Ceftriaxone-resistant salmonella septicemia and osteomyelitis in sickle cell disease adults.

Abstract: The majority of data evaluating Salmonella infections in sickle cell anemia (SCD) comes from studies performed in children. We report a SCD adult who presented with ceftriaxone-resistant Salmonella bacteremia. After appropriate initial therapy, persistent back pain prompted evaluation by magnetic resonance imaging of the spine, which revealed osteomyelitis and a psoas abscess. The patient responded to percutaneous drainage and antibiotics. This report summarizes some of the findings of large SCD studies evaluating Salmonella bacteremia and osteomyelitis, focusing on adults. Our case exemplifies the need for antibiotic coverage for Salmonella species in adult SCD patients with septicemia. We argue that imaging studies looking for osteomyelitis should be done routinely in SCD patients with Salmonella bacteremia.

Key Words: Salmonella, hemoglobinopathies, sickle cell, ceftriaxone resistance, bacteremia, osteomyelitis, psoas abscess.

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Bacterial infections are a significant cause of morbidity and mortality in sickle cell anemia (SCD) patients. In 306 autopsies of patients with SCD, infection was the most common cause of death (33-48%) for all age groups. (1) The most important infections include meningitis, pneumonia, osteomyelitis, urinary tract infection, and diarrhea. (2) Multiple factors have been postulated to render SCD patients more susceptible to bacterial infections (3,4); however, the reason SCD patients are more susceptible to Salmonella bacteremia and osteomyelitis is not well understood. Moreover, less is known about adults with SCD. We report this rare case to increase the knowledge base of Salmonella infections in adults with SCD, improve management, and stimulate research in this population.

Case Report

A 20-year-old man with SCD presented with fever, chills, and generalized pain for the preceding week. He had no headaches, photophobia, neck stiffness, nausea, vomiting, diarrhea, or urinary symptoms. He had prior hospitalizations for pain crises, an episode of red-cell aplasia secondary to Parvovirus infection, cholecystectomy and appendectomy. On examination, he was febrile, tachycardic, had mild scleral icterus, dry mucosa, no lymphadenopathy, clear lungs, a flow murmur, benign abdomen, normal neurologic examination, and no costovertebral angle or spine tenderness. Laboratory data demonstrated a leukocyte count of 17.8 [mm.sup.3], hemoglobin 5.1 g/dL, platelets 328 [mm.sup.3], and mild elevations in the liver enzymes, urea and creatinine. Chest roentgenogram was normal. IV fluids, pain medications, blood transfusions and IV ceftriaxone were initiated. On day 2, he remained febrile. Blood cultures grew Gram negative rods identified on hospital day 3 as Salmonella group C sensitive to ciprofloxacin and resistant to ceftriaxone, and antibiotic coverage was changed to IV ciprofloxacin. A 2D echocardiogram showed no valvular abnormalities. He continued to have abdominal pain. Computed tomography (CT) scan of the abdomen and pelvis showed mild hepatomegaly, a small hyperdense spleen, and a low attenuation area in the left psoas muscle but no abscess. On day 6 (day 3 of IV ciprofloxacin), he defervesced. Repeat blood cultures showed no growth. He was discharged home on day 8 to finish an additional two weeks of oral ciprofloxacin. Eight days after diseharge, he returned to the hospital with unrelenting lower back and left hip pain. CT scan of the abdomen and pelvis and MRI of the lumbar spine demonstrated a left psoas abscess and osteomyelitis but no epidural abscess. IV ciprofloxacin was started and a percutaneous drain of the psoas abscess returned 25 mL of pus. Blood and psoas abscess cultures showed no growth. Five days later, a follow-up CT scan demonstrated adequate drainage of the abscess. The patient finished a 6-week course of oral ciprofloxacin without further complications.

Discussion

The majority of the scientific data evaluating Salmonella infections in SCD comes from studies performed in children. Many times, physicians caring for adult SCD patients have to extrapolate information from pediatric populations. In this report, we describe an adult with SCD and Salmonella septicemia. After antibiotic therapy and appropriate initial clinical response, the patient returned to the hospital with a psoas muscle abscess and osteomyelitis that responded to active drainage and continued antibiotic treatment. Should imaging studies looking for osteomyelitis be done in all adult SCD patients presenting with Salmonella bacteremia?

The incidence of osteomyelitis in SCD patients with salmonella septicemia is very high. The Cooperative Study of Sickle Cell Disease (CSSCD) examined 178 episodes of bacteremia that occurred in 3,451 child and adult patients with SCD. (5) The pathogens most frequently cultured were found to differ by age groups. No episodes of Salmonella bacteremia occurred in children younger than three years, but accounted for approximately one-third of the bacteremia in the 6 to 9 age group. Only one instance of Salmonella septicemia was observed in 1,260 SCD patients older than 20 years. Bone was the most common source of Salmonella infection (nearly 80%) followed by lung (8%), and no source was identified in approximately 8% of patients with Salmonella bacteremia. (5)

A more recent study evaluated the most common microorganisms that cause bacteremia in SCD. (6) From January 1993 to May 2001, 163 positive blood cultures were obtained during febrile episodes in children with SCD. Of these cultures, 47% were pathogenic and 53% contaminants. Salmonella accounted for 17% of positive blood cultures in the pathogenic group, 67% of which were associated with osteomyelitis. However, age-specific incidence rates of Salmonella bacteremia were not calculated. (6)

Investigators from the Jamaican Sickle Cell Clinic retrospectively reviewed all Salmonella isolations from SCD patients during a 22-year period. (7) They identified 55 child and adult patients with Salmonella infections, 28 (51%) of whom initially had osteomyelitis and 27 (49%) with bacteremia. Four patients with bacteremia subsequently developed osteomyelitis and three patients with initial osteomyelitis became bacteremic with no apparent bone changes. Ninety-six percent of Salmonella isolations occurred before 10 years of age and 35% before 3 years of age. Of the 32 patients who had osteomyelitis, no patients died, 13 had recurrent or persistent bone lesions, and 19 had resolution of their symptoms. Of the 30 patients with bacteremia, 7 (23%) died as a result of their infection. Patients who died as a result of Salmonella septicemia ranged in age from 1 to 43 years and usually presented with abdominal or generalized pain. Mortality differences between patients with Salmonella osteomyelitis versus bacteremia were attributed to a higher index of suspicion in patients presenting with bone pain and thus earlier use of anti-Salmonella antibiotics. (7)

The differentiation of bone infarction from acute osteomyelitis in patients with SCD is challenging, as the clinical presentations of the two conditions are similar and laboratory studies are of limited value. (8) In a retrospective review of all cases of osteoarticular infections in SCD children from the Medical College of Georgia between 1973 and 1995, there were 14 cases of bone or joint infections (10 osteomyelitis, four septic arthritis). The most common presenting signs and symptoms were pain (79%), swelling (71%), fever (71%), tenderness (86%), leucocytosis (93%) and elevated Wester-gren sedimentation rates (93%). (9) Fifty-eight percent of the children had positive blood cultures, and 70% of the most common offending organisms found in osteomyelitis were Salmonella (8 of 10 cases). (9)

Specific radiographic studies can aid in making the initial assessment and to determine whether the patient has an infarct or osteomyelitis. (10) Investigators from the Children's Hospital Los Angeles studied a combination of radionuclide bone marrow and bone scans in 79 consecutive episodes of acute bone pain in children with SCD to aid in the differentiation between bone infarction and osteomyelitis. (11) This test accurately diagnosed 70 cases of bone infarction and 5 with normal scans. Four patients had a normal uptake on the bone marrow scan and abnormal uptake on the bone scan at the site of pain, suggestive of acute osteomyelitis. Three of these cases had positive cultures, and all responded to antibiotic treatment. (11) In small studies, gadolinium-enhanced MRI has proven useful in distinguishing between acute medullary bone infarct and osteomyelitis. (12)

The type of infection in our patient deserves some comments since most Salmonella are susceptible to ceftriaxone. A limited number of cases of ceftriaxone-resistant Salmonella have been reported in the United States, mostly in children. (13-16) This resistance to extended-spectrum cephalosporins among nontyphoidal Salmonella isolates has been attributed to the acquisition of multiresistant plasmids encoding a variety of extended-spectrum beta lactamase. Exchange of resistance determinants between salmonellae and nosocomial enterobacteria seems to be frequent, at least in developing countries. (17) The AmpC (CMY-2) beta lactamase has been linked to the use of antimicrobial agents in livestock, with the dissemination and transmission of these strains to humans. (14,15) Clinicians should be aware of the contribution of antibiotic use in livestock to antibiotic-resistant infections in humans.

Conclusions

In febrile adult SCD patients who present with bacteremia, an antibiotic regimen that includes coverage for Salmonella species must be promptly initiated and imaging studies searching for the source should be routinely performed.

References

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10. Wong AL, Sakamoto KM, Johnson EE. Differentiating osteomyelitis from bone infarction in sickle cell disease. Pediatr Emerg Care 2001;17:60-63.

11. Skaggs DL, Kim SK, Greene NW, et al. Differentiation between bone infarction and acute osteomyelitis in children with sickle-cell disease with use of sequential radionuclide bone-marrow and bone scans. J Bone Joint Surg Am 2001;83-A:1810-1813.

12. Umans H, Haramati N, Flusser G. The diagnostic role of gadolinium enhanced MRI in distinguishing between acute medullary bone infarct and osteomyelitis. Magn Reson Imaging 2000;18:255-262.

13. Herikstad H, Hayes PS, Hogan J, et al. Ceftriaxone-resistant Salmonella in the United States. Pediatr Infect Dis J 1997;16:904-905.

14. Dunne EF, Fey PD, Kludt P, et al. Emergence of domestically acquired ceftriaxone-resistant Salmonella infections associated with ampC [beta]-lactamase. JAMA 2000;284:3151-3156.

15. Fey PD, Safranek TJ, Rupp ME, et al. Ceftriaxone-resistant salmonella infection acquired by a child from cattle. N Engl J Med 2000;342:1242-1249.

16. Gupta A, Fontana J, Crowe C, et al. Emergence of multidrug-resistant Salmonella enterica serotype Newport infections resistant to expanded-spectrum cephalosporins in the United States. J Infect Dis 2003;188:1707-1716.

17. Miriagou V, Tassios PT, Legakis NJ, Tzouvelekis LS. Expanded-spectrum cephalosporin resistance in non-typhoid Salmonella. Int J Antimicrob Agents 2004;23:547-555.

Heirlooms we don't have in our family. But stories we've got.
--Rose Cherin

James S. Morgan, MD, and Damian A. Laber, MD, FACP 

From the Division of Hematology and Medical Oncology, Department of Medicine, University of Louisville, J.G. Brown Cancer Center. Louisville, KY.

Reprint requests to Damian A. Laber, MD, FACP, J.G. Brown Cancer Center, University of Louisville, 529 South Jackson Street, Louisville, KY 40202. Email: [e-mail]

Accepted March 8, 2006.

RELATED ARTICLE: Key Points

* In SCD adults with sepsis, empiric antibiotics that cover for Salmonella must be promptly implemented.

* Ceftriaxone-resistant Salmonella bacteremia can occur in adults with SCD.

* Imaging studies looking for osteomyelitis should be done routinely in SCD patients with septicemia.