Chapter 2.  Empiric Therapy Based on Clinical Syndrome

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Therapeutic Considerations:  CMV should be treated aggressively to minimize its potentiating immunoregulatory defects, which may predispose to non-viral opportunistic pathogens and ↑ risk of chronic rejection in SOT.. CMV antigen levels or quantitative PCR increase before CMV infection.. Therefore, when CMV antigen levels or quantitative PCR increase, begin early pre-emptive therapy with valganciclovir 900 mg (PO) q12h until CMV antigen levels or quantitative PCR return to previous levels.. There is no treatment for EBV..

Prognosis:  Treated early, CMV responds well to therapy.. CMV is associated with chronic allograft rejection in SOT recipient so that prevention or early diagnosis/therapy are critical..

Toxin-Mediated Infectious Diseases

Toxin-Mediated Infectious Diseases

	Usual		PO Therapy or
Subset	Pathogens	IV Therapy	IV-to-PO Switch
Toxic shock	S.. aureus	Preferred IV Therapy	Linezolid 600 mg (PO)
syndrome	(MRSA)	Vancomycin 1 gm (IV) q12h × 2 weeks	q12h × 2 weeks
(TSS)*		or	or
(Treat initially		Linezolid 600 mg (IV) q12h × 2 weeks	Minocycline 100 mg
		Alternate IV Therapy	(PO) q12h × 2 weeks
for MRSA; if
		Minocycline 100 mg (IV) q12h ×2 weeks
later identified
		or
as MSSA, treat
		Daptomycin 6 mg/kg (IV) q24h × 2
accordingly)
		weeks
	S.. aureus	Preferred IV Therapy	Cephalexin 500 mg (PO)
	(MSSA)	Cefazolin 1 gm (IV) q8h × 2 weeks	q6h × 2 weeks
		Alternate IV Therapy	or
		Nafcillin 2 gm (IV) q4h × 2 weeks	Clindamycin 300 mg
		or	(PO) q6h × 2 weeks
		Clindamycin 600 mg (IV) q8h × 2 weeks
	Clostridium	Preferred IV Therapy	Not applicable
	sordelli	Penicillin G 10 mu (IV) q4h × 2 weeks
		or
		Clindamycin 600 mg (IV) q8h × 2 weeks
		or
		Piperacillin 4 gm (IV) q8h × 2 weeks
		Alternate IV Therapy
		Meropenem 1 gm (IV) q8h × 2 weeks
		or
		Ertapenem 1 gm (IV) q24h × 2 weeks

MRSA/MSSA = methicillin-resistant/sensitive S. aureus. Duration of therapy represents total time IV, PO, or IV + PO.. Most patients on IV therapy able to take PO meds should be switched to PO therapy after clinical improvement..

*Treat only IV or IV-to-PO switch..

170 A n t i b i o t i c E s s e n t i a l s

Toxin-Mediated Infectious Diseases (cont’d)

	Usual		PO Therapy or
Subset	Pathogens	IV Therapy	IV-to-PO Switch
Botulism (food,	Clostridium	Preferred Therapy	Alternate Therapy
infant, wound)	botulinum	2 vials of type-specific trivalent (types	Amoxicillin 1 gm (PO)
		A,B,E) or polyvalent (types A,B,C,D,E)	q8h × 7 days (wound
		antitoxin (IV)	botulism only)
Tetanus	Clostridium	Preferred Therapy Tetanus immune globulin	Alternate Therapy
	tetani	(TIG)	Tetanus antitoxin
		3,000–6,000 units (IM) (50% into deltoid,	1,500–3,000 units (IM/IV)
		50% into wound site)	plus
		plus either	Metronidazole 1 gm (IV)
		Penicillin G 4 mu (IV) q4h × 10 days	q12h × 10 days
		or
		Doxycycline 200 mg (IV or PO) q12h × 3
		days, then 100 mg (IV or PO) × 7 days
Diphtheria	Coryne-	Diphtheria antitoxin (IV) over 1 hour	Diphtheria antitoxin (IV)
(pharyngeal,	bacterium	(pharyngeal diphtheria = 40,000 units;	over 1 hour (pharyngeal
nasal, wound,	diphtheriae	nasopharyngeal diphtheria = 60,000	diphtheria = 40,000
myocarditis)	C.. ulcerans	units; systemic diphtheria or diphtheria	units; nasopharyngeal
		> 3 days duration = 100,000 units)	diphtheria = 60,000 units;
		plus either	systemic diphtheria
		Penicillin G 1 mu (IV) q4h × 14 days	or diphtheria > 3 days
		or	duration = 100,000 units)
		Erythromycin 500 mg (IV) q6h × 14 days	plus
			Procaine penicillin
			600,000 units (IM) q24h
			× 14 days

Duration of therapy represents total time IV, PO, or IV + PO.. Most patients on IV therapy able to take PO meds should be switched to PO therapy after clinical improvement..

Toxic Shock Syndrome (S. aureus)

Clinical Presentation:  Scarlatiniform rash ± hypotension.. Spectrum ranges from minimal infection to multiorgan system failure/shock.. ↑ CPK common..

Diagnostic Considerations:  Diagnosis by clinical presentation with mucous membrane, renal, liver, and skin involvement/culture of TSS-1 toxin-producing strain of S.. aureus from mouth, nares, vagina, or wound.. Pitfalls:  Toxic shock syndrome wound discharge is clear, not purulent..

Therapeutic Considerations:  Remove source of toxin production if possible (e..g.., remove tampon, drain collections).. Clindamycin may be added for its anti-toxin effect..

Prognosis:  Good in early/mild form.. Poor in late/multisystem disease form..

Chapter 2.  Empiric Therapy Based on Clinical Syndrome

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Toxic Shock Syndrome (C. sordelli)

Clinical Presentation:  Resembles clostridial myonecrosis (gas gangrene) with soft tissue necrotizing infection are local edema.. Hypotension with acute onset of nausea/vomiting and weakness characteristic.. Associated with IVDA (black tar heroin), trauma, parturition, abortion, cadaver graft surgery.. Hemoconcentration with leukocytosis typical; leukemoid reactions common with WBC counts > 50k/ mm3..

Diagnostic Considerations:  Clinical diagnosis.. Culture of C.. sordelli from necrotic soft tissue.. Pitfalls:  Gas gangrene like clinical presentation but with hemoconcentration not hemolytic anemia.. Nausea/vomiting instead of diarrhea as with gas gangrene.. Shock with no/low fever and ↑ WBC should suggest the diagnosis.. Muscle involvement (clostridial myonecrosis) and bullae typical of gas gangrene not a feature of C.. sordelli TSS..

Therapeutic Considerations:  Early/adequate debridement critical.. Anti-anerobic antibiotics and supportive measures important..

Prognosis:  Like gas gangrene, prognosis related to early diagnosis and early/adequate surgical debridement..

Botulism (Clostridium botulinum)

Clinical Presentation:  Descending symmetrical paralysis beginning with cranial nerve involvement, induced by botulinum toxin.. Onset begins with blurry vision, followed rapidly by ocular muscle paralysis, difficulty speaking, and inability to swallow.. Respiratory paralysis may occur in severe cases.. Mental status is unaffected.. Usual incubation period is 10–12 hours.. Incubation is shortest for Type E strain (hours), longest for Type A strain (up to 10 days), and is inversely ­proportional to the quantity of toxin consumed (food botulism).. Wound botulism (Types A or B) may follow C.. botulinum entry into IV drug abuser injection site, surgical or traumatic wounds.. Infant (< 1 year) botulism (most commonly Type A or B) is acquired from C.. ­botulinum ­containing honey.. Patients with botulism are afebrile, and have profuse vomiting without ­diarrhea..

Diagnostic Considerations:  Detection of botulinum toxin from stool, serum, or food (especially home canned foods with neutral or near neutral pH [~ 7] or smoked fish [Type E]) is diagnostic of food botulism.. Wound botulism is diagnosed by culturing C.. botulinum from the wound or by detecting­ botulinum toxin in the serum..

Pitfalls:  Clinical diagnosis based on descending paralysis with cranial nerve involvement in an ­afebrile patient must be differentiated from Guillain-Barre (fever, ascending paralysis, sensory ­component) and polio (fever, pure ascending motor paralysis).. Do not diagnose botulism in the absence of ocular/pha­- ryngeal paralysis..

Therapeutic Considerations:  Antitoxin neutralizes only unbound toxin, and does not reverse toxin-induced paralysis.. Botulism is a toxin-mediated infection and antibiotic therapy (wound botulism) is adjunctive. . Guanidine has been used with variable effect. . Ventilator support is needed for respiratory paralysis. . Bioterrorist botulism presents clinically and is treated the same as naturallyacquired botulism..

Prognosis:  Good if treated early, before respiratory paralysis..

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Tetanus (Clostridium tetani)

Clinical Presentation:  Begins with jaw stiffness/difficulty chewing induced by C. . tetani toxin (tetanospasmin). . Trismus rapidly follows with masseter muscle spasm, followed by spasm of the abdominal/back muscles. . Rigidity and convulsions may occur. . Patients are afebrile unless there is hypothalamic involvement (central fever), in which case fevers may exceed 106°F.. Usual incubation period is 3–21 days..

Diagnostic Considerations:  Diagnosis suggested by muscle spasms/rigidity in a patient with trismus­.. Pitfalls:  In rabies, muscle spasms are localized and usually involve the face/neck, rather than primary involvement of the extremities, as in tetanus..

Therapeutic Considerations:  Tetanus is self-limited with intensive supportive care.. Sedation is important, and avoidance of all stimuli is mandatory to reduce the risk of convulsions. . Avoid unnecessary handling/movement of patient.. Antitoxin is effective only in neutralizing unbound toxin.. ­Tracheostomy/ respiratory support can be lifesaving in severe cases..

Prognosis:  Good if not complicated by spinal fractures, aspiration pneumonia, or CNS involvement (hyperpyrexia, hyper/hypotension)..

Diphtheria (Corynebacterium diphtheriae/Corynebacterium ulcerans)

Clinical Presentation:  Within 1 week following insidious onset of sore throat without fever, pharyngeal patches coalesce to form a gray diphtheric membrane (surrounded by a red border), which is adherent/bleeds easily when removed. . Membrane begins unilaterally; may extend to the soft palate, uvula and contralateral posterior pharynx; are accompanied by prominent bilateral anterior adenopathy; become necrotic (green/black); and have a foul odor (fetor oris).. Submandibular edema (“bull neck”) and hoarseness (laryngeal stridor) precede respiratory obstruction/death. . Cutaneous diphtheria may follow C. . diphtheriae contaminated wounds (traumatic, surgical) or insect/human bites, and is characterized by a leathery eschar (cutaneous membrane) covering a deep punched out ulcer.. Serosanguineous discharge is typical of nasal diphtheria (membrane in nares).. Diphtheric myocarditis may complicate any form of diphtheria (most commonly follows pharyngeal form), and usually occurs in the second week, but may occur up to 8 weeks after infection begins.. Diphtheric polyneuritis is a common complication.. Cardiac/neurologic complications are due to elaboration of a potent toxin..

Diagnostic Considerations:  Diagnosis is suggested by unilateral membranous pharyngitis/palatal­ paralysis, absence of fever, and relative tachycardia.. Diagnosis is confirmed by culture of C.. ­diphtheriae from nares, membrane, or wound..

Pitfalls:  Differentiated from Arcanobacterium (Corynebacterium) haemolyticum (which also forms a pharyngeal membrane) by culture and absence of scarlatiniform rash with C.. diphtheriae.. C..ulcerans has the same clinical features as C.. diphtheriae..

Therapeutic Considerations:  Antibiotic therapy treats the infection and stops additional toxin production.. Antitoxin is effective against unbound toxin, but will not reverse toxin-mediated myocarditis/ neuropathy.. Serum sickness is common 2 weeks after antitoxin.. Respiratory/cardiac support may be lifesaving.. C..ulcerans is treated the same as C.. diptheriae..

Prognosis:  Poor with airway obstruction or myocarditis.. Myocarditis may occur despite early ­treatment..