2003.
Schaefer F, Bruttin O, Zografos L, et al: Bacterial keratitis: a prospective clinical and microbiological study. Br J Ophthalmol 85(7):842–847, 2001.
49 TETANUS 037
(Lockjaw)
Terry D. Wood, MD
Portland, Oregon
Eric B. Suhler, MD
Portland, Oregon
Robert A. Egan, MD
Portland, Oregon
ETIOLOGY/INCIDENCE
Tetanus is an ancient malady. It was described by Hippocrates as early as the fifth century BCE. Its effects were perhaps most graphically depicted in a sketch by Charles Bell showing a 19th
84
century British soldier locked in agonizing opisthotonus. The causative organism is Clostridium tetani, a gram positive, spore-forming bacterium found in many environments, including soil and the gastrointestinal tracts of humans and many animals. C. tetani is an obligate anaerobe; as a result, it is most commonly found in places where oxygen tensions are low. This also accounts for its propensity to flourish in deep puncture wounds, especially if devitalized tissue is present. Contrary to popular belief, however, tetanus can develop in the setting of very superficial wounds, including insect bites. Parenteral drug abuse can also represent a portal of entry C. tetani.
Spore formation occurs in the presence of conditions unfavorable for vegetative growth. The spore is quite resistant to standard methods of disinfection. Spores may remain viable after treatment with chemical microbicides and can withstand boiling in water for up to an hour. This very hardy organism is able to produce infection after surviving for years in the spore form.
The clinical disease of tetanus occurs via elaboration of tetanospasmin by Clostridia tetani in the active, vegetative state. This very potent neurotoxin acts primarily at the pre-synaptic terminal of alpha motor neurons. It prevents release of the inhibitory neurotransmitters glycine and gamma aminobutyric acid (GABA). The result is sustained, uncontrolled muscular contraction. In addition to derangement of somatic muscle control, autonomic dysfunction frequently occurs due to loss of feedback inhibition at the adrenal gland. Excessive catecholamine secretion results in a hypersympathetic state that is the proximal cause of death in affected patients.
Clinical tetanus has become a rare entity in the developed world, due in large part to vaccination efforts. In the United States, the year 2002 saw only 25 reported cases. In less developed regions, however, tetanus remains a significant cause of morbidity and mortality. Worldwide, approximately one million new cases are estimated to occur each year, with upwards of 270,000 attributable deaths annually.
2.Cephalic tetanus, a rare variant, typically originates from head wounds or otitis, and is limited to cranial nerve involvement, often presenting as cranial nerve palsies. It may progress to the generalized form.
3.Local tetanus is anatomically limited to the region of the inciting wound. It may remain self-limited or progress to generalized tetanus.
●Neonatal tetanus is a significant cause of infant mortality in developing countries. It most commonly arises in the setting of inadequate care of the umbilical stump following delivery.
●Ophthalmic manifestations of tetanus.
●Blepharospasm is the most common eye finding in generalized and cephalic tetanus. It is usually bilateral. Tonic spasm may mimic ptosis.
●True ptosis may occur in the setting of a cranial nerve III palsy.
●Alignment and motility disturbances are frequently observed. These findings typically have nuclear or infranuclear origins.
●Supranuclear gaze palsies have been described.
●Downbeat nystagmus has been observed in the setting of bilateral cranial nerve IV palsy.
●Internal ophthalmoplegia may occur, usually in association with cranial nerve III dysfunction.
●Isolated accommodative paresis has been described.
DIAGNOSIS
Clinical signs and symptoms
History and clinical signs are fundamental to the diagnosis of tetanus. Diagnosis of tetanus in an individual with current vaccination status should be viewed with skepticism, as protection rates in appropriately vaccinated patients approaches 100%.
COURSE/PROGNOSIS |
Laboratory findings |
Laboratory studies are of little value in the diagnosis, as clos- |
|
|
tridia can often be found in non-disease states, and conversely, |
|
●The incubation period for C. tetani ranges from 3 to 21 days. culturing C. tetani in known cases of clinical tetanus is often
The time of onset for symptoms is directly related to the distance from the original wound to the central nervous system.
●Tetanospasmin is elaborated within the wound and travels in retrograde fashion along neurons.
●Tetanospasmin passes across synaptic clefts to invade connecting neurons.
●Although spinal inhibitory neurons are most affected, acetylcholine release may also be inhibited, causing muscle paralysis rather than spasm.
●Trismus is the classic early finding.
●Increased tone in masseter muscle group causes ‘lockjaw.’
●Facial muscle spasm progresses, leading to risus sardonicus or ‘fixed grin.’
●Dysphagia and laryngospasm occur commonly.
●Tetanus is classically divided into one of three forms, depending upon predominant clinical presentation.
1.Generalized tetanus, occurring most commonly, represents a descending pattern. Trismus is followed by nuchal rigidity, dysphagia, then rigidity of the abdominal muscles. Hyperthermia (two to four degrees Celsius above normal), hypertension, tachycardia, and diaphoresis are commonly observed.
impossible. Cerebrospinal fluid is typically normal in tetanus.
Differential diagnosis
A broad and etiologically diverse differential diagnosis should be considered when evaluating potential tetanus.
●Strychnine poisoning.
●Black widow spider bite.
●Alcohol or narcotic withdrawl.
●Dystonic phenothiazine reaction.
●Rabies.
●Meningitis.
●Subarachnoid hemorrhage.
●Seizures.
●Hypocalcemic tetani.
PREVENTION
Appropriate vaccination is the cornerstone of prophylaxis. This is accomplished via subcutaneous injection of tetanus toxoid (inactivated tetanospasmin). Current recommendations call for a series of four injections as part of a childhood vaccination regimen. Tetanus toxoid is usually co-administered with diph-
Tetanus • 49 CHAPTER
85
1DiseasesSECTIONInfectious •
theria and acellular pertussis vaccine. Boosters are recommended at 10 year intervals. It should be noted that a prior episode of tetanus does not confer immunity. This is because the very potent nature of tetanospasmin (lethal dose: 2.5 ng/kg of body weight) typically means that levels are too small to produce an adequate immune response.
Nearly any wound can potentially lead to tetanus. Wounds that are deeper than one centimeter, involve environmental contamination, or have extensively de-vitalized tissue are particularly at risk. Wounds that have not been cleaned within six hours of injury represent additional risk.
Ocular wounds that involve corneal or scleral penetration or perforation are considered to be tetanus-prone. Signs of endophthalmitis should prompt consideration of tetanus. Eyelid and periorbital injuries should be treated as having a tetanus risk equivalent to similar non-ocular injuries. Simple corneal abrasions are not associated with increased risk of tetanus.
TREATMENT
Treatment begins with proper wound management. Wounds should be cleaned in a fashion appropriate to type and location. Devitalized tissue should be debrided. Wounds should be examined carefully for foreign bodies; if present, they should be removed. Depending on immune status, administration of tetanus toxoid vaccine following injury may be part of the treatment algorithm. This does not, however, provide protection against the development of tetanus in the setting of acute injury, as development of vaccine mediated immunity is far slower than the development of disease.
In the setting of clinical tetanus, the mainstay of therapy is Tetanus Immune Globulin (TIG). TIG is given intramuscularly, but should not be administered at the same site as a recent tetanus toxoid injection. TIG is very effective at neutralizing free tetanospasmin, can only neutralize toxin that has not yet entered the nervous system. Unlike tetanospasmin, it is unable to cross the blood–brain barrier and cannot enter a neuron. There does not appear to be any advantage to administering TIG at the wound site. Intrathecal administration is advocated by some clinicians, but its superiority over the intramuscular route is debated.
Antibiotic control of infection is, however, an important part of treatment of tetanus. Penicillin has historically been considered the first line agent against C. tetani, but metronidazole shows similar efficacy.
Long term supportive measures are frequently required for the tetanus patient. Depending on area and degree of involvement, ventilatory support may be needed. Medical treatment of associated conditions, especially autonomic dysfunction, is complex and often requires admission to an intensive care unit. Benzodiazepines can increase release of GABA and reduce muscle spasm. Neuromuscular blockade can be achieved with several agents, such as pancuronium bromide. Beta blockers and alpha-2 agonists may be used to address the hyper-sympa- thetic state and autonomic instability that is a frequent cause of death in tetanus patients.
REFERENCES
Abrahamian FM: Management of tetanus: a review. current treatment options in infectious disease. 3:209–216, 2001.
Biglan AW, Ellis FD, Wade TA: Supranuclear oculomotor palsy and exotropia after tetanus. Am J Ophthalmol 86(5):666–668, 1978.
De Barros Miranda-Filho D, Arraes de Alencar Ximenes R, Barone AA, et al: Randomized controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ 328(7440):615. 2004.
Meienberg O, Burgunder JM: Sacchadic eye movement disorder in cephalic tetanus. Europ Neurol 24(3):182–190, 1985.
Orwitz JI, Galetta SL, Teener JW: Bilateral trochlear nerve palsy and downbeat nystagmus in a patient with cephalic tetanus. Neurology 49(3):894– 895, 1997.
Purvin VA: Bacterial diseases. Bacterial diseases. In: Walsh and Hoyt’s clinical neuro-ophthalmology. 5th edn. Baltimore, Williams and Wilkins, 1998:IV:4109–4117.
50 TRACHOMA 076
Anthony W. Solomon, MBBS, PhD
London, England
David C. W. Mabey, DM, FRCP
London, England
Allen Foster, OBE, FRCS
London, England
ETIOLOGY/PREVALENCE
Trachoma is caused by serovars A, B, Ba and C of the obligate intracellular bacterium Chlamydia trachomatis. These serovars have a predilection for conjunctival and nasopharyngeal epithelium. Infection is passed from person to person by eye-seeking flies, by direct contact with infected secretions on fingers and fomites (such as bed sheets and shared cloths), and possibly by droplet spread.
Trachoma is endemic in 55 countries in Africa, Asia, the Middle East, Latin America, and Australia. An estimated 84 million people worldwide have active trachoma, and some 1.3 million are blind from the disease, making it the leading cause of infectious blindness. Trachoma is found in communities where access to water, sanitation and medical care are inadequate and personal and environmental hygiene are poor. Such communities are generally located in hot, dry, remote areas.
Conjunctival C. trachomatis infection and the associated clinical signs of active trachoma are most common in preschool children. In adults, the prevalence of infection and active disease is usually higher in women than in men, perhaps because women usually take primary responsibility for child care and are therefore more frequently exposed to infection. The complications of trachoma leading to visual loss and blindness are seen more commonly with advancing age, with several times increased risk for women.
COURSE/PROGNOSIS
The clinical course is not strictly linear. Manifestations can be classified as being either acute (active) or late-stage (cicatricial), but multiple episodes of active trachoma are required for later development of cicatricial disease, and active and cicatricial signs can occur at the same time in the same individual.
After an incubation period of 5–10 days, conjunctival C. trachomatis infection may be marked by injection of conjunctival vessels and production of scant mucopurulent exudate. After
86
several weeks, the more specific signs of active trachoma may appear. Though these are signs of acute disease, they represent
achronic inflammatory process:
●Development of subepithelial follicles subjacent to the conjunctiva of the tarsal plates (Figure 50.1b), the fornices, and the limbus;
●Papillary hypertrophy (Figure 50.1c); and
●Thickening of the conjunctiva (Figure 50.1c).
Pannus (in-growing vessels) on the superior cornea can be associated with active disease, but rarely progresses to impair vision. A superficial punctate keratitis may also be noted. Repeated or prolonged episodes of severe active trachoma over many months constitute a risk factor for later development of cicatricial disease.
Inflammation results in deposition of conjunctival scar. With repeated infection over many years, accumulated scar may become visible in the everted conjunctivae (Figure 50.1d). In some individuals, contraction of scar eventually causes individual lashes or the whole upper eyelid to turn inwards, producing trichiasis (Figure 50.1e) and/or entropion. Corneal abrasion and opacification (Figure 50.1f) may ensue. Direct corneal damage from misdirected lashes is compounded by secondary bacterial and fungal infections of the cornea, and corneal drying due to trachomatous scarring of lacrimal and Meibomian glands.
DIAGNOSIS
Clinical signs and symptoms
Active trachoma is generally asymptomatic or mildly irritating. Trichiasis may be symptomatic, with the degree of discomfort dependant on the number of lashes touching the globe, the position of those lashes, and the presence or absence of blepharospasm and the other complications described above.
Examination requires use of binocular magnifying loupes (×2.5) and sunlight or strong torchlight. The eyelashes and cornea should be carefully inspected, and the upper lid everted to allow inspection of the tarsal conjunctivae, one eye at a time. Signs of interest are described above.
Laboratory findings
In most endemic areas, because laboratory tests are expensive and often unavailable, diagnosis relies on the clinical appearance. Laboratory confirmation of C. trachomatis conjunctival infection is possible using a commercial polymerase chain reaction (PCR)-based assay, which has high sensitivity and specificity. Various other assays are available, but all are less sensitive than PCR.
Grading
The WHO simplified trachoma grading system is widely used for research and programme monitoring purposes. The system includes five signs (Figure 50.1):
●Trachomatous inflammation — follicular (TF): the presence of five or more follicles at least 0.5 mm in diameter in the central part of the upper tarsal conjunctiva;
●Trachomatous inflammation — intense (TI): pronounced inflammatory thickening of the upper tarsal conjunctiva obscuring more than half the normal deep tarsal vessels;
●Trachomatous scarring (TS): the presence of easily visible scars in the tarsal conjunctiva;
●Trachomatous trichiasis (TT): at least one eyelash rubs on the eyeball, or evidence of recent removal of in-turned eyelashes;
●Corneal opacity (CO): easily visible corneal opacity over the pupil, so dense that at least part of the pupil margin is blurred when viewed through the opacity.
The presence or absence of each sign should be independently determined for each person examined. In the WHO system, the presence of TF and/or TI in one eye is necessary and sufficient to confer a diagnosis of active trachoma.
PREVENTION AND CONTROL
Because corneal grafting is difficult in (and generally unavailable to) patients with trachomatous corneal opacity, blindness from trachoma is difficult to cure. It is, however, possible to prevent:
●Primary prevention occurs through provision of adequate water and hygiene facilities combined with education to promote facial cleanliness and the use of hygiene facilities;
●Secondary prevention occurs through antibiotic treatment to clear ocular C. trachomatis infection;
●Tertiary prevention occurs through trichiasis surgery for individuals with trichiasis.
These activities are represented by the acronym SAFE: surgery for trichiasis, antibiotics to clear infection, and face washing and environmental improvement to reduce transmission. The SAFE strategy is endorsed by WHO, and involves much more than treatment of symptomatic individuals presenting to medical facilities: it is a comprehensive package of interventions delivered at the community level, requiring the coordination and cooperation of organizations from multiple sectors. Using this strategy, WHO and its partners aim to eliminate trachoma as a cause of blindness by the year 2020.
Differential diagnosis
The differential diagnosis of active trachoma includes:
●Bacterial conjunctivitis;
●Adult inclusion conjunctivitis (caused by infection by genital serovars of C. trachomatis);
●Viral conjunctivitis;
●Allergic conjunctivitis; and
Surgery
Individuals with trichiasis/entropion need corrective surgery. The recommended procedure is bilamellar tarsal rotation. This involves full-thickness division of the upper lid and external rotation of the margin using three sutures. It can be performed by trained eye nurses or other paramedical staff. Correction of trichiasis halts progression of visual loss; it may also margin-
●Toxic follicular conjunctivitis secondary to topical medicaally improve existing vision by reducing corneal oedema. Case
tions or cosmetics. |
identification is labor-intensive. Having identified people who |
|
need it, surgery should be offered within the village or at a |
In areas where trachoma is endemic, pannus, conjunctival scar- |
nearby health facility, at low or no cost to the patient. After |
ring, and trichiasis are nearly always attributable to trachoma. |
surgery, patients remain at risk for recurrence and require long- |
Corneal opacity, however, has many possible aetiologies. |
term intermittent follow-up. |
Trachoma • 50 CHAPTER
87
1DiseasesSECTIONInfectious •
a |
d |
b |
e |
c |
f |
FIGURE 50.1. The WHO simplified system. a) Normal conjunctiva, showing area to be examined. b) TF. c) TI (and TF). d) TS. e) TT. f) CO. (© World Health Organization. Reproduced with permission.)
Antibiotics
Two antibiotic regimens are recommended for trachoma: 6 weeks of twice-daily 1% tetracycline eye ointment, or a single oral dose of azithromycin 20 mg/kg body weight, to a maximum of 1 g. Azithromycin is expensive if not donated, but is easy to administer, well tolerated and allows monitoring of compliance by direct observation of treatment. Tetracycline ointment is inexpensive, but stings on application and requires a prolonged course: compliance in the community is thought to be poor. In
88
areas where the prevalence of TF in 1–9-year-old children is 10% or more, WHO currently recommends annual mass antibiotic treatment of the entire community. Where the prevalence of TF in 1–9-year-old children is 5% or more but <10%, family treatment (identification and treatment of families in which there are one or more members with TF or TI) should be considered. Where the prevalence of TF in 1–9-year-old children is <5%, community-based antibiotic treatment is not recommended.
Facial cleanliness
Facial cleanliness in children should reduce active trachoma prevalence, probably by reducing transmission of C. trachomatis by eye-seeking flies. However, changing personal hygiene habits is difficult, particularly in water-insecure communities.
Environmental improvement
Once highly endemic in Europe and North America, trachoma disappeared from those continents in the early twentieth century, as living standards improved. Socioeconomic development takes decades; in the interim, specific interventions to reduce transmission of ocular C. trachomatis have been suggested, including improving access to water, and control of flies (specifically Musca sorbens) through provision of latrines or spraying of residual insecticide. Proof of the effectiveness of sustainable environment-improving interventions is still awaited.
REFERENCES
Emerson PM, Lindsay SW, Alexander N, et al: Role of flies and provision of latrines in trachoma control: cluster-randomised controlled trial. Lancet 363:1093–1098, 2004.
Emerson PM, Lindsay SW, Walraven GE, et al: Effect of fly control on trachoma and diarrhoea. Lancet 353:1401–1403, 1999.
Mabey DC, Solomon AW, Foster A: Trachoma. Lancet 362:223–229,
2003.
Reacher M, Foster A, Huber J, Bauer B: Trichiasis surgery for trachoma: the bilamellar tarsal rotation procedure (WHO/PBL/93.29). Geneva, World Health Organization, 1993.
Schachter J, West SK, Mabey D, et al: Azithromycin in control of trachoma. Lancet 354:630–635, 1999.
Solomon AW, Holland MJ, Alexander ND, et al: Mass treatment with single-dose azithromycin for trachoma. N Engl J Med 351:1962–1971, 2004.
Solomon AW, Holland MJ, Burton MJ, et al: Strategies for control of trachoma: observational study with quantitative PCR. Lancet 362:198– 204, 2003.
Solomon AW, Peeling RW, Foster A, Mabey DC: Diagnosis and assessment of trachoma. Clin Microbiol Rev 17:982–1011, 2004.
Thylefors B, Dawson CR, Jones BR, et al: A simple system for the assessment of trachoma and its complications. Bull World Health Organ 65:477–483, 1987.
West SK, Munoz B, Lynch M, et al: Impact of face-washing on trachoma in Kongwa, Tanzania. Lancet 345:155–158, 1995.
51 TUBERCULOSIS 010.0
Dieudonne Kaimbo Wa Kaimbo, MD, PhD
Kinshasa, Democratic Republic of Congo
Tuberculosis is an acute or chronic communicable disease caused by the acid-fast bacterium Mycobacterium tuberculosis, which most commonly involves the lungs but may affect virtually any organ or tissue in the body. Tuberculosis is a leading cause of mortality and morbidity worldwide. Ocular tuberculosis can show a variety of different clinical presentations ranging from an amelanotic choroidal mass to panophthalmitis. It can simulate ocular neoplasms. A high degree of clinical suspicion is important in suspecting and managing this condition. Late diagnosis and delay in management can result in loss of the eye and can even be life-threatening.
ETIOLOGY/INCIDENCE
The tubercle bacilli can gain entrance to the body by several routes. The only one of practical importance is the respiratory tract. Tuberculosis is transmitted by airborne particles that are 1 to 5 μm in diameter, the Mycobacterium tuberculosis spreads by droplet infection from coughing or sneezing; the organisms spread from the lungs to regional lymph nodes, producing lymphadenitis. Subsequently, lymphatic drainage delivers the tubercle bacilli to the systemic circulation, whence it has the potential to spread to all organs of the body. During this primary phase of tuberculosis the infection is usually subclinical; the likehood that the disease is radiographically or clinically apparent is approximately 5%.
The most common outcome for the initial infection with Mycobacterium tuberculosis is healing with granuloma formation; this occurs over a period of months and is for most people accompanied by the development of tuberculin skin test reactivity. Generally, the granulomas remain stable, and frequently they calcify. In a minority of cases (5 to 15%), occasionally, the granulomas break down; tubercle bacilli multiply and disperse, producing systemic disease. Active tuberculosis is defined as tissue invasion by Mycobacterium tuberculosis bacilli that may progress to produce signs and symptoms. Approximately 5% of infected patients may develop a progressive primary disease and an additional 5% may reactivate in future years. Although the majority of cases of active tuberculosis are thought to arise from a reactivation of latent infection, exogenous reinfection with a second strain of Mycobacteriim can occur, particularly in profoundly immunocompromised persons and in those heavily exposed to new bacilli.
According to the World Health Organization, it is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis, with an annual incidence approaching 8.7 million. There are remarkable geographic variations in the distribution of tuberculosis and 22 countries, including India, China, Indonesia, Bangladesh, Pakistan, Nigeria, Philippines and South Africa, have been identified as contributing 80% of the world’s total burden of tuberculosis. In the United States, the prevalence of tuberculosis has been rising after decades of decline.
Although the lung is the primary site of disease in 80 to 84% of cases of tuberculosis, extrapulmonary tuberculosis has become more common with the extent of HIV infection, and the risk of tuberculosis increases as immunosuppression progresses. The most commonly reported extrapulmonoray sites of disease are the lymph nodes, pleura and bones or joints. Other sites include the genitourinary system, the central nervous system, the abdomen and pericardium, and in rare cases, virtually any other organ. The incidence of ophthalmic manifestations is approximately 1 to 2%. Ocular and periocular involvement may occur as a consequence of active infection from hematogenous or contiguous spread of viable bacilli or as a local manifestation of an allergic or hypersensitivity reaction to circulating tuberculoproteins.
DIAGNOSIS
Clinical signs and symptoms
Ocular
●Tuberculosis of the eyelids may present as a localized nodule or an abscess simulating chalazion. Lupus vulgaris, a progressive form of cutaneous tuberculosis, can involve the
Tuberculosis • 51 CHAPTER
89
1DiseasesSECTIONInfectious •
lids, the lacrimal sac area, and the conjunctiva. Association with systemic tuberculosis occurs in 9 to 19% of patients, and biopsy should be performed to confirm the diagnosis. Tuberculous dacryocystitis is a rare secondary cause of nasolacrimal duct obstruction. Conjunctival involvement may be bilateral and may present as a swelling or painless infiltration responsible for a red eye. Phlyctenulosis, a rare and uncommon presentation, is a localized hypersensitivity reaction to antigens of Mycobacterium tuberculosis. A nodule is formed at the limbus and occurs more frequently in children with malnutrition. Phlyctenules may occur on the conjunctiva, but are more frequently observed at the limbus. Phlyctenulosis may be associated with lymph node enlargement of the neck and responds promptly to topical application of steroids. Primary tuberculosis of nasolacrimal mucosa may occur without any symptoms. Therefore, pathologic examination and PCR have been used to confirm the presence of Mycobacterium tuberculosis. The cornea may be involved during tuberculosis or nontuberculous mycobacterial infections. Interstitial keratitis is rare but usually unilateral and painless. It may occur as isolated finding or in association with scleritis. Nontuberculous mycobacteria are the most frequently reported agents causing keratitis (M. kansasii, M. fortuitum, and M. chelonei). Interstitial keratitis secondary to tuberculosis may be associated with uveitis. Tuberculosis is a rare, but classic, cause of scleritis, which is usually anterior and necrotizing, associated with scleral ulceration. Scleral perforation may occur if patients are not treated. Lacrimal gland involvement by the Mycobacterium tuberculosis leads to localized granuloma.
●Orbital infection is uncommon; it represents as a lid abscess or a soft tissue mass causing proptosis and resulting from tuberculous periostitis or/and preseptal cellulitis, often with fever, lymphadenopathy, ophthalmoplegia, cutaneous fistula. It may result from either hematogenous spread or from adjacent structures such as the paranasal sinuses or lacrimal gland. The clinical presentation can include panophthalmitis.
Intraocular
●Uveitis is usually granulomatous, with mutton-fat keratic precipitates, iris granulomas, and posterior synechiae. Vitritis can be associated with vasculitis, retinal vein occlusion with subsequent retinal ischemia, and macular edema. Anterior uveitis secondary to tuberculosis is characterized by mutton-fat keratic precipitates. The iris shows both Koeppe and Busacca nodules. Posterior synechiae occur in patients with chronic uveitis and may cause posterior adhesions to the anterior lens capsule, which may cause papillary block angle closure glaucoma. The lens may become cataractous, and the anterior vitreous shows evidence of vitritis secondary to involvement of the ciliary body.
●Ciliary body masses respond very slowly to treatment and may cause secondary angle-closure glaucoma. This can mimic a tumor but can be differentiated on B-scan, which will show variable internal reflectivity consistent with an inflammatory process.
●Solitary or multiple iris nodules can occur.
●Multifocal choroiditis with one to five lesions varying in size from 0.3 to 4.0 mm appear mainly in the posterior pole. The choroidal tubercles are yellow to gray-white. Retinal tuberculosis is rare, but a periphlebitis due to direct infection, a hypersensitivity reaction, or both may occur.
However, it is more common for the retinal blood vessels to be normal. On fluorescein angiography, the choroidal tubercles are initially hypofluorescent and then show a late hyperfluorescence that increases in size. After treatment, a chorioretinal scar will remain and may occur with or without a subretinal neovascular membrane. The scars are hyperfluorescent and have sharp margins.
●Solitary choroidal tuberculoma as solitary elevated masslike lesion (4 to 14 mm in size) may be present. The lesion results from a progressive, liquefied caseation necrosis with rapid multiplication of tubercular bacilli and tissue destruction.
●Endophtalmitis may be present as acute onset endogenous endphthalmitis due to rapidly progressive disease, which does not respond to antitubercular therapy. In young children, clinically the endophthalmitis may simulate retinoblastoma.
●Tubercular neuroretinitis is usually seen as a retrobulbar optic neuritis complicating meningitis.
Systemic
●Central nervous system involvement can encompass meningoencephalitis, spinal column disease, and intracranial tuberculomas. Isolated brain stem tuberculomas can be present in association with ocular involvement.
Laboratory findings
●Cultures of sputum, urine, or feces are most commonly done, but any sterile body fluid, including aqueous and vitreous fluids, can be cultured if thought to be infected. Sputum collection exhibits a higher yield of positive cultures than bronchoalveolar lavage or biopsy. Microscopic examination and smear of any fluid for acid-fast bacilli can be done but are much less sensitive than culture. Cultures should be done on both liquid albumin and solid media (Lowenstein– Jenson/egg and Middlebrook/agar base) and kept for a minimum of 8 weeks. A DNA fingerprint pattern of the suspicious isolate can be compared with other laboratory isolates and, if they are identical, the isolate is readily identified as a false-positive result.
●Fine needle aspirate or biopsy with culture is most frequently done on lymph nodes, bone marrow, or liver, (i.e. extrapulmonary tuberculosis).
●Polymerase chain reaction is sensitive for pulmonary infection (89%) but is somewhat less sensitive (42%) for nonpulmonary infections. Clinical trials for an automated Q-beta replicase amplification assay for mycobacteria are being carried out, and so far they have been positive in 69% of smear-negative, culture-positive samples; the specificity is 97%.
●Blood-soluble antigen fluorescent antibody and enzymelinked immunosorbent assay can be used to detect systemic mycobacterial antigens (even with ocular involvement) as well as antibodies in the aqueous and vitreous fluids.
●The degree of tuberculin test reactivity can correlate to the likelihood of infection in immunocompetent patients, but even 5 mm of reactivity is significant in immunocompromised patients. The bacille Calmette–Guérin (BCG) vaccination can also serve as a test; reactivity within 3 days of vaccination is considered evidence of prior infection.
Differential diagnosis
Establishing the diagnosis of ocular tuberculosis can be challenging because presentations can be varied and similar to
90
other conditions that are often difficult to confirm except with tissue or culture. Tuberculous uveitis must be differentiated from other granulomatous infections such as sarcoidosis, brucellosis, leprosy, cat-scratch disease, syphilis, toxoplasmosis, and fungal infection. Choroidal tubercles can resemble metastatic foci from breast, lung, prostate, and other primary sites.
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) has been associated with several agents, including pulmonary tuberculosis. The typical lesions of APMPPE were multiple flat, gray-white lesions of the retinal pigment epithelium occurring posterior to the equator. A granulomatous anterior uveitis with mutton-fat precipitates and Koeppe’s nodules has also been associated with APMPPE.
drugs for adults include amikacin, ciprofloxacin, clofazimin, cycloserin A, ethionamide, ofloxacin, and rifabutin. The Centers for Disease Control recommends that all tuberculosis patients be observed taking their medication by healthcare providers (direct observed therapy, DOT).
The treatment period for immunocompromised patients is extended to 6 months after negative cultures first appear.
Surgical
A tissue biopsy can be considered if diagnosis cannot be established any other way. Procedures for secondary glaucoma may be necessary for patients with ciliary body tuberculosis because the masses respond slowly to medical therapy. Cataract surgery can be performed in patients with complicated cataract and quiet eyes.
PROPHYLAXIS
An efficacious and safe vaccine is not available. BCG vaccination causes tuberculin skin test conversion, but the duration of hypersensitivity varies, and the size of induration fades with time. The BCG vaccine is also more effective at preventing disseminated disease in children than in preventing pulmonary disease in adults. BCG causes disseminated infection in patients with symptomatic human immunodeficiency virus infection or AIDS; BCG also is not recommended for health care workers exposed to multiple-drug-resistant tuberculosis.
TREATMENT
Topical
Topical isoniazid and streptomycin can be used to enhance the systemic treatment of external and anterior segment lesions. Topical corticosteroids and mydriatric agents can also be useful in tuberculous uveitis and should be used while systemic antimycobacterial treatment is under way. Nontuberculous mycobacterial keratitis, especially M. fortuitum, is responsive to topical ciprofloxacin; amikacin is less effective.
Systemic
Treatment of tuberculosis has changed over the past decades. For the patient with documented systemic tuberculosis, medical therapy should be administered by an internist or specialist in infectious diseases. A course of 4-drug combination chemotherapy (isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin) for a period of 6 months has been advocated for systemic tuberculosis. Similar therapy is recommended for active ocular tuberculosis. Resolution of the ocular condition depends on treatment of the underlying disease. The initial phase of treatment lasts for 2 months and is followed, depending upon the circumstances, by a 4–7 month continuation phase to complete therapy. Ethambutol is usually discontinued 2 months after the initiation of therapy, and the remaining 3 drugs can be continued for 4 months. This drug regimen has been found to be as effective as standard 9-month course. In adults, the dosage for isoniazid is 300 mg orally per day (10 to 15 mg/kg/d, maximum dose of 300 mg/kg/d), rifampin 600 mg orally per day (10 to 20 mg/kg/d, maximum dose of 600 mg/kg/d), pyrazinamide 2 g orally per day (15 to 30 mg/kg, maximum dose of 2 g/d in children), and ethambutol 800 mg orally per day (15 to 25 mg/kg/d, maximum dose of 2.5 g); pyridoxine 50 mg orally per day (15 to 30 mg/kg/day in children) should be given to prevent isoniazid neurotoxicity. Alternative
COMPLICATIONS
General considerations
The incidence of adverse hepatic reactions is greater when rifampin is combined with isoniazid, but it is not statistically significant; the therapeutic response rate is much better with combination treatment. The threat of optic neuritis and optic atrophy resulting from the use of isoniazid, rifampin, and ethambutol mandates color vision monitoring while these agents are being used. Pattern-reversal visual evoked potentials may detect an early prolongation of the P100 wave secondary to these agents before clinical signs appear.
Specific drug considerations
Isoniazid
A hypersensitivity reaction can occur. Hepatotoxicity, peripheral neuropathy and CNS effects also are possible. Overdose may be fatal. Drug interactions include coumadin, benzodiazepines, theophylline, phenytoin, alcohol, disulfiram and alumi- num-containing antacids.
Rifampin
Causes orange-pink discoloration of body fluids, secretions (urines, sweat, tears, etc.) and contact lenses. Antacids may reduce the absorption of rifampicin. Hypersensitivity reactions can occur, as well as hematologic abnormalities such as anemia, thrombocytopenia, leucopenia, hepatotoxicity and influenzalike syndrome. Drug inhibits effects of warfarin, corticosteroids, oral contraceptives, theophylline, dapsone, ketoconazole, protease inhibitors and nonnucleoside reverse-transcriptase inhibitors, digoxin diazepam, quinidine, methadone and oral hypoglycemic agents.
Pyrazinamide
Reactions include hepatitis, hyperuricemia, nausea, vomiting and drug fever. It can cause thrombocytopenia and sideroblastic anemia; mild arthralgias.
Ethambutol
An optic neuritis and retinal ganglion cell toxicity are the most common and serious side effects, but skin rash and hyperuricemia can also occur. It decreases red-green discrimination and visual acuity.
Streptomycin
Ototoxicity (vestibular and auditory) is the most common and serious side effect. Neuromuscular blockage can occur. Renal
Tuberculosis • 51 CHAPTER
91
1DiseasesSECTIONInfectious •
toxicity and hypersensitivity with skin rash and fever are uncommon. The drug potentiates the action of neuromuscular blocking agents.
Rifabutin
The most common side effect is hepatotoxicity; other complications include hypopyon iritis, fever, flushing pruritus, intestinal nephritis, rash, orange-colored body fluids, neutropenia and rarely thrombocytopenia. This orange staining in the tear film can permanently color soft contact lenses.
Miscellaneous
Drug resistance should be considered if there are any of the following:
●Treatment failure;
●Poorly compliant patient;
●Contact with known resistant strains of tuberculosis;
●Large inoculum;
●Positive cultures after 3 months of therapy.
REFERENCES
Biswas J, Shome D: Choroidal tubercles in disseminated tuberculosis diagnosed by the polymerase chain reaction of aqueous humor. Ocul Immunol Inflamm 10:293–298, 2002.
Bodaghi B, LeHoang P: Ocular tuberculosis. Curr Opin Ophthalmol 11:443–448, 2000.
Demirci H, Shields CL, Shields JA, Eagle RC: Ocular tuberculosis masquerading as ocular tumors. Surv Ophthalmol 49:78–89, 2004.
Gupta A, Gupta V: Tubercular posterior uveitis. Int Ophthalmol Clin 45:71–88, 2005.
Myers JP: New recommendations for the treatment of tuberculosis. Curr Opin Infect Dis 18:133–140, 2005.
Small PM, Fujiwara PI: Management of tuberculosis in the United States. N Engl J Med 345:189–200, 2001.
Tabbara KF: Ocular tuberculosis: anterior segment. Int Ophthalmol Clin 45:57–69, 2005.
Torres RM, Calonge M: Macular edema as the only ocular finding of tuberculosis. Am J Ophthalmol 138:1048–1049, 2004.
52 TYPHOID FEVER 002.0
(Enteric Fever)
Theodore H. Curtis, MD
Portland, Oregon
David T. Wheeler, MD
Portland, Oregon
ETIOLOGY/INCIDENCE
Typhoid fever is an acute febrile illness caused by the ingestion of and intestinal invasion by Salmonella enterica serotype typhi, a gram-negative bacillus found only in humans. Prevalent in those regions of the world lacking in sanitary water and sewage systems, its transmission can occur through ingestion of contaminated food or water, contact with an acute case of
typhoid fever, or contact with an asymptomatic carrier. Adults and children of all ages and both genders appear equally susceptible to infection. Transmission through direct fecal-oral contact is more common among children.
Sustained fever, abdominal pain or other manifestations of gastroenteritis, and non-specific symptoms such as headache, chills, diaphoresis, anorexia, cough, sore throat, dizziness and myalgias characterize typhoid fever. The onset is usually gradual and, without antibiotics, the illness achieves maximum severity during the second or third week with marked weakness, abdominal discomfort and distension, skin rash (rose spots), cervical adenopathy, hepatosplenomegaly, and occasional neuropsychiatric manifestations such as delirium or seizures. Recovery, characterized by declining fever, begins by the end of the third or fourth week. The most prominent major complications are intestinal hemorrhage and perforation, which can occur during the third week and is often heralded by a sudden drop in temperature and increased pulse.
Ocular manifestations of typhoid fever are rare and may include lid edema or abscess, dacryoadenitis, conjunctival petechiae or chemosis, corneal ulceration, uveitis, vitreous hemorrhage, retinal hemorrhage and detachment, stellate maculopathy, pigmentary retinopathy, optic neuritis, internal or external ophthalmoplegia, and orbital hemorrhage or abscess. These complications are probably a result of direct invasion by the organism into ocular tissues, but some may be hypersensitivity phenomena, such as vitreous hemorrhage reported after first generation typhoid vaccination.
COURSE/PROGNOSIS
Following penetration of intestinal mucosa, S. enterica typhi replicate in mononuclear phagocytes of ileal Peyer’s patches and mesenteric lymph nodes. After incubation of 1 to 3 weeks, hematogenous spread occurs to spleen, liver and bone marrow where further replication takes place. Bacteremia and humoral mediators are responsible for fever and other non-specific symptoms of illness. A relative bradycardia (given the degree of fever) occurs in up to 50% of patients. Rose spots can occur on the trunk, consisting of erythematous maculopapules 1 to 5 mm in diameter, which initially blanch with pressure but may become hemorrhagic. Altered mental status out of proportion to systemic illness may occur; seizures are more common in children. Intestinal manifestations are caused by hyperplasia of Peyer’s patches with ulceration of overlying mucosa resulting in pain, diarrhea, bleeding or perforation. Without antibiotic therapy, fever and most symptoms resolve by the fourth week of infection in approximately 90% of individuals who survive.
Typhoid fever carried a case fatality rate of 15% in the preantibiotic era. Mortality was reduced to 2% after chloramphenicol became available. Case fatality rates >10% continue to be reported in developing countries despite availability of antibiotics, whereas developed countries show case fatality rates <1%. With antibiotic treatment, most patients become afebrile within 4 to 7 days. There is a 10% relapse rate.
Around 3% of patients develop a chronic carrier state after recovery; this rate is higher in women and older men and is associated with biliary abnormalities. Most carriers are asymptomatic and up to 25% have no history of typhoid, making identification difficult.
92
DIAGNOSIS
Laboratory findings
●Isolation of S. enterica typhi from blood culture is most likely in the first two weeks of illness but is positive in only 50% to 70% of cases.
●Stool cultures are positive less frequently but may increase the diagnostic yield; other sources include urine, rose spots and gastric or intestinal secretions.
●Bone marrow culture is the most sensitive (positive in nearly 90% of cases) and can be used when diagnosis is crucial or following antibiotic treatment.
●The time-honored Widal test for agglutinating antibodies to H or O antigen is of limited value; recent agglutination tests to Vi antigen are more sensitive and specific. PCR to this antigen has been developed but is not commercially available.
●Anemia, thrombocytopenia, and relative neutropenia of variable severity may be present.
●Liver function tests may show elevated aminotransferases and bilirubin.
●Renal failure is an infrequent complication.
Differential diagnosis
●In travelers returning from developing countries, infections such as hepatitis, malaria, typhus, amoebiasis, shigellosis, visceral leishmaniasis, Dengue fever, or leptospirosis should be considered.
●In non-travelers, infections associated with prolonged fever such as the rickettsioses, brucellosis, tularemia, miliary tuberculosis, bacterial endocarditis, infectious mononucleosis, cytomegalovirus infections, influenza, or meningococcemia must be ruled out.
●Non-infectious causes of fever (such as lymphoma or connective tissue disease) should be considered.
●Ocular manifestations are rare and will generally only be seen in the setting of systemic illness.
PROPHYLAXIS
Improvement of environmental sanitation, including water supplies and sewage disposal, sharply reduces the incidence of typhoid fever. Travelers to developing countries should avoid consuming untreated water, drinks served with ice, peeled fruits, and other food not served hot as the organism is resistant to drying and cooling. American international travelers face an overall risk of developing typhoid fever of <1 case in 10,000 trips but this increases to 4 in 10,000 with travel to high-risk countries. Immunization is at best an adjunct to typhoid avoidance because of limited vaccine efficacy.
The traditional heat-killed, phenol-extracted whole typhoid vaccine is no longer recommended because of its limited efficacy, short duration of protection, and the high frequency of local reactions and fever. Children over 6 years of age and adults can receive three doses of a first-generation live oral vaccine (Ty21a) that is invasive but metabolically defective, so dies after a few cycles of replication. This vaccine is safe, provides as much protection as the killed vaccine (42% to 67%), and continues to be protective for at least several years. One parenteral dose of purified Vi polysaccharide vaccine has proved as effective (55% to 77%) and long-lasting as multiple doses of Ty21a
and may be used in children over 2 years of age and in at-risk HIV-infected patients. Genetically engineered live typhoid vaccine strains are being developed. No ocular complications have been reported with use of any modern typhoid vaccines.
TREATMENT
Systemic
●Since 1989, numerous reports have surfaced regarding multi-drug resistant strains of S. typhi on the Indian subcontinent and throughout Southeast Asia, Africa and the Middle East. This has influenced the medical treatment of typhoid fever.
Ocular
●Ocular infection should be treated with ophthalmic chloramphenicol (0.5% solution or 1% ointment) or ciprofloxacin (0.3% solution), frequency correlated with severity of infection (from BID for conjunctivitis to hourly for corneal ulceration). Although newer generation fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin) are likely effective, there are no clinical trials on their efficacy. Smears for culture and sensitivity should be obtained prior to initiating chemotherapy.
●Lid or orbital abscesses require surgical drainage and debridement, copious irrigation and appropriate cultures. The only ophthalmic ointment with activity against S. enterica typhi is 1% chloramphenicol.
●Uveitis (iritis, iridocyclitis or choroiditis) should be treated with appropriate topical, periocular or systemic corticosteroids or non-steroidal anti-inflammatory agents based on the clinical presentation. Patients with anterior uveitis should also receive topical mydriatic-cycloplegic medication and severe intraocular inflammation (e.g. endophthalmitis or panophthalmitis) may require systemic analgesics.
●Retinal detachment is rare. Reported cases have been due to serous detachment from presumed choroiditis. Medical management with systemic corticosteroids may hasten resolution and improve visual outcome. Choroiditis is also blamed for stellate maculopathy and pigmentary retinopathy.
●The specific etiology of dacryoadenitis, optic neuritis and ophthalmoplegia is unknown and treatment is therefore directed at the underlying systemic infection and inflammatory response as outlined above.
Medical
●Oral chloramphenicol, introduced in 1948, is no longer the drug of choice due to widespread resistance, high rates of relapse and chronic carriage, and the risk of bone marrow toxicity.
●Alternative antibiotics include trimethoprim-sulfamethox- azole, ampicillin, amoxicillin, and third generation cephalosporins and can be used if the risk of multi-drug resistance is thought to be low or if sensitivities are available.
●The current drug of choice for adults is oral ciprofloxacin (500 mg b.i.d. for 10–14 days). Although there have been increasing reports of organisms resistant to quinolone therapy, especially in Asia, this drug is the most effective and has the additional advantage of excellent penetration into macrophages and the biliary system which may reduce the incidence of relapse and carrier states.
Fever Typhoid • 52 CHAPTER
93