9107MichaelMorganMD

Infectious Disease Case Conference: 

Infectious Disease Case Conference Michael Morgan, MD Wake Forest Baptist University Hospital September 10, 2007

DisclosuresSection of Infectious Diseases: 

Disclosures Section of Infectious Diseases Kevin High, M.D. Grant/Research Support – Cubist Pharmaceuticals, Astellas Pharma US, Inc. Consultant – Merck & Co., Inc. Speaker’s Bureau – Pfizer Pharmaceuticals Sam Pegram, M.D. Grant/Research Support – Roche, Bristol-Myers Squibb, Gilead, Schering-Plough, Tibotec Pharmaceuticals Consultant – Abbott Laboratories, GlaxoSmithKline, Boehringer Ingelheim, Gilead, Roche Speaker’s Bureau – Abbott Laboratories, GlaxoSmithKline, Boehringer Ingelheim, Merck, Pfizer Pharmaceuticals

Disclosures cont.: 

Disclosures cont. Aimee Wilkin, M.D. Grant/Research Support – Abbott Laboratories, GlaxoSmithKline, Tibotec Pharmaceuticals, Bristol-Myers Squibb Company, Gilead Christopher Ohl, M.D. Grant/Research Support – Cubist Pharmaceuticals, Gene-Ohm Sciences, Merck Pharmaceuticals Speaker’s Bureau/Consultant – Ortho-McNeil Pharmaceuticals, Cubist Pharmaceuticals, Sanofi-Aventis Pharmaceuticals, Pfizer Pharmaceuticals, Bayer Pharmaceuticals James Peacock, M.D. Ownership in Common Stock – Pfizer Pharmaceuticals

Cases A and B: 

Cases A and B Mr. A is a 53yobm with remote history of IDU, ongoing crack cocaine abuse Admitted to the hospital for CP, HTN urgency, and found to have a creatinine 5.5. Social: Drinks 12ppd, Smoke 2ppd

Hospital Workup: 

Hospital Workup Echo: Concentric LVH w/EF 40% Renal U/S: Bilateral increased echogenicity suggestive of chronic medical kidney disease Renal Duplex: Normal Urine Protein/Creatinine Ratio: 2.77 Normal Serum Protein Electrophoresis Negative Serum Cryoglobulins Normal C3, C4 levels

Case A Labs: 

Case A Labs CBC: WBC 8.0, Hbg 9.4, Plts 243 LFT’s: AST 55, ALT 44, Alk Phos 51, Total Protein 7.4, Albumin 4.2 Other electrolytes Nml CHL 220, TRIG of 122, HDL 39, LDL157 HbgA1C 5% No Renal Biopsy

Renal Workup: 

Renal Workup Hepatitis Panel Hep A Ab NR Hep BcAb Positive Hep BsAb Positive Hep BsAg NR Hep C Ab Positive Hep C RNA 297,800 IU/ml

Referred to ID clinic: 

Referred to ID clinic Referred to ID clinic for: “renal dysfunction likely secondary to cocaine use, as well as hepatitis C and likely HCV associated glomerulonephritis” Further information from first ID visit: Hep C Genotype 1a Hep C RNA 527,700 IU/ml Hep B DNA <100 IU/ml FibroSURE: F1 Fibrosis and A1-A2 Inflammation

Initial Thoughts: 

Initial Thoughts No clear evidence that his renal disease was Hepatitis C associated Withhold treatment

Case B: 

Case B Mr. B is a 46yobm with history of EtOH/cocaine abuse who was referred to ID clinic by nephrology for chronic HCV. Initially admitted to hospital with N/V/D, ARF with creatinine 11.9

Mr. B’s Labs: 

Mr. B’s Labs Initial CBC: WBC 3.0 w/nml diff, Hbg 8.6 w/MCV 92, Plts 134 LFT’s: AST 64, ALT 82, Alk Phos 81, TB 0.2, TP 6.4, Alb 2.9 BUN/Creatinine 114/11.9 RPR: 1:1, MHATP NR HIV AB NR

Case B—Hospital Workup: 

Case B—Hospital Workup Hepatitis Panel Hep A Ab NR Hep BcAb Positive Hep BsAb NR Hep BsAg NR Hep C Ab Positive Hep B DNA <100 IU/ml Hep C RNA 119,300 IU/ml

Case B—Hospital Workup: 

Case B—Hospital Workup Renal U/S: Markedly increased echogenicity and decrease size of the kidneys bilaterally consistent with end-stage renal disease. Liver U/S: Hepatomegaly with steatosis Renal Biopsy: Focal segmental glomerulosclerosis (collapsing variant) with advanced tubular atrophy

Slide14: 

Per Nephrology: Patient’s kidney disease felt to be too advanced to warrant treatment as they do not anticipate any meaningful renal recovery. Patient referred to ID for treatment of his chronic HCV infection.

Patient B—At time of Consult: 

Patient B—At time of Consult CBC: WBC 4.1, Hbg 12.9, Plts 200 Cryoglobulins: Neg BUN/Creatinine 35/12.8 on HD LFT’s: AST 50, ALT 48, Alk Phos 55, Alb 4.1 FibroSURE: Fibrosis F3 Inflammatory Score A1-2 Denies Tobacco/EtOH/Drugs for last 2 months

Hepatitis C and Chronic Kidney Disease: 

Hepatitis C and Chronic Kidney Disease Membranoproliferative Glomerulonephritis both with and without cryoglobulinemia is most common Treating active Hepatitis C reduces cryoglobulinemia and may improve kidney functions in some patients. Other forms of Kidney disease have been reported to be associated with Hep C: IgA nephropathy FSGM Fibrillary glomerulonephritis Thrombotic microangiopathy

HCV and ESRD: 

HCV and ESRD In 2002, 7.8% of patients on HD were anti-HCV seropositive. Nosocomial transmission of HCV in HD patients has decreased in the last several years with stricter precautions such as isolating HCV positive patients during dialysis.

HCV and ESRD: 

HCV and ESRD Unclear if progression of HCV liver disease is accelerated in HD patients Relative mortality risk in HCV/HD patients is 1.5 compared to non-HCV infected HD patients.

Can you treat HCV in patients with ESRD?: 

Can you treat HCV in patients with ESRD? NO large randomized study has been done. Fabrizi (UCLA) did meta-analysis of 14 trials totaling 269 patients treated with interferon monotherapy. Total SVR rates were 37%, but only 30% for Genotype 1. Dropout Rate was also 37% In 5 studies that had standard interferon, 3million units SQ 3xweek, had total cure rate of 39% Among studies with control groups, the HD patients did worse and had more side effects. Fabrizi. Aliment Pharmacol Ther. 2003. 18: 1071-81

Interferon and Ribavirin: 

Interferon and Ribavirin Ribavirin is renally excreted but not cleared by HD. 2 small series identified, n=11, using standard interferon and ribavirin, 170-300mg PO daily. Ribavirin was d/c in 2 patients High Dose epoetin was given 5 of 11 patients acheived SVR 9/11 obtained undetectable viral load on treatment.

Peg-IFN and HD: 

Peg-IFN and HD Kokoglu (Turkey) published study of PEG-IFN for 48 weeks in 12 patients ESRD/HCV1 SVR of 75% PEG-IFN alpha-2a 135 mcg weekly Every patient finished treat Russo (UNC) published a trial using either 1.0 or 0.5 mcg/kg of PEG-IFN alpha-2b2 Trial was stopped due to adverse events and poor outcomes. 2/9 patients of 1.0mcg group acheived SVR Only 5/9 were able to complete 24 weeks of therapy No patients on 0.5mcg group obtained SVR Strong statement: No one on HD should receive Peg-IFN unless in a study. Kokoglu. Journal of Gastroenterology and Hepatitis. 2006; 21: 575-580 Russo. Nephrology Dial Transplant. 2006; 21: 437-43.

Newest Data in HCV/HD patients: 

Newest Data in HCV/HD patients Data from Italy published in May 2007 N=35. Patients excluded if Hbg<8.5, cirrhosis, WBC < 2.0, Plts < 100, HIV, psychiatric illness peg-IFN alfa-2a 135mcg with 200mg ribavirin qd and titrate to qod when Hbg < 8.5 despite epoetin 40,000 units qwk 30/35 patients completed treatment 2 transplant, 1 anemia, 1 dermatitis, 1 non-responder FibroScan in HD patients, consistent w/biopsy 90% of the time 1st to report FibroScan results while on HD. Always consistent w/F0-F2

Study cont: 

Study cont Average Age 45±9 years Genotype I in 16/35 Average baseline RNA 323,535 ± 223,294 Duration of dialysis was 9.9 ± 5.6 years 34/35 were HCV neg at week 4—34/35 had SVR’s Rendina. Journal of Hepatology. 2007; 26: 768-774.

Can patients with HCV receive kidney transplants?: 

Can patients with HCV receive kidney transplants? All patients with Positive HCV RNA should undergo liver staging as cirrhotics should be referred for dual liver/kidney transplant. HCV RNA positive patients will go on list to get either hepatitis C positive or negative patient’s kidneys. (outcome unchanged by donor HCV status in these patients--Spain) There is a risk of infecting with new strain HCV antibody+, RNA- patients should receive kidneys from HCV negative donors.

Kidney Transplant Protocol Here: 

Kidney Transplant Protocol Here Check HCV AB (ELISA and confirmed by RIBA if positive) At initial evaluation, annually on list, at time of transplant, 3 mo after transplant, annually post-txp If pre-transplant +RIBA, order HCV RNA and genotype. PCR neg: the patient should be listed as HCV negative on the wait list PCR pos: refer to Dr. High and obtain liver U/S and biopsy Repeat liver biopsy and liver U/S every 2 years while on transplant wait list

Protocol, cont: 

Protocol, cont Check HCV RNA If positive RIBA 3 mo after transplant Then Annually Use as a screening lab post-transplant only (patients who acquire HCV post-transplant often remain ELISA neg because of immunosuppression) If HCV RNA+ LFT’s, Genotype, Liver U/S, and Refer to Dr. High.

Caveats of Protocol: 

Caveats of Protocol Only patients who are HCV RNA+ genotype 1 should be listed as “HEP C” to receive a HCV+ donor organ Other genotypes may more readily respond to medical therapy which should be completed prior to transplant, and we do not want to “co-infect patients” Patients with a liver biopsy >Grade 2 and >Stage 1 should not be listed nor undergo transplantation except if warranted by high medical need for transplant

HCV and Transplant: 

HCV and Transplant HCV viral load increases s/p transplant. Most data show increased risk of post-transplant liver failure, but may not be directly associated with HCV. Is liver fibrosis accelerated s/p transplant? Some data show increasing rates of cirrhosis Other data show that immunosuppressive effects may actually slow progression of fibrosis

HCV and Transplant: 

HCV and Transplant HCV positive patient do have Higher Mortality S/P transplant than HCV negative patients, mostly attributed to increase rates of sepsis, cirrhosis, and hepatocellular carcinoma. No difference in acute rejection, although graft survival in some studies was shown to be significantly lower in HCV positive patients

HCV Treatment after Transplant: 

HCV Treatment after Transplant Harder for several reasons HCV viral load is typically higher after transplant Rates of acute graft rejection are increased in patients starting standard interferon monotherapy Cure rates low, 2/191,2 8/19 developed renal failure. Ozgur. Nephrol Dial Transplant. 1995;10: 2104-6. Rostaing. Nephrol Dial Transplant 1995;10 Suppl 6:93-6

Other treatment s/p transplant: 

Other treatment s/p transplant Some data using either ribavirin or amantadine can improve aminotransferase levels. Neither alone or in combination affects viral load. Ribavirin may be beneficial in HCV associated glomerulopathy and proteinuria

Conclusions: 

Conclusions No clear consensus on who should be treated. If decide to treat, probably best to attempt pre-transplant to avoid graft rejection, decrease post-transplant morbidity and mortality Unsure best regimen. Ribavirin is considered contraindicated in patients with creatinine clearance <50 Most available data is with standard interferon monotherapy, although newer studies are showing promise with ribavirin and PEG-IFN

What should I do with my two patients?: 

What should I do with my two patients? One is already on dialysis the other is close. Both are middle-aged, but both former drug/alcohol abusers Viral load is ~ 100,000 in one patient and ~ 300,000 in the other. Neither has yet been referred for transplant.

CASE TWO: 

CASE TWO Mr. W is a 46yomale with previous history of DM and PVD/osteomyelitis with transmetatarsal amputation of Lft Foot Referred for admission after being evaluated by ophthalmology for bilateral red swollen eyes (L>R), left eye pain, and worsening blurry vision for one week. Ophthalmology felt this was endophthalmitis and wanted ID input for antibiotic treatment.

Admission: 

Admission Patient refused intravitreal aspiration for culture and intravitreal antibiotics because of pain. They were able to get aqueous cultures that were negative for fungus or bacteria. Other PE exam findings included No Murmur, but Rt Great Toe with redness and open lesion with purulent drainage and able to probe to bone.

Further History: 

Further History Two weeks prior presented to outlying ED for fevers and the toe drainage. Felt to have possible osteomyelitis, but at least a DM foot ulcer and d/c home on Cipro bid. Both Wound ctx of the toe and 1/1 blood ctx grew MRSA (CA-phenotype). MRSA was sensitive to TMP/SMX, tetracycline, Cipro, levofloxacin, linezolid, Synercid, and rifampin He was switch from PO ciprofloxacin after 5 days to PO Bactrim, 2DS bid.

Hospital Course: 

Hospital Course Empirically started on vancomycin, cefepime, ciprofloxacin, and fluconazole; rifampin was added on HD 2 Blood ctx here grew MRSA at 79hours HD 6 patient had Amputation of Rt Great Toe and finally had intravitreal antibiotic injections of vancomycin and ceftazidime to both eyes. All eye ctx and repeat blood ctx were negative Bone ctx the toe was positive for MRSA

Endophthalmitis: 

Endophthalmitis Serious intraocular inflammatory disorder resulting from infection of the vitreous cavity. Exogenous endophthalmitis from intraocular surgery, penetrating trauma, or contiguous spread. 70% cause by CoNS Endogenous endophthalmitis from hematogenous spread

Endogenous Endophthalmitis : 

Endogenous Endophthalmitis Also called metastatic endophthalmitis Only account for only 2-8% of all endo Most common source of extra ocular infections were liver abscess; then pneumonia, endocarditis, soft tissue infx, UTI, meningitis, and septic arthritis Only 57% of patients had systemic systems

Most likely organisms: 

Most likely organisms In East Asia—80-90% are Klebsiella sps In US—32% are gram negatives, 32% Strep sps, 25% Staph aureus. The rest are other gram positives and fungus with Candida > Aspergillus Ocular ctx are positive an anywhere from 36-73% of the time ID the organisms 70-80% of time by blood, urine, or CSF ctx’s

Treatment: 

Treatment Must use systemic antibiotics because must need to treat underlying infection. Exogenous endophthalmitis can many times just be treated with intraocular abx Empiric treatment with vancomycin, third generation cephalosporins, quinolones, or aminoglycosides are suggested. Empiric fungal treatment with amphotericin or voriconazole are recommended if fungus is suspected and can change to fluconazole if susceptible isolate.

Treatment cont.: 

Treatment cont. Intravitreal injections of abx is also recommended—Vanc 1mg/0.1ml and ceftazidime 2.25mg/0.1ml For fungal infections can give intravitreal amphotericin or voriconazole Also most ophthalmologist recommend topical steroids to reduce inflammation Vitrecotromy may be beneficial for severe infections especially exotoxin-producing streps and B cereus infections

Quinolone treatment: 

Quinolone treatment Quinolones have good intraocular eye penetration Rabbit model Used IV moxifloxacin to treat both MSSA and MRSA strains. Vitreous levels were 28-52% serum at 1hr. Both strains had significant decrease in bacterial density but the MSSA>MRSA

Prognosis with endogenous endo: 

Prognosis with endogenous endo Different Studies had different results Jackson’s review of endogenous infx found that 32% could count fingers or better, 44% were blind, and 25% require evisceration.1 Greenwald found 60% of eyes visual acuity of hand motion or worse.2 29% had enucleation or evisceration Jackson. Surv Ophthalmol. 2003 Jul-Aug;48(4):403-23. Greenwald. Surv Ophthalmol 1986;31:81–101.

Further review: 

Further review Jackson reviewed total cases of bacteremia in his hospital in 17 year period. n=2740 CA n=3119 HA Only two patient of the HA patients developed EE (exogenous endophthalmitis)—1 was S.aureus 12 of the CA with only one being S. aureus. (8 patients had strep sps. of that GBS in 4) Jackson. Surv Ophthalmol. 2003 Jul-Aug;48(4):403-23.

Total Cases: 

Total Cases Of all cases reviewed from the literature since 1935 through 2001… Out of 447 total cases only 45 cases of S.aureus EE infection. 10% of the cases in each time period, 1935-1975, 1976-1985, 1986-2001. Only 3 cases of MRSA isolated and all from 1986-2001 Jackson. Surv Ophthalmol. 2003 Jul-Aug;48(4):403-23.

CA-MRSA: 

CA-MRSA Study from UCSF found 11 positive MRSA eye infection in 11month period. 9/11 were USA-300 strain. Infections were lid abscess (n=4), endopthalmitis (n=3), orbital cellulites and superior ophthalmic vein thrombosis, and panophthalmitis. All patients with EE had disseminated MRSA infection and all 3 had endocarditis plus other sites of dissemination—2/3 patients grew MRSA from vitreous Ages of patients w/EE were 39-43, with one with DM, one on HD, and last homeless and HIV pos All patients with EE were treated with both six weeks of IV Vanc, and intravitreal Vanc. (1 also got rifampin and gentamycin as well). All had good visual outcomes. Rutar. Ophthalmology. 2006 Aug;113(8):1455-62.

MRSA Endophthalmitis: 

MRSA Endophthalmitis Still relatively rare. In study of out UCSF, in 8 year review of all S.aureus positive eye cultures only 88/915 were MRSA and only 2 had endophthalmitis. The percentage of MRSA infections went up from 4% in 1998 to 16% in 2006. The rate of ~ 2% total incidence of endophthalmitis was unchanged either MSSA or MRSA group Friedlin. Am J Ophthalmol. 2007 Aug;144(2):313-5.

New Studies: 

New Studies Still no large study for EE to know if Intravitreal antibiotics are helpful, although most ophthalmologist do this Intravitreal steroids provide benefit If vitrectomy is truly beneficial Also no recent data if the new CA-MRSA strain with PVL toxin will increase rates of EE, compared to previous years

Back to the our patient: 

Back to the our patient The Patient was D/C home on A total of Six weeks of IV Vancomycin and Rifampin And a total of 4 weeks of high dose ciprofloxacin and fluconazole Rt eye vision is at baseline Lft eye he has some vision can see large shapes, colors, and movement, but cannot read