In April, the infectious diseases world received bad news when Achaogen, the developers of plazomicin (Zemdri), announced that they were filing for bankruptcy. The company’s demise serves notice that the recent boom in antibiotic development, which led to the incredible success of the Infectious Diseases Society of America’s 10 x ’20 drug development initiative, comes with a notorious asterisk. 

I am still amazed by the success of the focus on the desperate need for new antimicrobials. The goal of “10 new antibiotics by 2020” was reached ahead of schedule, and the pipeline contains several new agents with possible approvals in 2019 and 2020. Push incentives, which encourage antibiotic development by helping to reduce research and development costs, have been effective in lowering barriers of entry to the market for new entities, such as plazomicin. With the abandonment of antibiotic development by nearly all large pharmaceutical companies, small companies such as Achaogen with limited resources are left as the driving forces of drug development. I am thankful for these small companies and their interest in creating new antibiotics, but they are vulnerable to setbacks and are dependent on venture capitalists in ways that more robust companies are not. 

Achaogen faced several setbacks. Their prospective study of plazomicin for carbapenem-resistant Enterobacteriaceae (CRE) infections was dogged by low enrollment, though it showed a significant difference in mortality, at the level of a 90% confidence interval. The US Food and Drug Administration ultimately did not grant the indication for CRE infections, leaving plazomicin with only the ubiquitous “complicated urinary tract infection” indication in its label. Although the results showed that fewer relapses occurred than with the β-lactam comparator, most of the pathogens studied were not the highly resistant organisms that clinicians would actually use the drug to treat. 

On the other side, plazomicin is an aminoglycoside, and I think it should have been expected that any uptake of a new drug in this class would be slow. Aminoglycosides have well-known toxicity, which has probably become magnified in the minds of clinicians as more time passes from when they were commonly used. It was the third of 3 drugs with activity against CRE to be approved this decade, losing a race to establish a foothold in a limited market to 2 β-lactams with likely better safety margins (ceftazidime-avibactam and meropenem-vaborbactam). Plazomicin faced an uphill battle. 

So what’s the lesson here? Now that we finally have new antibiotics, does the Achaogen story portend a future in which the companies fail after they are approved, or is it the tale of a company with an antibiotic that was a reach in the first place? I feel that it is a little bit of both. Other antibiotic companies with newly approved products have seen their stock prices drop and may face difficulty generating the investment they require before their drugs become profitable. Formulary uptake of new antibiotics is consistently delayed, even when they successfully address unmet medical needs. Expectations for new products need to be tempered. 

What would help? Pull incentives. Now that antibiotics are being approved and delivered to the market, we need to ensure that they stay there and remain available for patients. Models such as transferable patent extensions could both reenergize large pharmaceutical companies into antibiotic development and reward smaller companies for successful research. As it stands, our need for new antimicrobials, continuously fed by bacterial evolution, is being falsely met by our current drug development model. 

this month, by Christina G. Rivera, PharmD, BCPS, AAHIV-M, discusses whether outpatient antimicrobial stewardship is a field of dreams or land of opportunity for pharmacists. 

As always, enjoy this issue, and keep up with us at ContagionLive.com. 

Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia, Pennsylvania. He is also the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple. *He is an active member of the Society of Infectious Diseases Pharmacists.

Articles

Editor-in-Chief Letter

The June Editor-in-Chief letter by Dr. Jason Gallagher tackles the story of Achaogen and what its bankruptcy means for antibiotic development.

Achaogen&mdash;Canary in the Coal Mine or Developer of an Unwanted Product?

The critical importance of antimicrobial stewardship (AMS) to contain health care costs, combat antimicrobial resistance, and avoid unnecessary medication-related adverse events has become well accepted within the medical community. This widespread recognition has fostered the development of robust, outcome-driven, multidisciplinary AMS programs across a wide range of health care settings, from small, rural community hospitals to large, tertiary health care systems. Formal AMS programs have evolved and remained largely established within acute care hospitals given the prevalence of broad-spectrum antimicrobial use, higher rates of multidrug antimicrobial resistance, and risks of hospital-acquired infections. 

Though the majority of AMS efforts have been directed toward inpatient practices, 60% of all antibiotic expenditures in the United States occur in the outpatient setting.

 In the United States alone during 2013, 269 million antibiotic prescriptions were dispensed from outpatient pharmacies.

 It has been estimated that up to 30% of outpatient antibiotic prescriptions may be inappropriate, based upon professional society endorsed national guidelines for infectious syndromes.

 Further, the burden of community acquired 

 is significant, with up to 35% of adult and 70% of pediatric 

 cases occurring in patients who had no recent overnight stay in a health care facility.

 In response to the need for systematic outpatient AMS, the US Centers for Disease Control and Prevention (CDC) released the Core Elements of Outpatient Antibiotic Stewardship in 2016. The recommendations center around 4 cornerstone elements: commitment, action for policy and practice, tracking and reporting, and education and expertise.

Pharmacists have garnered an established role on inpatient AMS teams, as evident in the CDC’s Core Elements of Hospital Antibiotic Stewardship Programs. The drug expertise element states that a pharmacist leader should be appointed to improve antibiotic use.

 In contrast, the proposed involvement of pharmacists in outpatient-based AMS as described by the Core Elements of Outpatient Antibiotic Stewardship is more subtle.

 The document’s intended audience members represent several areas that pharmacists commonly work in, such as primary care clinics, emergency departments, retail health clinics in pharmacies, and health care systems, though pharmacists themselves are not specifically mentioned in these settings. Community pharmacies and pharmacists are described as a potential partner for outpatient AMS activities, along with health insurance companies, local microbiology laboratories, long-term care facilities, and others.

 Certainly, community-based pharmacists are well situated to be key players in outpatient AMS. Most outpatient antibiotic prescriptions in the United States are dispensed at community pharmacies, and virtually all of those for acute infectious syndromes would be processed through a local pharmacy. 

To date, published literature focusing on pharmacist-led AMS interventions in community pharmacies centers around the use of pharmacist—prescriber collaborative practice agreements (CPAs) and point-of-care testing. CPAs create a formal practice agreement between the pharmacist(s) and prescriber(s) that specifies the functions a pharmacist can perform outside the usual scope of practice.

 Although legal throughout most of the United States, rules and regulations governing CPAs vary from state to state. Of interest within the realm of outpatient AMS, CPAs may grant pharmacists prescribing authority within predefined infection-related clinical scenarios or specifically for antimicrobials. Point-of-care testing dovetails nicely with community pharmacist CPAs. In nearly all states, pharmacists can use Clinical Laboratory Improvement Amendments (CLIA)—waived tests, which are defined by the FDA as “so simple and accurate as to render the likelihood of erroneous results negligible; or pose no reasonable risk of harm to the patient if the test is performed incorrectly.’’

 Two such examples of CLIA-waived tests used in pharmacist-led outpatient AMS are the rapid influenza diagnostic test (RIDT) and group A 

From December 2013 to April 2014, a pilot program involving 55 community pharmacies in 3 states (Michigan, Nebraska, and Minnesota) used a pharmacist CPA and RIDT with the aim of shortening the time to receipt of antivirals and reducing inappropriate antimicrobial use in patients with suspected influenza infection.

 Of the 75 adult patients included in the study, just 8 (11%) were positive for influenza by RIDT and, per CPA, were dispensed oral oseltamivir by the pharmacist. Patients with a negative test were counseled on symptomatic management without provision of an antiviral or antibacterial. All patients were followed up in 24 to 48 hours, and no adverse events were reported. Interestingly, patient satisfaction was >90%, despite the majority of patients not receiving an antibacterial or antiviral medication. The authors suggest this program demonstrated that a physician—pharmacist collaboration for seasonal influenzalike illness can improve appropriate use of antivirals and decrease unnecessary antibiotic prescribing. Given that a large proportion of patients presented after regular physician office hours or had no primary care physician (39% and 35%, respectively), the authors hypothesized that emergency department and urgent care visits were also avoided.

During the same time frame, this group of investigators evaluated the use of a pharmacist CPA and GAS testing coupled with a bacterial pharyngitis scoring tool in patients who presented with pharyngitis symptoms.

Adult patients with a Centor score of 1 or greater, younger than 46 years, and clinically stable with a positive GAS test qualified for treatment with amoxicillin or azithromycin per protocol. Of 316 patients screened, 273 were eligible for testing, of which 48 (17.5%) were positive and received antimicrobial treatment. Similar to the pharmacist—physician collaborative pilot on influenzalike illness, there were no adverse outcomes and patient satisfaction was high (>80%), with a large percentage of patients presenting during off-hours and not having primary care providers (43.9%).

 In comparison, the literature suggests rates of 60% to 80% antimicrobial prescribing for adult pharyngitis in usual care. Taken together, these studies offer evidence that community pharmacists armed with the right tools can be a significant asset in guiding the judicious use of outpatient antimicrobials.

EMERGENCY DEPARTMENTS AND ACADEMIC DETAILING AMS 

Data also demonstrate that emergency department (ED) pharmacists can play a key role in AMS efforts. From October 2011 to September 2012 at The University of Utah, ED pharmacists retrospectively reviewed 180 positive urine culture results (>100,000 CFU/mL), patient symptoms, diagnosis, and discharge antibiotics for patients discharged from the ED. Following an ED protocol, the pharmacists determined that 42 (23%) of empiric discharge antibiotics were considered inappropriate and required pharmacist intervention. All but 7 patients (17%), who were lost to follow-up, had a change made in their therapies.

 The authors concluded that ED pharmacists can improve patient care and reduce inappropriate antimicrobial use after discharge. 

Tailored education delivered to health care professionals by a content expert to encourage best practices, also known as academic detailing,

 is a typical component of inpatient antimicrobial stewardship programs. Outpatient AMS—focused academic detailing had mixed results, with 1 study showing a decrease in cephalexin prescribing after a face-to-face meeting with a pharmacist and others showing no statistically significant change with pharmacist education efforts.

 AMS education is generally recommended to combine with a corresponding AMS intervention such as audit and feedback, clinical decision support, delayed prescribing, and/ or public display of provider pledges to AMS.

In fall 2018, the Society of Infectious Diseases Pharmacists released a position statement on the essential role of pharmacists in outpatient AMS and, the summer preceding, a call to action for outpatient antimicrobial stewardship in Journal of American Pharmacists Association.

 The aforementioned studies, among others, are cited as evidence that pharmacists must be leaders in outpatient AMS.

 Road maps and other diverse potential areas for outpatient AMS programs, from vaccination to direct patient education (

), are discussed, along with barriers to outpatient AMS, including perceived lack of financial incentives. 

In conclusion, there is widespread recognition of the need for outcomes-based, systematic outpatient AMS programs. Pharmacists, particularly those enabled with a CPA and point-of-care testing, are poised to be change leaders in the betterment of outpatient infectious diseases care. 

Rivera is an outpatient infectious disease clinic—based pharmacist at Mayo Clinic in Rochester, Minnesota, and an instructor of pharmacy at Mayo Clinic College of Medicine and Science. She welcomes professional correspondence on this and related topics at rivera. christina@mayo.edu. *She is a member of the Society of Infectious Diseases Pharmacists.

Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Danziger LH. A national evaluation of antibiotic expenditures by healthcare setting in the United States, 2009. 

 2013;68(3):715-8. doi: 10.1093/jac/dks445.

Outpatient antibiotic prescriptions — United States, 2013. US Centers for Disease Control and Prevention website. cdc.gov/antibiotic-use/community/programs-measurement/state-local-activities/outpatient-antibiotic-prescriptions-US-2013.html. Updated September 12, 2017. Accessed April 28, 2019.

Fleming-Dutra KE, Hersh AL, Bartoces M, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011.

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Lessa FC, Mu Y, Bamberg WM, et al. Burden of 

 2015;372(9):825-834. doi: 10.1056/NEJMoa1408913.

 infection among children across diverse US geographic locations. 

Core elements of outpatient antibiotic stewardship. US Centers for Disease Control and Prevention website. 

cdc.gov/antibiotic-use/community/improving-prescribing/core-elements/core-outpatient-stewardship.html

Core elements of hospital antibiotic stewardship programs. US Centers for Disease Control and Prevention website. 

cdc.gov/getsmart/healthcare/implementation/core-elements.html

Advancing team-based care through practice agreements: a resource and implementation guide for adding pharmacists to the care team. US Centers for Disease Control and Prevention website. ttps://www.cdc.gov/dhdsp/pubs/docs/CPA-Team-Based-Care.pdf. Published 2017. Accessed TK.

Buss VH, Deeks L, Shield A, Kosari A, Naunton M. Analytical quality and effectiveness of point-of-care testing in community pharmacies: a systematic literature review. 

. 2018 Jul 20. pii: S1551-7411(18)30315-2. doi: 10.1016/j.sapharm.2018.07.013.

Klepser ME, Klepser DG, Dering-Anderson AM, Morse JA, Smith JK, Klepser SA. Effectiveness of a pharmacist-physician collaborative program to manage influenza-like illness. 

 2016;56(1):14-21. doi: 10.1016/j.japh.2015.11.008.

Klepser ME, Adams AJ, and Klepser DG. Antimicrobial stewardship in outpatient settings: leveraging innovative physician-pharmacist collaborations to reduce antibiotic resistance. 

 2015;13(3):166-173. doi: 10.1089/hs.2014.0083.

Klepser DG, Klepser DG, Dering-Anderson A, et al. Implementation and evaluation of an innovative pharmacist-physician collaborative group A streptococcus disease state management program. National Community Pharmacists Association Annual Meeting. 2014.

Klepser DG, Bisanz SE, Klepser ME. Cost-effectiveness of pharmacist-provided treatment of adult pharyngitis. 

Linder JA, Stafford RS. Antibiotic treatment of adults with sore throat by community primary care physicians: a national survey, 1989-1999.

Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. 

 2014;174(1):138-140. doi: 10.1001/jamainternmed.2013.11673.

Lingenfelter E, Drapkin Z, Fritz K, Youngquist S, Madsen T, Fix M. ED pharmacist monitoring of provider antibiotic selection aids appropriate treatment for outpatient UTI. 

. 2016;34(8):1600-1603. doi: 10.1016/j.ajem.2016.05.076.

Bishop C, Yacoob Z, Knobloch MJ, Safdar N. Community pharmacy interventions to improve antibiotic stewardship and implications for pharmacy education: a narrative overview [published online September 17, 2018]. 

Avorn J, Soumerai SB. Improving drug-therapy decisions through educational outreach. a randomized controlled trial of academically based “detailing”. 

Ray WA, Schaffner W, Federspiel CF. Persistence of improvement in antibiotic prescribing in office practice.

Schaffner W, Ray WA, Federspiel CF, Miller WO. Improving antibiotic prescribing in office practice. A controlled trial of three educational methods.

Erramouspe J. Impact of education by clinical pharmacists on physician ambulatory care prescribing of generic versus brand-name drugs. 

De Santis G, Harvey KJ, Howard D, Mashford ML, Moulds RF. Improving the quality of antibiotic prescription patterns in general practice. the role of educational intervention. 

Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. 

 2016;62(10):e51-e77. doi: 10.1093/cid/ciw118.

Blanchette L, Gauthier T, Heil E, et al; Outpatient Stewardship Working Group. The essential role of pharmacists in antibiotic stewardship in outpatient care: an official position statement of the Society of Infectious Diseases Pharmacists. 

. 2018;58(5):481-484. doi: 10.1016/j.japh.2018.05.013.

Klepser ME, Dobson EL, Pogue JM, et al; SIDP Community Pharmacy Antimicrobial Stewardship Task Force. A call to action for outpatient antibiotic stewardship. 

. 2017;57(4):457-463. doi: 10.1016/j.japh.2017.03.013.

Dobson EL, Klepser ME, Pogue JM, et al; SIDP Community Pharmacy Antimicrobial Stewardship Task Force. Outpatient antibiotic stewardship: interventions and opportunities. 

. 2017;57(4):464-473. doi: 10.1016/j.japh.2017.03.014.

Feature - Stewardship & Prevention

Relevant existing reports, though limited, demonstrated positive outcomes and suggest a promising space for pharmacy practice growth in outpatient antimicrobial stewardship. 

Outpatient Antimicrobial Stewardship: Field of Dreams or Land of Opportunity for Pharmacists?

A 42-year-old man presented to the hospital with approximately 2 weeks of right testicular pain and swelling. He received a diagnosis of epididymo-orchitis and was treated with ceftriaxone 250 mg intramuscularly and doxycycline 100 mg twice daily for 14 days. During a follow-up visit at his primary HIV provider’s office, the patient noted that he had less pain, but his swelling had not resolved. He denied any history of fever, weight loss, night sweats, cough, or hemoptysis. 

The patient had a history of HIV, which was diagnosed in 2014 and had been treated with abacavir/dolutegravir/ lamivudine (Triumeq). One month prior to admission, his CD4 count was 304 (22%), and his HIV RNA by polymerase chain reaction (PCR) was undetectable. Early in his diagnosis, he had frequent episodes of syphilis, now with a nonreactive rapid plasma regain after adequate treatment. 

The patient was born in the United States and lived on the East Coast. He denied any national or international travel. He denied smoking, alcohol, and illicit drug use. He had a pet dog. He had a history of incarceration for approximately 6 months many years ago. 

The patient appeared well. His temperature was 98.6°F; heart rate, 75 beats per minute; blood pressure, 110/70 mm Hg; and respirations, 14 per minute. His lungs were clear to auscultation bilaterally. A cardiac exam showed normal S1 and S2 with no murmurs. An abdominal examination showed normoactive bowel sounds with no tenderness and no hepatosplenomegaly. On a genital exam, the patient’s right testicle was swollen and nontender; the left was normal. The inguinal lymph nodes were not palpable. 

Lab studies revealed normal leukocyte, hemoglobin, and platelet counts. The blood urea nitrogen was 12 mg/dL; creatinine level, 1.15 mg/dL; aspartate aminotransferase, 27 U/L; and alanine aminotransferase, 15 U/L. A urine nucleic acid amplification test for 

 was negative, as was a urine culture. A computed tomography scan of his abdomen and pelvis with contrast showed a large right testicle measuring 8.3 × 3.5 × 3.5 cm with heterogeneous enhancement and adjacent fluid. The serum tumor markers β—human chorionic gonadotropin and β-fetoprotein were within normal limits. 

The patient was referred to urology to rule out malignancy. After a long discussion, a decision was made to pursue a right inguinal exploration. Despite negative malignancy markers and due to the appearance of the testicle, the patient underwent a right orchiectomy. On gross examination, the testicle was 8 cm, with a smooth-walled cyst and 2 ill-defined masses/thickened areas in the testis and epididymis with purulent material. 

The operating room specimen was sent to pathology, and the right testicle and epididymis showed large areas of destruction by multiple caseating and noncaseating epithelioid granulomas with scattered foreign body giant cells and surrounding fibrosis (

). The auramine-rhodamine stain showed a few rodlike bacteria, highly suspicious for Mycobacterium species (

). There was not enough of the sample to be sent for an acid-fast bacilli (AFB) culture. The testicular specimen was sent to the US Centers for Disease Control and Prevention for PCR testing, and tuberculosis (TB) was confirmed. Because this was PCR, susceptibilities could not be performed. Three early-morning urine specimens were sent to the lab for AFB stain and culture. All urine specimens grew Mycobacterium tuberculosis (Mtb). 

The patient was started on a 4-drug treatment regimen of isoniazid, ethambutol, pyrazinamide, and rifabutin along with pyridoxine pending susceptibility testing. After 2 months, his susceptibility testing was available (

), and the isolate was susceptible to all first-line drugs. Subsequently, ethambutol and pyrazinamide were discontinued. 

Tuberculosis, a disease affecting one-fourth of the world’s population, is primarily caused by Mtb, an acid-fast aerobic bacillus.

 Infection occurs when bacilli are inhaled from a patient with active pulmonary infection. These bacilli reach the alveoli, where they are phagocytized by alveolar macrophages and then replicate before diffusing to nearby endothelial and epithelial cells.

 At this early stage of disease, bacilli can spread lymphatically or hematogenously to other organs before the development of an effective immune response. This stage, known as primary infection, is usually clinically and radiographically silent. In patients with a normal immune system, T cells and macrophages surround the organism in granulomas that limit their multiplication and spread. At this point, the infection is contained but not eradicated, which is known as latent tuberculosis infection (LTB). Active infection will develop in approximately 5% of individuals with LTB, with half of these cases occurring within 2 years after primary infection.

 Although TB is a known multisystem disease, it exclusively affects the lungs in 75% to 80% of cases, with the majority of extrapulmonary disease manifesting in the pleura and lymph nodes.

Urogenital TB is rare, thought to make up just 30% to 40% of these extrapulmonary cases.

 Involvement of just the genital organs is described in 5% to 30% of these urogenital cases, with higher rates observed where TB is more prevalent.

 The mechanism of dissemination of disease into the scrotal sac is debated. In most cases, TB epididymo-orchitis occurs via retrograde spread from the urinary tract, but it also may gain entry via the early hematogenous and lymphatic spread of primary pulmonary disease.

 Sexual transmission with primary penile TB is also thought to be possible. Of note, half of patients with urogenital disease have renal involvement.

Presentation of this disease is variable and can occur at any age, although it most commonly presents in the fourth and fifth decade. History of prior TB infection, close contact with TB infected individuals, travel to endemic areas, or immune system compromise may be helpful diagnostically, but these data points are not always present.

 Eighty percent of hosts infected with genital TB may develop a scrotal swelling, which is painful in approximately 44% of cases.

 It is often accompanied by ulceration or a draining sinus tract and may present with lower urinary tract symptoms such as dysuria and hematuria.

 Genital TB without evidence of pulmonary disease can occur, and systemic symptoms such as fever, chills, and night sweats are not reliably present.

 Presentation may mimic multiple conditions including testicular tumor, testicular torsion, hydrocele, acute infections, or testicular sarcoidosis.

Because of the disease’s nonspecific symptoms, it is recommended that TB always be considered in the differential diagnosis of cases with prolonged, unresolved urinary symptoms.

 Early diagnosis is critical to preventing destruction and fibrosis, which can lead to infertility, contracted bladder, bilateral kidney injury, and end-stage renal disease.

 Microscopic analysis of the urine may yield nonspecific findings such as sterile pyuria, microscopic or macroscopic hematuria, or acidic urine. Definitive diagnosis can be made by urine acid-fast culture cultures, a method that is time intensive, with relatively low sensitivity due to sporadic shedding of bacilli.

 Due to these constraints, PCR testing can be performed on urine, expressed prostatic secretions, or ejaculate. PCR is less sensitive and similarly specific compared with culture, but it is advantageous due to its rapidity. PCR cannot, however, differentiate between live and dead organisms.

 In this case, histopathological examination should be attempted with inguinal exploration, yielding caseous necrosis or stained AFB testing for definitive diagnosis. Necrotizing granulomatous inflammation without evidence of AFB suggests TB but can also represent another infectious agent, such as species of 

, and nontuberculous mycobacteria, as well as others.

 For this reason, tissue PCR for TB is still useful in optimizing diagnostic precision. 

Of the 10 million incident cases of TB in 2017, 9% were coinfected with HIV.

 Patients with HIV are more susceptible to all manifestations of TB infection, including epididymo-orchitis, due partly to the critical role of CD4-positive T lymphocytes in the control of the disease.

 First-line treatment for drug-susceptible strains in both immunocompetent and immunocompromised hosts is antimycobacterial chemotherapy including a course of isoniazid, rifampin, ethambutol, and pyrazinamide with pyridoxine. A 6-month course is likely as effective in urogenital TB as it is in pulmonary TB because pulmonary TB is the more standard presentation.

 No randomized control trial has been performed to identify the ideal treatment duration. Despite the effectiveness of treatment with this regimen, regular annual follow-ups are recommended to evaluate for relapse. 

Abernethy is a fourth-year medical student at Perelman School of Medicine at the University of Pennsylvania in Philadelphia. 

Innis is an associate professor of pathology and laboratory medicine at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia in Pennsylvania. 

Glaser is an assistant professor of clinical pathology and laboratory medicine at Perelman School of Medicine at the University of Pennsylvania in Philadelphia. 

Short is an associate professor of medicine at Perelman School of Medicine at the University of Pennsylvania in Philadelphia. 

 Geneva, Switzerland: World Health Organization; 2018. who.int/tb/publications/global_report/en/. Published 2018. Accessed February 2018.

2. Wolf AJ, Desvignes L, Linas B, et al. Initiation of the adaptive immune response to 

 depends on antigen production in the local lymph node, not the lungs. 

. 2018;205(1):105-115. doi: 10.1084/jem.20071367. 

3. Nienhaus A, Schablon A, Preisser AM, Ringshausen FC, Diel R. Tuberculosis in healthcare workers — a narrative review from a German perspective. 

4. Balasubramanian V, Pavelka MS Jr, Bardarov SS, et al. Allelic exchange in 

 with long linear recombination substrates. 

5. Kulchavenya E, Kim CS, Bulanova O, Zhukova I. Male genital tuberculosis: epidemiology and diagnostic. 

 2012;30(1):15-21. doi: 10.1007/s00345-011-0695-y.

6. Kulchavenya E, Khomyakov V. Male genital tuberculosis in Siberians. 

 2006;24(1):74-78. doi: 10.1007/s00345-005-0048-9.

7. Das A, Batabyal S, Bhattacharjee S, Sengupta A. A rare case of isolated testicular tuberculosis and review of literature. 

 2016;5(2):468-470. doi: 10.4103/2249-4863.192334.

8. Figueiredo AA, Lucon AM, Srougi M. Urogenital tuberculosis. 

 2017;5(1). doi: 10.1128/microbiolspec.TNMI7-0015-2016.

9. Yadav S, Singh P, Hemal A, Kumar R. Genital tuberculosis: current status of diagnosis and management. 

 2017;6(2): 222-233. doi: 10.21037/tau.2016.12.04

10. Suankwan U, Larbcharoensub N, Viseshsindh W, Wiratkapun C, Chalermsanyakorn P. A clinicopathologic study of tuberculous epididymo-orchitis in Thailand. 

11. Thompson RW, Yu H, Dahl DM, Hurtado RM, Sajed DP. Case 10-2018: an 84-year-old man with painless unilateral testicular swelling. 

 2018;378(13): 1233-1240. doi: 10.1056/NEJMcpc1712224.

12. Cek M, Lenk S, Naber KG, et al; Members of the Urinary Tract Infection (UTI) Working Group of the European Association of Urology (EAU) Guidelines Office. EAU guidelines for the management of genitourinary tuberculosis. 

. 2005;48(3): 353-362. doi: 10.1016/j.eururo.2005.03.008.

13. Kumar R. Reproductive tract tuberculosis and male infertility. 

 2008;24(3):392-395. doi: 10.4103/0970-1591.42624.

14. Yazdani M, Shahidi S, Shirani M. Urinary polymerase chain reaction for diagnosis of urogenital tuberculosis. 

15. Sharma SK, Kadhiravan T, Banga A, Goyal T, Bhatia I, Saha PK. Spectrum of clinical disease in a series of 135 hospitalised HIV-infected patients from north India. 

16. Pawlowski A, Jansson M, Skold M, Rottenberg ME, Källenius G. Tuberculosis and HIV co-infection. 

. 2012;8(2):e1002464. doi: 10.1371/journal.ppat.1002464.

17. Kadhiravan T, Sharma SK. Medical management of genitourinary tuberculosis. 

 2008;24(3):362-368. doi: 10.4103/0970-1591.42619.

Case Study

Being immunocompromised increases risk of rare Mycobacterium tuberculosis epididymo-orchitis. 

An Unusual Case of Testicular Swelling in a Patient With HIV

Blood cultures remain the gold standard for diagnosing bacterial and 

 bloodstream infections (BSIs), but they are limited by slow turnaround and suboptimal sensitivity.

 Data from some but not all retrospective studies suggest that rapid initiation of active antimicrobial therapy correlates with reduced mortality among patients with bacterial or 

 Although such findings have not been validated in prospective studies,

 the limitations of blood cultures and quality standards for sepsis and septic shock provide a rationale for aggressive empiric broad-spectrum antimicrobial therapy.

These practices may promote unnecessary antimicrobial usage, drug toxicity, and emergence of resistance.

Culture-independent diagnostic tests (CIDTs) that detect pathogens and antimicrobial resistance genes within clinical samples are transforming clinical practice.

 Syndromic CIDT panels for respiratory specimens, stool, and cerebrospinal fluid facilitate rapid identification or exclusion of infections due to particular organisms and antimicrobial initiation or de-escalation strategies.

 Likewise, commercial molecular tests of positive blood cultures for pathogen or resistance determinant identification are valuable patient care and stewardship tools.

 CIDTs of whole blood samples from patients with suspected BSIs have not gained widespread acceptance, in part because costs are high and clinicians are unsure how to incorporate testing into rational management paradigms.

 This paper reviews the performance of blood cultures and direct-from-whole-blood CIDTs for bacterial and 

 BSIs and provides a conceptual framework for using CIDTs in the clinic. 

Blood culture sensitivity for detecting bacteremia is ~73%, 90%, and 98% if 1, 2 and 3 sets of aerobic and anaerobic bottles, respectively, are collected in the absence of antimicrobial treatment.

 Such performance is contingent upon collecting ≥20 mL of blood in each culture set. Smaller volumes, as often collected in hospitalized patients, increase false negativity.

 Blood cultures may require several days for bacteria to achieve detectable concentrations and additional time for species identification and resistance testing.

 Blood cultures are ~50% sensitive for diagnosing invasive candidiasis.

 Moreover, blood cultures become positive late in the course of invasive candidiasis, and incubation times prior to positivity are typically longer than those for detecting bacteria.

 Antimicrobial treatment reduces sensitivity for bacteria and 

 which is notable because 28% to 63% of blood cultures are collected from patients who are receiving antimicrobial agents.

Several direct-from-whole-blood CIDTs couple nucleic acid amplification with novel technologies for target detection, including Iridica, SeptiFast, SepsiTest, Magicplex, and T2Direct (T2Bacteria, T2Candida) assays.

 T2Direct is the only FDA-cleared system.

 Assay characteristics and performance are summarized in the 

. Interpretation of performance is complicated by study heterogeneity and limitations of blood cultures as gold standard. CIDTs require ≤5 mL of blood and provide results within 4 to 10 hours. In general, DNA amplification-based technologies are more sensitive than blood cultures in patients receiving antimicrobials.

We will focus on SeptiFast and T2Direct as examples of broad- and narrow-spectrum platforms, respectively.

 Concepts presented here can be applied to other tests. 

In patients presenting to the hospital with fever or those with sepsis in the absence of septic shock, anticipated SeptiFast and T2Bacteria PPVs for targeted bacteria are each ~50% to 75%. SeptiFast offers an advantage of detecting ~85% to 90% of bacteria and fungi that cause BSIs, whereas T2Bacteria detects 5 bacteria that account for ~50% of BSIs.

 A potential disadvantage of broad-spectrum panels is that some targets are uncommon causes of BSI and therefore more likely to generate false-positive results. Although T2Bacteria NPVs are excellent for targeted bacteria, they are inferior to SeptiFast NPVs in excluding BSIs due to any bacteria. 

 are typically rare causes of BSI in these populations,

 and T2Candida PPVs and NPVs are unlikely to be useful in most cases. Anticipated T2Candida PPVs may approach 67%, and NPVs are 99.7% among septic patients with risk factors for candidemia in whom a causative bacterium is not identified. T2Candida detects species that account for >95% of candidemia at most centers.

 BSI increases in septic shock, and anticipated PPVs of each test are ≥70%. However, SeptiFast and T2Bacteria NPVs are just 78% and 62%, respectively, for excluding BSIs in the setting of septic shock; T2Candida NPV remains excellent (99.5%). 

INCORPORATING CIDTS INTO CLINICAL AND STEWARDSHIP PRACTICES 

Surviving Sepsis guidelines endorse empiric broad-spectrum antibiotic therapy within 1 hour of triage for suspected sepsis and septic shock and rapid de-escalation based on susceptibility of causative organisms or if infection is excluded.

 Other experts propose more nuanced, case-by-case approaches, in which empiric antibiotics are administered immediately for suspected septic shock, but clinical observation and diagnostic testing may be undertaken prior to treatment decisions in at least some patients with suspected sepsis in the absence of shock.

In patients with possible sepsis in whom treatment decisions have been deferred pending workup, positive SeptiFast or T2Bacteria results may shorten the time to antibiotic treatment compared with waiting for positive blood cultures. If blood or other cultures are negative and an alternative, noninfectious diagnosis is not established, there is a good chance based on predictive values that a positive CIDT has identified a BSI that would have been missed otherwise. In such cases, continuing antibiotic treatment against the CIDT-identified pathogen is reasonable. Detection of resistance genes by SeptiFast may guide early selection of active antibiotics. T2Bacteria does not include resistance genes, but the panel is directed against ESKAPE pathogens (

Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, 

) that are often resistant to first-line antibiotics.

 In high-risk patients, such as those colonized by a resistant pathogen included in the panel, a positive T2Bacteria result may justify use of an alternative agent. 

If SeptiFast or T2Bacteria results are negative and a patient with suspected sepsis is stable, clinicians may decide to withhold antimicrobials pending blood and other culture results. This strategy is reasonable because empiric treatment has not proved superior to culture-directed treatment of BSIs or suspected sepsis, and ~50% of suspected sepsis is ultimately ascribed to noninfectious etiologies.

 If antimicrobials have been administered, combined negative CIDT and culture results may offer an argument for de-escalation. Approaches to using CIDTs similar to those described for possible sepsis also may be useful for managing febrile patients in the emergency department. 

In patients with presumed septic shock, clinicians will not wait for CIDT results before initiating broad-spectrum antibiotics (often in combination). In these patients, SeptiFast and T2Bacteria may have value if antibiotics are administered before blood cultures or whole blood samples are collected. Positive CIDT results may help in streamlining empiric antibiotic regimens. T2Candida is likely to be useful in septic shock (and perhaps in sepsis with risk factors for candidemia),

These tests have the potential to transform patient care and antimicrobial stewardship, but they have not gained widespread acceptance, partly because of uncertainty over how to use them clinically. 

June 2019

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June 2019

Achaogen&mdash;Canary in the Coal Mine or Developer of an Unwanted Product?

Outpatient Antimicrobial Stewardship: Field of Dreams or Land of Opportunity for Pharmacists?

An Unusual Case of Testicular Swelling in a Patient With HIV

Bringing Culture-Independent Diagnostic Tests for Bloodstream Infections Into Rational Patient Management

What's in the Pipeline?

Tick, Tick, Tick: Vector-Borne Diseases Ramp Up

More Than Surviving Sepsis: Everything Old Is New Again

DTG/3TC Offers Dual-Drug Therapy for Initial HIV Treatment

Daptomycin Dosing in Obesity: Consideration for a Fixed-Dose Strategy

Optimal Vancomycin Dosing in Obese Patients: Moving Toward the AUC

Latest News

Achaogen—Canary in the Coal Mine or Developer of an Unwanted Product?