Therapeutic Considerations:  In spite of early aggressive antibiotic therapy and supportive care, patients often die within hours from overwhelming infection, especially due to S.. pneumoniae.. Prognosis:  Related to degree of splenic dysfunction..

Sepsis (Chronic High Dose Steroids)

Clinical Presentation:  Subacute onset of fever with disseminated infection (Candida, Aspergillus) in multiple organs..

Diagnostic Considerations:  Diagnosis by positive blood cultures for fungi or demonstration of invasive fungal infection from tissue biopsy specimens.. Sepsis is most commonly due to fungemia.. Pitfalls:  Obtain blood cultures to diagnose fungemias and rule out bacteremias (uncommon).. Therapeutic Considerations:  Empirical approach is the same as for invasive candidiasis (p.. 153) or invasive aspergillosis (p.. 159 and p.. 164).. Therapy focused solely on candidiasis (e..g.., fluconazole alone) should be used only if aspergillosis seems unlikely following careful review of the epidemiologic and clinical presentation..

Prognosis:  Related to degree of immunosuppression..

Miliary (Disseminated) TB (Mycobacterium tuberculosis)

Clinical Presentation:  Unexplained, prolonged fevers without localizing signs.. Diagnostic Considerations:  Diagnosis by AFB on biopsy/culture of liver or bone marrow..

Pitfalls:  Chest x-ray is negative early in 1/3.. Subtle miliary (2 mm) infiltrates on chest x-ray 1–4 weeks).. Therapeutic Considerations:  Treated the same as pulmonary TB ± steroids initially.. Prognosis:  Death within weeks without treatment..

Miliary (Disseminated) BCG (Bacille Calmette-Guérin)

Clinical Presentation:  Fever, circulatory collapse, DIC days to weeks after intravesicular BCG.. Diagnostic Considerations:  Usually occurs in compromised hosts (e..g.., transplants, active TB, congenital/acquired immunodeficiencies [e..g.., HIV], leukemias/lymphomas).. Rare in normal hosts..

Pitfalls:  Avoid intravesicular BCG immediately after traumatic catheterization, bladder biopsy, TURP.. Therapeutic Considerations:  Treat with 4 anti-TB drugs plus steroids.. Do not repeat BCG therapy.. Prognosis:  Good with early treatment..

Febrile Neutropenia

Febrile Neutropenia

Febrile Neutropenia (cont’d)

MSSA = methicillin-sensitive S. aureus. Duration of therapy represents total time IV or IV + PO.. * Treat until neutropenia resolves..

†If clinically possible, remove CVC..

§Treat for 2 weeks post--CVC removal..

¶Neutropenia, per se, does not predispose to MSSA/MRSA bacteremias.. MSSA/MRSA bacteremias in febrile neutropenia are 2° to CVC associated infection, not neutropenia..

Clinical Presentation:  Incidence of infection rises as PMN counts fall below 1000/mm3..

Diagnostic Considerations:  Febrile neutropenia < 7 days ± positive blood cultures.. After blood cultures are drawn, anti-P.. aeruginosa coverage should be initiated.. Do not overlook ischiorectal or perirectal abscess as sources of fever..

Pitfalls:  Suspect fungemia if abrupt rise in temperature occurs after 7 days of appropriate anti-P.. aeruginosa antibiotic therapy.. Fungemias usually do not occur in first 7 days of neutropenia.. Viridans­ streptococci (S.. mitis) may present with bacteremia, shock, ARDs, and rash in febrile neutropenia..

Therapeutic Considerations:  If a patient is neutropenic for > 2 weeks and develops RUQ/LUQ pain/increased alkaline phosphatase, suspect hepatosplenic candidiasis; confirm diagnosis with abdominal CT/MRI showing mass lesions in liver/spleen and treat as systemic/invasive candidiasis (p.. 79).. S.. aureus is not a common pathogen in neutropenic compromised hosts without central IV lines, and B.. fragilis/anaerobes are not usual pathogens in febrile neutropenia.. If IV line infection/perirectal abscess are ruled out, consider tumor fever or drug fever before changing antibiotic therapy..

Prognosis:  Related to degree and duration of neutropenia..

Transplant Infections

Transplant Infections

BMT/SOT = bone marrow/solid organ transplant, CO/HA-MRSA = community-onset/hospital-acquired methicillinresistant S. aureus (see p. 14), MSSA = Methicillin-sensitive S. aureus.

† Levofloxacin 750 mg or Moxifloxacin 400 mg..

*Treat until neutropenia resolves..

Transplant Infections (cont’d)

BMT/SOT = bone marrow/solid organ transplant, CO/HA-MRSA = community-onset/hospital-acquired methicillinresistant S. aureus (see p. 14), MSSA = methicillin-sensitive S. aureus.

† Levofloxacin 750 mg or Moxifloxacin 400 mg..

*Treat until neutropenia resolves..

‡Loading dose is not needed PO if given IV with the same drug..

¶Significant drug interactions are possible with usual immunosuppressive agents (e..g.., sirolinus, cyclosporine, tacrolimus)..

Review all concomitant medications for potential interactions.. Voriconazole contraindicated in patients with sirolinus..

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

Transplant Infections (cont’d)

*IVIG: 500 mg/kg (IV) q48h..

††CMVIG:

Renal Transplants: 150 mg/kg (IV) within 72 hours post-transplant, then 100 mg/kg (IV) at weeks 2, 4, 6, 8, then 50 mg/kg (IV) at weeks 12 and 16..

Non-Renal Transplants: 150 mg/kg (IV) given within 72 hours post-transplant, then 150 mg/kg (IV) at weeks 2, 4, 6, 8, then 100 mg/kg (IV) at weeks 12 and 16 after transplant..

Transplant Infections (cont’d)

§Probenecid 2 gm (PO) 3 hours prior to cidofovir, 1 gm at 2 hours and 8 hours after completion of infusion..

Patient should receive 1 liter normal saline (IV) prior to each infusion of cidofovir; a second liter may be administered over 1-3 hours at the start of cidofovir infusion or immediately following infusion..

*With hydration/probenecid (see Cidofovir Drug Summary)..

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

Transplant Infections (cont’d)

¶Significant drug interactions are possible with usual immunosuppressive agents (e..g.., sirolimus, cyclosporine tacrolimus).. Review all concomitant medications for potential interactions.. Voriconazole contraindicated in patients on sirolimus.

Transplant Infections (cont’d)

CNS INFECTIONS (cont’d)

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

*If < 40 kg, use 100 mg (PO) maintenance dose..

¶Significant drug interactions are possible with usual immunosuppressive agents (e..g.., sirolimus, cyclosporine, tacrolimus).. Review all concomitant medications for potential interactions.. Voriconazole contraindicated in patients on sirolimus.

Diagnostic Considerations:  CSF usually reveals a lymphocytic predominance with a normal or normal CSF lactic acid and low glucose.. The diagnosis of HSV, CMV, HHV-6 encephalitis can be made by CSF PCR..

Pitfalls:  Patients with Listeria encephalitis often have a negative CSF Gram stain, but Listeria nearly always grows on CSF culture.. HSV and listeria encephalitis typically have RBCs in the CSF.. Head CT/MRI rules out CNS mass lesions.. Nuchal rigidity may be absent in meningitis..

Therapeutic Considerations:  CMV encephalitis is rare but treatable, resulting in clinical/radiological improvement.. However, neurological deficits usually remain.. CMV retinitis, common in HIV (p.. 327), is unusual in BMT/SOT..

Prognosis:  Related to underlying immune status and promptness of therapy..

CNS Infections (Brain Abscess/Mass Lesions)

Clinical Presentation:  BMT/SOT patients with brain abscesses/mass lesions present with seizures/ cranial nerve abnormalities.. Mental status is clear, in contrast to patients with encephalitis, and nuchal rigidity is absent, in contrast to most patients with meningitis..

Diagnostic Considerations:  Head CT/MRI is the preferred diagnostic modality, and brain biopsy is the definitive diagnostic method.. CSF analysis is not usually helpful in mass lesions, with the exception of infection due to M.. tuberculosis or C.. neoformans.. With C.. neoformans, the CSF cryptococcal antigen test is positive, and the CSF India ink preparation may be positive.. With M.. tuberculosis, acid fast smear of the CSF is sometimes positive, but culture has a higher yield and PCR is the preferred diagnostic modality..

Pitfalls:  Patients with brain abscesses/mass lesions should have a head CT/MRI before lumbar ­puncture.. To avoid herniation during lumbar puncture when a mass lesion is present, lumbar puncture should be performed by an experienced operator, and a minimal amount of CSF should be withdrawn..

Therapeutic Considerations:  M.. tuberculosis and C.. neoformans are readily treatable.. Be sure to use antimicrobial therapy that penetrates into CSF/brain.. If TMP, TMP–SMX, or minocycline cannot be used for CNS Nocardia, linezolid or meropenem (meningeal doses) may be useful..

Prognosis:  Related to underlying immune status and promptness of therapy..

Pneumonias (Focal, Segmental, or Nodular Pulmonary Infiltrates)

Clinical Presentation:  Acute or subacute community-acquired pneumonia (CAP) with respiratory symptoms and fever..

Diagnostic Considerations:  BMT/SOT patients with focal/segmental infiltrates are most commonly infected with the usual CAP pathogens affecting normal hosts (e..g.., S.. pneumoniae, H.. influenzae, Legionella).. The clinical presentation of CAP in organ transplants is indistinguishable from that in normal hosts.. However, BMT/SOT patients presenting subacutely with focal/segmental infiltrates are usually infected with pulmonary pathogens with a slower clinical onset (e..g.., Nocardia, Aspergillus).. L.. micdadei common in BMT/SOT, and may cavitate.. Empiric therapy will not cover all possible pathogens; tissue biopsy is necessary for definitive diagnosis and specific therapy.. Preferred diagnostic modalities include transbronchial lung biopsy, percutaneous thin needle biopsy, or open lung biopsy, not BAL which may be negative in tissue invasive infections, e..g.., Aspergillus..

Pitfalls:  Patients presenting with subacute onset of CAP have a different pathogen distribution than those presenting with acute CAP.. PCP/CMV does not present with focal/segmental infiltrates.. Unlike other Legionella sp.., L.. micdadei partially acid fast, and susceptible to TMP-SMX (as well as doxycycline and quinolones).. Therapeutic Considerations:  BMT/SOT patients with acute onset of CAP are treated with the same antibiotics used to treat CAP in normal hosts.. Empiric coverage is directed against both typical and atypical

bacterial pathogens.. If no improvement in clinical status after 72 hours, proceed to transbronchial biopsy or lung biopsy to identify nonbacterial pathogens (e..g.., Nocardia, Aspergillus).. Nocardia reinfection may require 6–12 months of therapy..

Prognosis:  Best with acute focal/segmental infiltrates.. Not as good with subacute or chronic focal/ segmental infiltrates..

Pneumonias (Diffuse Pulmonary Infiltrates)

Clinical Presentation:  Insidious onset of interstitial pneumonia usually accompanied by low-grade fevers.. Focal/segmental infiltrates are absent..

Diagnostic Considerations:  Bilateral diffuse infiltrates, which can be minimal or extensive, fall into two clinical categories: those with and without hypoxemia/↑ A-a gradient.. Diffuse pulmonary infiltrates without hypoxemia suggest a noninfectious etiology (e..g.., CHF, pulmonary drug reaction, pulmonary hemorrhage).. The differential diagnosis of diffuse pulmonary infiltrates with hypoxemia includes PCP, CMV, HSV, RSV, HHV-6, VZV.. Quantitative PCR testing of BAL fluid for CMV, VZV, RSV, HHV-6 may be diagnostically helpful.. For interstitial infiltrates with hypoxemia, the chest x-ray may be only minimally abnormal, but chest CT scans are more revealing.. CMV/PCP may require tissue biopsy for definitive diagnosis.. A very highly elevated LDH suggests PCP.. PCP = b 1,3 D-glucan +, aspergillus galactomannan –.. Transbronchial biopsy is preferable, but BAL may be used.. The incidence of CMV pneumonia is highest in lung transplants and BMTs..

Pitfalls:  Because infections in BMT/SOT are sequential, many patients with PCP pneumonia may have underlying CMV or HHV-6.. In BMT, CMV found alone on lung biopsy suggests it is the primary pathogen.. Serological tests are helpful for CMV (↑CMV IgM); ↑ CMV viral loads reflective of peripheral WBC reactivation, not pneumonia.. CMV pneumonia diagnosed by demonstrations CMV CPEs (intracellular inclusions) on lung BAL/biopsy.. Candida pneumonia does not exist as a separate entity but only rarely as part of disseminated/invasive candidiasis..

Therapeutic Considerations:  Among the subacute diffuse pneumonias, PCP is readily treatable.. Initiate treatment for CMV pneumonia with ganciclovir IV; after clinical improvement, complete therapy with valganciclovir (PO) until cured.. If after treatment, there is an ↑ in CMV antigen levels or quantitative PCR, treat pre-emptively to prevent CMV pneumonia with valganciclovir 900 mg (PO) q24h until CMV antigen levels return to previous levels or quantitative PCR becomes undetectable..

Prognosis:  Related to underlying immune status, promptness of therapy, and general health of host..

Hepatitis (Viral)

Clinical Presentation:  Fever with ↑ SGOT/SGPT ± RUQ pain..

Diagnostic Considerations:  Because CMV is of such critical importance in BMT/SOT, CMV testing should always be done in organ transplants with ↑ SGOT/SGPT.. Liver biopsy with immunohisto chemical staining is diagnostic; quantitative PCR may be helpful.. Prior to SOT, HIV, HBV, HCV testing should be performed on donor and recipient.. Other viruses causing acute viral hepatitis post-transplant include EBV, HHV-6, VZV, adenovirus, and influenza. . Viral hepatitis is usually accompanied by some degree of leukopenia. . A few atypical lymphocytes may be present, and serum transaminases may be mildly or markedly elevated.. CMV viremia is the commonest manifestation of CMV infection in BMT/SOT patients.. CMV has a predilection for infecting the organ transplanted, and CMV hepatitis is particularly common in liver transplants.. Anicteric hepatitis is more common than icteric hepatitis..

Pitfalls:  The diagnosis of active CMV hepatitis in organ transplant patients is critical because it is an immunomodulating virus, adding to the net immunosuppressive effect of immunosuppressive therapy.. Do not rely on CMV IgM/IgG titers for diagnosis..