Tag Archives: ID

Is vancomycin/zosyn the answer for everything?

Authors: Mariam Abdelghany, PA-C1, Minela Subasic, PA-C1, Anthony Scoccimarro, MD1, Joel Gernsheimer, MD2, and Muhammad Waseem, MD, MS1,3 (Lincoln Medical & Mental Health Center Bronx, New York1; SUNY Downstate Medical Center New York2; St. Georges University Grenada West Indies3) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case:

A 65-year-old man is brought to the ED in shock. His vital signs include temperature 102 F, heart rate 132 beats/minute, respiratory rate 36 breaths/minute, blood pressure 80/50 mm Hg, and oxygen saturation 91%. His abdomen is markedly tender. After initial stabilization, he is taken to the operating room for emergency laparotomy for suspected peritonitis secondary to perforated appendicitis. Which antibiotic regimen should be administered?

Emergency Physicians are faced with the dilemma of antibiotic selection in patients with presumed sepsis or serious bacterial infection. Suspected sepsis is one of the most common causes of ED evaluation and hospital admission. Broad-spectrum agents, such as piperacillin-tazobactam (Zosyn) and vancomycin, are commonly used for empirical antibiotic coverage in suspected early sepsis and critically ill patients. Several studies show a disturbing trend toward increasing use of broad-spectrum antibiotics.[1],[2] It has been estimated that 55% of all antibiotic prescriptions may be unnecessary.[3] The broad administration of vancomycin is of special concern, as it may lead to the emergence of vancomycin resistant gram-positive cocci.[4] Appropriate antibiotic administration means that the indication for antibiotic use, the choice of the drug, timing of administration, route, dosage, frequency, and duration of administration have been carefully considered and determined to be warranted. In this article, we will discuss instances where the classic combination of vancomycin and Zosyn may be indicated, and where its use may not be warranted.

Medication Background

Before we get started, let’s go over some of the basics for Zosyn and Vancomycin.

Piperacillin/tazobactam (Zosyn)

Piperacillin/tazobactam (Zosyn) is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. This antibiotic has activity against many Gram-positive, Gram-negative, and anaerobic pathogens.  It covers Streptococci, Staphylococci (but not methicillin-resistant S. aureus [MRSA]), Hemophilus, Moraxella, Enterobacteriaceae, and Pseudomonas aeruginosa.[5],[6] It is an excellent anti-anaerobic agent, but does not treat clostridium difficile infections. As an anti-pseudomonal penicillin plus a beta-lactamase inhibitor (which prevents it from being broken down by organisms that possess resistance by producing a beta-lactamase), piperacillin/tazobactam inhibits cell wall mucopeptide synthesis by binding to one or more of the penicillin-binding proteins in the cell wall.[7] It is therefore not effective against organisms that do not have a cell wall like viruses, chlamydia, mycoplasma, and rickettsia, or those with an atypical cell wall like legionella.

The recommended dosing for severe infections, other than nosocomial pneumonia, in patients with normal renal function, is 3.375 g IV Q6h (a total daily dose of 13.5 g, which comes to a total daily dose of 12 g of piperacillin and 1.5 g of tazobactam) for 7-10 days. However, in patients where severe nosocomial pneumonia is a concern, 4.5 g IV can be given in patients with normal renal function. The dose should be adjusted in patients with significant renal dysfunction.

For patients with a creatinine clearance between 20-40 mL/minute, the dose of Zosyn should be 2.25 g IV Q6h for the usual indications, and 3 g IV Q6h IV for nosocomial pneumonia.

For patients with a creatinine clearance less than 20 mL/minute, the dose should be 2.25 g IV Q8h for the usual indications, and 2.25 g IV Q6h for nosocomial pneumonia.  Zosyn should be administered IV no faster than over 30 minutes.

Indications for Piperacillin/Tazobactam Administration:

Intra-abdominal infections

Severe Sepsis (without source)

Bacteremia associated with intravascular line

Skin and skin structure infection

Postpartum/ Puerperal endometritis or pelvic inflammatory disease

Bone and joint infection

Community acquired pneumonia (severe, sepsis)

Nosocomial pneumonia

Zosyn is especially useful when a life-threatening infection with a resistant gram negative organism, particularly pseudomonas, is suspected.

Vancomycin

Vancomycin is a glycopeptide that inhibits cell-wall biosynthesis.[8] Intravenous vancomycin is indicated for serious infections with gram positive organisms, such as staphylococcus (specifically MRSA), streptococcus, and most strains of enterococcus. Intravenous vancomycin remains the drug of choice for serious deep seated MRSA infections.[9] It is also indicated for possible meningitis in children and adults, pending the results of CSF cultures, as it has excellent coverage against pneumococcus, including forms resistant to penicillins and cephalosporins. Vancomycin is poorly absorbed in the GI tract and cannot be used orally, except for treating serious or resistant clostridium difficile infections. It can also be instilled in the peritoneal cavity as part of the dialysate in patients who have peritonitis from peritoneal dialysis.

The recommended dose includes 15-20 mg/kg (actual body weight) every 8-12 hours in patients with normal renal function, with a maximum of 2 g IV. In critically ill patients, a loading dose of 25-30 mg/kg can be administered (though the maximum dose remains the same).[10],[11] Vancomycin should never be administered faster than over one hour in both children and adults. In adults, it should not be administered faster than 10 mg per minute. Administering vancomycin too rapidly may cause a “Red Man Syndrome” with flushing, erythema, pruritis, and even hypotension.

Vancomycin/piperacillin-tazobactam regimen indications               

Vancomycin and piperacillin-tazobactam is a good antibiotic combination to use in critically ill patients with an unclear source of infection, sepsis, or septic shock.  Empiric antibiotic therapy should be started as early as possible and should cover all likely pathogens.  If possible, obtain blood cultures and other appropriate cultures before starting the medications, but if the patient is sick, provide broad spectrum coverage first. The regimen can be modified based on the specific pathogen shown on culture and sensitivity reports when available (this is more for the ICU/floor). [12] Decisions to continue empiric antimicrobial should be based on both clinical assessment and culture results.[13] When possible antibiotics with very broad-spectrum coverage, such as the combination of Zosyn and vancomycin, should be changed to an antibiotic regimen with a narrower spectrum in order to prevent the emergence of resistant organisms to these very important medications.

Consider combination therapy with the following conditions:

  1. Severe intra-abdominal infections: for patients with complicated infections, particularly those who have had recent intra-abdominal surgery, as they are more likely to have MRSA infection that requires Vancomycin, rather than just gram negative and anaerobic infection that usually could be treated with Zosyn alone.[14]
  2. Bacteremia associated with the presence of an intravascular line: if the patient is extremely ill, neutropenic, possesses a line in the femoral area, or in the setting of resistant microbe. If the patient is not too ill, then some experts might use Vancomycin alone initially.[15]
  3. Hospital Acquired Pneumonia: Most experts would agree on combination therapy, especially if the patient is severely ill.[16]
  4. Neutropenic fever: If the patient is very ill and the source may be from a line or skin source, then Vancomycin should be added to a gram-negative drug like Zosyn or Cefepime to cover MRSA. If the patient is not severely ill and if a line or skin source is not suspected, then some experts would just use Zosyn or Cefepime without adding Vancomycin.[17]

Vancomycin/piperacillin-tazobactam coverage

Vancomycin /piperacillin-tazobactam regimen spectrum of activity includes:

Gram positives: MRSA, strep viridans, strep pneumoniae, beta-hemolytic streptococci, coagulase negative staphylococcus, MSSA, E. Faecalis

Gram negatives: pseudomonas, Enterobacter spp, serratia spp, proteus spp., klebsiella spp, E. coli, H. Influenzae

Anaerobes – oral and abdominal

-This regimen has great penetration at the following sites: lungs, abdomen, skin, soft tissues, and urine

When is vancomycin/piperacillin-tazobactam not the answer?

The rationale for combination therapy includes prevention of resistance to a single agent, treatment of polymicrobial infection, empiric therapy for immunocompromised and critically ill patients, and using synergistic antibiotics to treat a serious, hard to treat infection due to relatively resistant organisms, such as endocarditis. Double beta-lactam therapy in most situations is not needed. In fact, if it is deemed necessary to add a second antibiotic to a beta-lactam drug, it is usually recommended to add an antibiotic from another drug class.

According to the Antimicrobial Stewardship program, the practice of giving two agents to cover anaerobes (double coverage) accounts for 20% of interventions although this practice is not supported by susceptibility profiles.[18] One common instance of this is in the case of intra-abdominal infections. According to the Infectious Disease Society of America (IDSA) guidelines, piperacillin-tazobactam is appropriate as monotherapy, as it has excellent gram negative and anaerobic coverage.[19] The exception to this would be intra-abdominal infections secondary to a biliary etiology (e.g. cholangitis), in which case it is recommended to add metronidazole.

For gram negative organisms, a carbapenem by itself usually gives very effective coverage, including coverage against organisms that produce an extended spectrum beta lactamase (ESBL). Carbapenems also have excellent coverage for most anaerobes and gram positive organisms. Third and fourth generation cephalosporins have excellent gram negative coverage, as does aztreonam. However, for life threatening infections with gram positive organisms that may be resistant to beta-lactams antibiotics, including MRSA and resistant pneumococci, vancomycin is usually needed. Other antibiotics that can be used to treat life-threatening infections caused by MRSA are Linezolid and Daptomycin. Bactrim, doxycycline, and clindamycin can be used orally to treat less serious community acquired MRSA infections. IV Clindamycin may be used as an addition to other antibiotics (such as vancomycin/pipercillin-tazobactam) to treat necrotizing soft tissue infections by helping to block toxin production.

Decisions to use broad spectrum antimicrobials should include clinical assessment with a range of diagnostic information which includes, but is not limited to, culture-based microbiology if available.[20]

In a recent study, up to 12% of the total antibiotic costs could have been avoided if all prescriptions were optimal.[21] In this study, Infectious Disease consultants evaluated the appropriateness of antibiotic selection using a modification of Kunin’s criteria, which are a set of validated criteria for antibiotic use.[22] This study reviewed antibiotic selection for both admitted and discharged patients from the emergency department. In another study 29% of empiric antibiotic administration was inappropriate in surgical and trauma patients.[23] In terms of indications, studies have noted increased association between inappropriate antibiotic selection and peritoneal, urinary tract, catheter-associated, and bloodstream infections.[24-26]

Finally, it should go without saying that not all causes of sepsis and septic shock are bacterial: the clinician should also consider adding anti-viral and anti-fungal antimicrobials where appropriate.

Vancomycin/piperacillin-tazobactam: what does it not cover?

-Vancomycin-resistant Enterococcus

-Fungal, viral, and parasitic infections

-Atypical infections including illness caused by: chlamydia, mycoplasma, legionella

-Organisms that produce extended spectrum beta-lactamases (ESBLs) – some strains of Escherichia coli (E. coli) and Klebsiella. The risk factors for an infection with an ESBL producing organism are recurrent UTIs, hospitalizations, urinary tract instrumentation, elderly, and being male.

-Infection caused by an abscess or infected line if not drained or removed, respectively.

It should be emphasized again that Zosyn is a broad-spectrum antibiotic that covers many gram positive, gram negative (including pseudomonas), and anaerobic organisms. When anaerobic and pseudomonal coverage is not needed, it may be better to use a drug like ceftriaxone, that has excellent gram negative coverage, but no significant anti-anaerobic or anti-pseudomonal activity. When it is believed that infection with pseudomonas is present, but there is no need for anaerobic coverage, then Cefepime may be a more appropriate choice. These types of decisions should be made on the basis of the patient’s clinical status, the possible site of infection, whether the patient is at risk for nosocomial acquired infections, and the antibiograms of the institution. Vancomycin has great gram positive coverage, and it is especially useful for treating serious infections with MRSA. When it is believed that infection with MRSA is unlikely, then another antibiotic with excellent gram positive coverage like a penicillin, cephalosporin, or clindamycin may be used. Again this should be based on the considerations noted above.

What are the consequences of inappropriate antibiotic administration?

-Increased duration of antibiotic treatment

-Development of multidrug-resistant (MDR) organisms

-Increased hospital length of stay

-Increased cost

-Adverse drug effects: nausea/vomiting, diarrhea, rash (SJS, TENS, etc.), renal toxicity, and many others

Is piperacillin-tazobactam nephrotoxic?

This question has been one of considerable debate in the FOAM world, especially in the last year.[27],[28] Piperacillin-tazobactam has been associated with risk of developing AKI.[29]  Other studies have also shown no association with AKI[30] or the need for renal replacement therapy.[31]  Although the exact mechanism for AKI due to beta-lactams and vancomycin is not known, the most common proposed mechanism is acute interstitial nephritis or toxic effects on the renal tubule. Four independent risk factors for AKI have been identified.[32]

  • Gram-positive infection
  • Sepsis (the greater the severity, the higher the risk of AKI)
  • Administration of Vancomycin loading dose. However, in another report initial dosing of vancomycin > 20 mg/kg was not associated with an increased rate of nephrotoxicity.[33]
  • Administration of any other nephrotoxic agent

It is suggested that piperacillin-tazobactam is associated with an increased creatinine due to a reduction in tubular creatinine secretion. In a retrospective analysis by Jensen et. al, the use of piperacillin-tazobactam was identified as a cause of delayed renal recovery in critically ill patients.[34] Interestingly, after the piperacillin/tazobactam was discontinued, the subgroup had more rapid recovery of glomerular filtration rates.

There remains considerable debate as to whether piperacillin-tazobactam is nephrotoxic in its own right or in combination with vancomycin, or if it is a matter of elevating serum creatinine by a mechanism similar to trimethoprim or probenecid.

Is Vancomycin nephrotoxic?

Many believe that vancomycin induced nephrotoxicity is overstated.[35] A recent study has suggested that vancomycin is minimally nephrotoxic and has a similar nephrotoxic profile as compared with linezolid when appropriate dosing is used, even among critically ill patients.[36] The trough serum vancomycin concentrations and duration of therapy are associated with increased risk of nephrotoxicity.[37] Other studies have identified following factors linked with vancomycin-associated nephrotoxicity.[38]

  • Total daily dose > 4 grams
  • Trough levels > 20 mg/L
  • Therapy exceeding 6 days
  • Concurrent use of other nephrotoxic agents
  • Preexisting renal disease
  • Obesity
  • Hypotensive episodes
  • Severe illness

There is also concern for higher risk of acute kidney injury with combined use of vancomycin/piperacillin-tazobactam.[39]

Summary / Pearls

-Vancomycin/piperacillin-tazobactam should be used judiciously in order to limit the emergence of resistant organisms.

-Vancomycin should be administered in suspected or proven serious MRSA infections.

– Most intra-abdominal infections do not require coverage for MRSA, unless the patient has had recent abdominal surgery or instrumentation, such as catheter insertion.

– Coverage against pseudomonas and other very resistant gram negative organisms is often not needed in patients with uncomplicated intra-abdominal infections, who are otherwise healthy, not had recent intra-abdominal procedures, not recently been on antibiotics, and not life-threateningly ill.

Do not delay administering Vancomycin/piperacillin-tazobactam to severely ill patients when the source of infection is not known.

-Give piperacillin-tazobactam before Vancomycin, as Zosyn possesses broader coverage and can be given more rapidly than vancomycin.

-Concomitant use of Vancomycin and piperacillin-tazobactam may increase the incidence of acute kidney injury.

Correct dosing of vancomycin is also important.

 

References / Further Reading

[1] Steinman MA, Landefeld CS, Gonzales R. Predictors of broad spectrum antibiotic prescribing for acute respiratory tract infections in adult primary care. JAMA 2003; 289:719-725

[2] Roumie CL, Halasa NB, Grijalva CG. Trends in antibiotic prescribing for adults in the United States-1995 to 2002. J Gen Intern Med 2005;20:697-702

[3] Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States.  Clin Infect Dis.2001; 33:757-762

[4] Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin—United States, 2002. MMWR Morb Mortal Wkly Rep2002; 51:565-567

[5] http://www.fda.gov/ohrms/dockets/dockets/06p0195/06P-0195-EC1-Attach-1.pdf Last accessed December 16, 2016

[6] Chambers H.F.: Other B-lactam antibiotics. In (eds): Philadelphia: Churchill Livingstone, 2000. pp. 291-299

[7] http://reference.medscape.com/drug/zosyn-piperacillin-tazobactam-342485#10 Last Accessed December 16, 2016

[8] http://reference.medscape.com/drug/vancocin-vancomycin-342573#10 Last Accessed December 16, 2016

[9] Barbara E. Murray, Cesar A. Arias, Esteban C. Nannini. Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition, 2015: 30, 377-400.e4 Saunders

[10] Wang JT, Fang CT, Chen YC, et al: Necessity of a loading dose when using vancomycin in critically ill patients. J Antimicrob Chemother 2001; 47:246

[11]  Truong J, Levkovich BJ, and Padiglione AA: Simple approach to improving vancomycin dosing in intensive care: a standardized loading dose results in earlier therapeutic levels. Int Med J 2012; 42: 23-29

[12] Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM; Infectious Diseases Society of America.; Society for Healthcare Epidemiology of America. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007 Jan 15;44(2):159-177

[13] Shallcross LJ, Freemantle N, Nisar S, Ray D. A cross-sectional study of blood cultures and antibiotic use in patients admitted from the Emergency Department: missed opportunities for antimicrobial stewardship. BMC Infect Dis. 2016 Apr 18;16:166

[14] Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, O’Neill PJ, Chow AW, Dellinger EP, Eachempati SR, Gorbach S, Hilfiker M, May AK, Nathens AB, Sawyer RG, Bartlett JG. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010 Jan 15;50(2):133-64

[15] Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009 Jul 1;49(1):1-45

[16] Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL.Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e11

[17] Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011 Feb 15;52(4): e56-93

[18] Double Anaerobic Coverage: What is the role in clinical practice?  Available at http://www.nebraskamed.com/App_Files/pdf/careers/education-programs/asp/DoubleAnaerobicCoverage.pdf. Last Accessed January 13, 2017

[19] Solomkin, J. S., Mazuski, J. E., Bradley, J. S., Rodvold, K. A., Goldstein, E. J., Baron, E. J., & Gorbach, S. (2010). Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surgical infections, 11(1), 79-109

[20] Shallcross LJ, Freemantle N, Nisar S, Ray D. A cross-sectional study of blood cultures and antibiotic use in patients admitted from the Emergency Department: missed opportunities for antimicrobial stewardship. BMC Infect Dis. 2016 Apr 18;16(1):166

[21] Ojeniran M, Shouval R, Miskin IN, Moses AE, Shmueli Costs of appropriate and inappropriate use of antibiotics in the emergency department. Isr Med Assoc J. 2010 Dec;12(12):742-476

[22] Vlahovic-Palcevski V, Francetic I, Palcevski G, Novak S, Abram M, Bergman U. Antimicrobial use at a university hospital: appropriate or misused? A qualitative study. Int J Clin Pharmacol Ther. 2007; 45(3): 169-174

[23] Davies SW, Efird JT, Guidry CA, Hranjec T, Metzger R, Swenson BR, Sawyer RG. Characteristics of surgical patients receiving inappropriate empiric antimicrobial therapy. J Trauma Acute Care Surg. 2014 Oct;77(4):546-554

[24] Kawanami GH, Fortaleza CM. Factors predictive of inappropriateness in requests for parenteral antimicrobials for therapeutic purposes: a study in a small teaching hospital in Brazil. Scand J Infect Dis. 2011; 43 (6–7): 528-535

[25] Edelsberg J, Berger A, Schell S, Mallick R, Kuznik A, Oster G. Economic consequences of failure of initial antibiotic therapy in hospitalized adults with complicated intra-abdominal infections. Surg Infect (Larchmt). 2008; 9 (3): 335-347

[26] Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999; 115 (2): 462-474

[27] Hayes, B. (2016, April 16). Piperacillin/Tazobactam and Risk of Acute Kidney Injury with Vancomycin (Web log post). Retrieved from https://www.aliem.com/2014/piperacillin-tazobactam-acute-kidney-injury/

[28] Farkas, J. (2016, July 9). PulmCrit Wee: Is piperacillin-tazobactam nephrotoxic? (Web log post).  Retrieved from <http://emcrit.org/pulmcrit/piperacillin-tazobactam-nephrotoxic/

[29] Peyko V, Smalley S, Cohen H. Prospective Comparison of Acute Kidney Injury During Treatment With the Combination of Piperacillin-Tazobactam and Vancomycin Versus the Combination of Cefepime or Meropenem and Vancomycin. J Pharm Pract. 2016 Feb 23

[30] Davies, S. W., Efird, J. T., Guidry, C. A., Dietch, Z. C., Willis, R. N., Shah, P. M., & Sawyer, R. G. (2016). Top Guns: The “Maverick” and “Goose” of Empiric Therapy. Surgical infections, 17(1), 38-47

[31] Hammond, D. A., Smith, M. N., Painter, J. T., Meena, N. K., & Lusardi, K. (2016). Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin‐Tazobactam or Cefepime: A Retrospective Cohort Study. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(5), 463-471

[32] Karino S, et al. Epidemiology of Acute Kidney Injury Among Patients Receiving Concomitant Vancomycin and Piperacillin/tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chmother. 2016 Apr 11.

[33] Rosini JM, Davis JJ, Muenzer J, Levine BJ, Papas MA, Comer D, Arnold R. High Single-dose Vancomycin Loading Is Not Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients. Acad Emerg Med. 2016 Jun;23(6):744-746

[34] Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr T, Andersen MH, Thornberg KJ, Løken J, Steensen M, Fox Z, Tousi H, Søe-Jensen P, Lauritsen AØ, Strange DG, Reiter N, Thormar K, Fjeldborg PC, Larsen KM, Drenck NE, Johansen ME, Nielsen LR, Ostergaard C, Kjær J, Grarup J, Lundgren JD; Procalcitonin And Survival Study (PASS) Group. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomized trial. BMJ Open. 2012 Mar 11;2(2):e000635

[35] Moffett BS, Kim S, Edwards M. Vancomycin nephrotoxicity may be overstated. J Pediatr. 2011 May;158(5):865-866

[36] Davies SW, Guidry CA, Petroze RT, Hranjec T, Sawyer RG. Vancomycin and nephrotoxicity: just another myth? J Trauma Acute Care Surg. 2013 Nov;75(5):830-835

[37] Hanrahan TP, Harlow G, Hutchinson J, Dulhunty JM, Lipman J, Whitehouse T, Roberts JA. Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis. Crit Care Med. 2014 Dec;42(12):2527-36

[38] Mergenhagen KA, Borton AR. Vancomycin nephrotoxicity: a review. J Pharm Pract. 2014 Dec;27(6):545-553

[39] Hellwig TR, Hammerquist R, Loecker B, et al. Retrospective evaluation of the the incidence of Vancomycin and/or piperacillin-tazobactam induced acute renal failure. Crit Care Med 2011:39 (supp)301

Must Know Antimicrobial Regimens – Adults

Authors: Marina N. Boushra, MD (EM Resident Physician, Vidant Medical Center) and Cassandra Bradby, MD (EM Attending Physician, Vidant Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

A 75-year-old man with a history of diabetes, hypertension, and dementia presents to the emergency department with a complaint of altered mental status. His nursing home caretaker endorses a dry cough for one week that has recently become productive and fevers with a Tmax of 38.9 ºC. She notes that he is not “acting like himself,” and elaborates that he is sleeping more, talking less, and has had multiple episodes of urinary incontinence, which is unusual for him. His vitals on arrival are T 38.5º C, HR 110, RR 30, BP 100/70. His exam is notable for somnolence, increased work of breathing with accessory muscle use, coarse rales at the base of the right lung, tachycardia, and dry mucus membranes.

Bacterial infections are a common diagnosis in the emergency department, and emergency physicians are often tasked with providing antibiotics for outpatient management or beginning antibiotics prior to admission. Antibiotic treatment is not without side effects, and treatment started in the emergency department is frequently empiric. Therefore, an understanding of the most likely causative organisms as well as local patterns of susceptibility and resistance is paramount to adequate treatment, appropriate antibiotic selection, and responsible antibiotic stewardship. Important historical details to elicit include allergies, recent antibiotic use, prior antibiotic failure, dialysis use, use of immunosuppressants or history of immunocompromise, culture results of prior infections, and contact with healthcare facilities, including recent hospitalization, living in a care facility, or recent invasive procedures such as ureteral catheterizations or intubation. These details offer vital information regarding possible bacterial resistance or the presence of opportunistic infection. Because multiple empiric regimens exist for infectious disease in the emergency department, contacting the hospital pharmacy about the local antibiogram may help tailor the empiric regimen to local microbial susceptibilities. Please keep this in mind with the recommendations discussed in each table. The following is a discussion of the most common or most emergent ED-diagnosed bacterial infections, their most likely causative organisms, and current recommendations for empiric treatment.

Pneumonia

Pneumonia is infection of the pleural parenchyma and can be broadly divided into community-acquired (CAP) and hospital-acquired pneumonia (HAP). A third category of pneumonia, healthcare-associated pneumonia, is discussed in more detail later in this paper. The majority of pneumonia is community-acquired but historical details such as recent hospitalization, intubation, or ventilator dependence should raise concern for HAP and multi-drug resistant organisms (MDROs). Travel history may be important for more rare causes of pneumonia. In patients with known or suspected HIV or AIDS, pneumocystis pneumonia should be strongly considered.

Community-Acquired Pneumonia (CAP)

CAP can be caused by a variety of pathogens, with the most common bacterial cause being Streptococcus pneumonia1–3. Other common organisms include respiratory viruses, Haemophilus influenza, and Mycoplasma pneumoniae1–3. In patients requiring ICU admission, S. pneumoniae is still common, but there is increased prevalence of Legionella pneumophila, Staphylococcus aureus, gram-negative bacilli, and influenza4. It is important to remember these differences in etiology and to cover adequately for these serious organisms in patients requiring ICU admission. Patients with risk factors for aspiration pneumonia should receive additional anaerobic coverage. Treatment for CAP has become increasingly more complicated due to rising resistance to antibiotics. Risk factors for drug resistance include age >65, alcoholism, medical comorbidities, immunosuppressive illness or medication use, and use of beta-lactam, macrolide, or fluoroquinolone antibiotics in the last 3-6 months5,6.

Treatment should be initiated as soon as a diagnosis of CAP is made to prevent decompensation. CAP can often be treated on an outpatient basis. Studies have shown that physicians often use inconsistent criteria when making the decision to admit patients for the treatment of CAP and overestimate short-term patient mortality, leading to an increased rate of unnecessary hospitalizations7. The 2007 guidelines for the Infectious Disease Society of America (IDSA) and the American Thoracic Society (ATS) recommend using the CURB-65 score or Pneumonia Severity Index (PSI), both well validated prediction rules and decision aids, to aid in the risk stratification of patients and making the decision to admit for inpatient treatment7–9. Interestingly, a recent article investigating oral vs. intravenous fluoroquinolones for non-critically ill patients with CAP showed no difference in mortality, ICU transfers, or need for vasopressors or intubation10. Studies have shown shorter time to treatment and shorter hospital stays for patients started on oral rather than intravenous antibiotics11. As such, it is important to consider oral therapy in non-critically ill patients with CAP who are being admitted for treatment but are able to tolerate oral medication.

Studies have shown similar efficacy in CAP for fluoroquinolones and macrolides plus a penicillin or cephalosporin12. Importantly, there is a high rate of macrolide resistance in S. pneumoniae in the United States; as such, macrolides should not be used as empiric monotherapy in areas where resistance to macrolides is >25%5,13–15. Recommended regimens are outlined in the Table 1 below. The IDSA is expected to publish new guidelines for the treatment of CAP that better reflect current trends in resistance in the summer of 2017.

Hospital-Acquired (nosocomial) Pneumonia (HAP)

Pneumonia patients with recent hospitalizations present a challenge in antibiotic selection. While the pneumonia may be caused by an MDRO picked up in the healthcare environment, it is also possible that the patient has a simple community-acquired organism. The multi-drug resistant (MDR) score assesses a particular patient’s risk for infection with an MDRO16,17. Patients with a high MDR score should be presumed to have a pneumonia due to a resistant organism and treated accordingly with broad-spectrum coverage as outlined in Table 1 below. Patients with low MDR scores can be treated with the more narrow-spectrum coverage used for CAP, with the possibility of widening the spectrum in the event of treatment failure. The Shorr score is a similar scoring tool to assess the risk of infection by an MDR and tailor empiric coverage appropriately18.  Antibiotic treatment for presumed HAP should cover for Staphylococcus aureus and Pseudomonas aeruginosa19. Local antimicrobial prevalence and susceptibility, especially within the hospital, is helpful to determining a regimen, but can often be deferred to the judgement of the admitting team. Empiric regimens as recommended in the 2016 IDSA/ATS guidelines for empiric management of HAP are outlined in Table 1 below.

Healthcare-Associated Pneumonia (HCAP)

Healthcare-associated pneumonia (HCAP) refers to pneumonia that may have been acquired in healthcare facilities such as nursing homes and dialysis centers. It was formerly grouped with HAP due to presumed increased susceptibility to MDROs. Several studies, however, have shown no increased susceptibility to MDROs in patient with HCAP, and it is conspicuously missing from the IDSA/ATS guidelines on the management of HAP19–24. As such, in the absences of other historical susceptibilities to MDROs such as comorbidities or severe illness, patients with HCAP may be treated as CAP19–24.

Table 1: Empiric Treatment of Pneumonia based on type, setting, and patient-specific factors8,19

Type Setting Patient Factors Regimen
CAP Outpatient No recent antibiotics, co-morbidities, high-rate of resistance -Doxycycline 100mg bid for five days

-Azithromycin 500mg on day 1 followed by 250mg for four days.*

-Clarithromycin 500mg bid for seven days*

Recent antibiotics, co-morbidities, high-rate of resistance -Levofloxacin 750mg daily for five days

-Moxifloxacin 400mg daily for five days

-Gemifloxacin 320mg daily for five days

-Combination therapy with a beta-lactam (amoxicillin 1g tid, amoxicillin-clavulanate 2g bid, cefpodoxime 200mg bid, or cefuroxime 500mg bid) PLUS either a macrolide (azithromycin 500mg on day 1, followed by 250mg for four days, or clarithromycin 500mg bid for five days) or doxycycline 100mg bid for five days.

Inpatient Mild-Moderate disease, managed on general floor -Levofloxacin 750mg IV or po

-Moxifloxacin 400mg IV or po

-Combination therapy with a beta-lactam (cefotaxime 1-2g, ampicillin-sulbactam 1.5-3g, ceftriaxone 1-2g) PLUS a macrolide (azithromycin 500mg IV, or clarithromycin 500mg orally)

Severe disease requiring ICU admission -Combination therapy with a beta-lactam (cefotaxime 1-2g, ampicillin-sulbactam 1.5-3g, ceftriaxone 1-2g) PLUS a respiratory fluoroquinolone (levofloxacin 750mg IV, or moxifloxacin 400mg IV) OR azithromycin 500mg IV.

-If penicillin allergic, a respiratory fluoroquinolone PLUS aztreonam 1g

-If MRSA suspected, add vancomycin 15-20mg/kg IV

HAP Inpatient Combination therapy is warranted, with one from each of the following 3 categories:

1) Piperacillin-tazobactam 4.5 g IV, Cefepime 2 g IV, Ceftazidime 2g IV, Imipenem/cilastatin 500mg IV

2) Azithromycin 500mg IV, Ciprofloxacin 400mg IV, Levofloxacin 750mg IV, or Gentamicin 5-7mg/kg IV

3) Vancomycin 15-20mg/kg IV, Linezolid 600mg IV

*Macrolide antibiotics should not be used as empiric monotherapy in areas of known S. pneumoniae resistance >25% to macrolides. If such resistance exists, pair with a beta-lactam as shown in the table above.

Urinary Tract Infection

Urinary tract infections can involve the lower urinary tract (cystitis) or the upper tract (pyelonephritis). Urinary tract infections are very common in women, with sexually active women being at higher risk. Risk factors for urinary tract infections include recent sexual intercourse, prior urinary tract infections, and recent spermicide use25. When present in men, urinary tract infections are typically associated with underlying anatomical anomalies, recent catheterization, or other risk factors. While not all urinary tract infections in males are necessarily complicated, a search for these risk factors should be conducted when a male is diagnosed with a urinary tract infection.

Uncomplicated Cystitis

Urinary tract infections in women begin by bacterial colonization of the vagina by fecal bacteria, which may ascend via the urethra to infect the bladder and kidneys. Uncomplicated cystitis and pyelonephritis in women is typically caused by Escherichia coli, though Proteus mirabilis, Klebsiella pneumoniae, and Streptococcus saprophyticus are occasionally found26,27. Empiric treatment for uncomplicated urinary tract infections is best tailored to the regional E. coli sensitivities and is outlined in Table 328. Of note, this table may be modified based on local resistance patterns. Sterile pyuria should raise concern for a possible sexually-transmitted infection (STI) and patients who fail to improve despite appropriate antibiotic treatment should be tested for STI.

Complicated Urinary Tract Infection

A complicated urinary tract infection is one which is associated with a condition that increases the risk for therapeutic failure, as outlined in Table 2. The microbial spectrum of complicated UTI is more broad, including not only the typical organisms associated with uncomplicated UTI but also more varied and resistant pseudomonal, staphylococcal, and Serratia species as well as fungi29,30. Complicated lower urinary tract infections may be managed as an outpatient, but indications for hospitalization include inability to tolerate oral therapy or suspected/ documented infection with a resistant organism such as extended-spectrum beta-lactamase producing organisms (ESBLs). Complicated pyelonephritis is the progression of infection resulting in emphysematous pyelonephritis, corticomedullary or perinephric abscess, or papillary necrosis. Complicated pyelonephritis is an indication for admission and intravenous antibiotic treatment.

Table 2: Conditions that increase the risk of treatment failure in UTI (complicated UTI)

Diabetes
Pregnancy
Renal failure
Hospital-acquired infection
Immunosuppression
Renal transplantation
Anatomic abnormality of the urinary tract
Symptoms >7 days prior to presentation
Presence of an indwelling foreign body (ureteral catheter, nephrostomy tube, ureteral stent)
Ureteral calculus

UTI and Asymptomatic Bacteriuria in the Pregnant Patient

Urinary tract infection and colonization in pregnant patients are worth special mention. While asymptomatic bacteriuria in a non-pregnant female does not warrant treatment, studies have shown a high rate of progression to symptomatic cystitis and pyelonephritis in pregnant patients31. As such, current recommendations suggest that any bacteriuria in a pregnant patient should be treated with antibiotics32. Additionally, although urinary tract infection in a pregnant woman is, by definition, complicated, fluoroquinolones, the first-line treatment for complicated cystitis, are a pregnancy class C medication and should be avoided33. Mild urinary tract infections in pregnant females are treated similarly to uncomplicated UTIs, as shown in Table 3 below. Follow-up cultures for resolution are important in this patient population34.

Table 3: Empiric treatment of uncomplicated and complicated urinary tract infections28,31,35.

Urinary Tract Infection Recommended regimen
Uncomplicated cystitis -Nitrofurantoin 100mg bid for five days*

-Trimethoprim-sulfamethoxazole 160/800mg bid for three days

-Cephalexin 500mg BID for 3-7 days

-Fosfomycin 3g in a single dose*

-Ciprofloxacin 250mg bid or Levofloxacin 250mg once per day for three days**

Complicated cystitis Outpatient:

-Ciprofloxacin 500mg bid or 1000mg daily for five to ten days

-Levofloxacin 750mg daily for five to ten days

Inpatient:

-Levofloxacin 500mg IV

-Ceftriaxone 1g IV

-Ertapenem 1g IV

-Gentamicin 3-5mg/kg IV +/- ampicillin 1-2g every 4-6 hours***

-Tobramycin 3-5mg/kg IV +/- ampicillin 1-2g every 4-6 hours***

Uncomplicated Pyelonephritis

 

 

Outpatient:

-Ciprofloxacin 500mg po bid for seven days or 1000mg daily for seven days

-Levofloxacin 750mg po daily for five to seven days

Inpatient:

-Levofloxacin 500mg IV

-Ceftriaxone 1g IV

-Ertapenem 1g IV

-Gentamicin 3-5mg/kg IV

-Tobramycin 3-5mg/kg IV

Complicated Pyelonephritis – Inpatient, mild-moderate disease:

-Ceftriaxone 1g IV

-Ciprofloxacin 400mg IV

-Levofloxacin 750 mg IV

-Aztreonam 1g IV

Inpatient, severe disease:

-Cefepime 2g IV

-Ampicillin 1g IV four times per day plus Gentamicin 5mg/kg IV daily

-Piperacillin-tazobactam 3.375g IV

-Meropenem 500mg IV

-Imipenem 500mg IV

-Doripenem 500mg IV

Asymptomatic bacteriuria and acute cystitis in the pregnant patient -Nitrofurantoin 100mg po bid for five to seven days (in second or third trimester)*

-Trimethoprim-sulfamethoxazole 160/800 mg po bid for three days****

-Fosfomycin 3g po in a single dose*

-Amoxicillin-clavulanate 500mg po tid for three to seven days

-Cephalexin 500mg po bid for three to seven days

-Cefpodoxime 100mg po bid for three to seven days

*Fosfomycin and nitrofurantoin should be avoided if there is concern for early pyelonephritis.

**Fluoroquinolones, if possible, should be reserved for other important uses to avoid resistance against this class of antibiotics.

***Adding ampicillin provides Enterococcus coverage

****Should be avoided in first trimester and at term

Cellulitis and Soft-Tissue Infection

Cellulitis and Erysipelas

Cellulitis and erysipelas are bacterial skin infections that differ in that erysipelas involves the upper dermis and superficial lymphatics while cellulitis involves the deeper dermis and subcutaneous fat tissue. Both manifest with localized skin erythema, edema, warmth, and pain. Because of the more superficial nature of erysipelas, these lesions are typically more raised and better demarcated than cellulitis. Erysipelas also presents more acutely and with more systemic symptoms such as fevers and chills. The most common pathogens in cellulitis are beta-hemolytic streptococci and S. aureus, including methicillin-resistant S. aureus (MRSA)36–38. Beta-hemolytic streptococci are the most common cause of erysipelas36,39.

Lesions consistent with cellulitis should be examined closely for the presence of a drainable abscess. History is particularly important in the patient with possible cellulitis as cellulitis associated with human or animal bites or with water exposure needs different coverage than uncomplicated cellulitis. The presence of an indwelling device near the region of cellulitis is also important, as it is an indication of device infection.

The treatment of uncomplicated cellulitis is based on whether or not there is associated purulence. Current guidelines group erysipelas with non-purulent cellulitis in terms of treatment, as the lesions are often difficult to distinguish from each other and are caused by a similar spectrum of organisms. Patients with purulent cellulitis should receive empiric coverage for MRSA pending culture results40. Patients with non-purulent cellulitis or erysipelas should receive empiric coverage for beta-hemolytic streptococcus and MSSA, although patients with systemic symptoms, recurrent infection, or prior infection with MRSA should receive additional MRSA coverage36. Cellulitis can typically be managed as an outpatient; patients with signs of systemic toxicity, rapid progression, indwelling devices, or failure of outpatient management should be admitted for parenteral antibiotics. In addition to antibiotics, elevation of the affected area is an important aspect of treatment as it helps promotes drainage of edema and inflammatory substances, speeding symptomatic improvement36.

Table 4: Empiric treatment of cellulitis and erysipelas36

Infection Recommended regimen
Uncomplicated nonpurulent cellulitis without MRSA risk factors or erysipelas Outpatient -Dicloxacillin 500mg po qid for 5-10 days

-Cephalexin 500mg po qid for 5-10 days

-Clindamycin 450mg po tid for 5-10 days

Inpatient -Cefazolin 1-2g IV tid

-Ceftriaxone 1g IV every 24 hours

-Oxacillin or nafcillin IV every 4 hours

-Clindamycin 600-900mg IV tid

Uncomplicated purulent cellulitis or nonpurulent cellulitis with MRSA risk factors

 

Outpatient -Clindamycin 300-450mg po 3-4 times per day for 5-7 days

-Trimethoprim/sulfamethoxazole 1-2 DS tablets po bid for 5-7 days

-Doxycycline 100mg bid for 5-7 days

Inpatient -Vancomycin 15-20mg/kg/dose IV bid

-Clindamycin 600mg IV tid 

-Linezolid 600mg IV two times per day

-Daptomycin 4mg/kg/dose IV once daily

Skin abscesses

Skin abscesses are most commonly due to S. aureus (MRSA or MSSA), although polymicrobial infection with flora from the skin or adjacent mucosal tissues is also common36,40–42. Risk factors for MRSA infection include recent hospitalization or antibiotic use, contact with healthcare environments, institutionalization, HIV infection, intravenous drug use, and diabetes. Source control, in the form of warm compresses to promote drainage or incision and drainage, is important. The role of antibiotics following source control is debated. Studies have shown a slightly increased cure rate with the use of antibiotics following incision and drainage of uncomplicated abscesses, but also a higher rate of diarrhea and adverse effects43,44. Antibiotics should be started for large (>2cm) or multiple abscesses, extensive surrounding cellulitis, systemic symptoms, immunocompromise or co-morbidities, the presence of an indwelling device, or in cases where incision and drainage alone fails to achieve adequate clinical response36. Hospitalization and parenteral antibiotics should be considered for patients with extensive skin involvement or signs of systemic toxicity.

Table 5: Empiric antibiotic treatment of abscesses following source control36

Outpatient If suspicion for MRSA:

-Clindamycin 300-450mg po 3-4 times per day for 5-7 days

-Trimethoprim/sulfamethoxazole 1-2 DS tablets po bid for 5-7 days

-Doxycycline 100mg po bid for 5-7 days

If no suspicion for MRSA:

-Dicloxacillin 500mg po bid for 5-7 days

-Cephalexin 500mg po bid for 5-7 days

Inpatient -Vancomycin 15-20mg/kg/dose IV bid

-Clindamycin 600mg IV tid 

-Linezolid 600mg IV two times per day

-Daptomycin 4mg/kg/dose IV once daily

Sexually-Transmitted and Vulvovaginal Infections

Sexually transmitted infections (STI) are a diagnosis of immense public health importance. While the results of lab testing are often not available in the emergency department, physicians should have a low threshold for the initiation of treatment in patients with presentations consistent with STI. Treatment for common STIs is outlined in Table 6 below45. Counseling patients about safe sex practices and urging them to inform their partners is paramount to infection control.

Pelvic Inflammatory Disease

Pelvic inflammatory disease (PID) is infection of the upper genital tract (uterus, endometrium, fallopian tubes, ovaries) in women. PID may extend to involve adjacent structures, causing periappendicitis, pelvic peritonitis, and perihepatitis (Fitz-Hugh-Curtis syndrome). The majority of PID is caused by ascending sexually-transmitted infections (STI), with Neisseria gonorrhea and Chlamydia trachomatis being the most commonly implicated pathogens in PID45. The diagnosis of PID is often a presumptive one based on presentation. Due to the risk for tubal scarring leading to infertility or risk of ectopic pregnancy, even minimal symptoms without an alternative diagnosis warrant the start of antibiotic therapy to reduce the risk of serious complications due to delay of therapy. Mild to moderate disease can be treated as an outpatient. Indications for hospitalization and intravenous antibiotics include pregnancy, clinically severe disease, complicated PID (pelvic abscess), and intolerance to, noncompliance with, or failure of oral antibiotics. Empiric coverage for inpatient and outpatient management of pelvic inflammatory disease are outlined in Table 646,47.

Table 6: Recommended treatment regimens for select genitourinary infections45–47

Chlamydia -Azithromycin (1g po in one dose)

-Doxycycline (100mg bid for 7 day)

Gonorrhea* -Ceftriaxone (250mg IM or IV in one dose) plus azithromycin (1g po in one dose) or doxycycline (100mg bid for 7 days)
Trichomonas -Metronidazole (2g po in a single dose or 500mg bid for seven days)

-Tinidazole (2g po in a single dose)

Bacterial Vaginosis -Metronidazole (500mg  po bid for seven days)

-Metronidazole vaginal gel 0.75% (5g intravaginally for five days)

-Clindamycin vaginal gel 2% (5g intravaginally for seven days)

Candida Vulvovaginitis Fluconazole (150mg po in one dose)
Pelvic Inflammatory

Disease

Outpatient management -Ceftriaxone (250mg IM in one dose) plus doxycycline (100mg po bid for 14 days)

-Cefoxitin (2g IM) with probenecid (1g orally) plus doxycycline (100mg po bid for 14 days)

Inpatient management -Ceftriaxone (250mg IM in one dose) plus doxycycline (100mg po bid for 14 days)

-Cefoxitin (2g IM) with probenecid (1g orally) plus doxycycline (100mg po bid for 14 days)

*Patients with gonorrhea should also be treated for chlamydia due to high rates of concomitant infection.

Bacterial meningitis

While meningitis is not as common an emergency department diagnosis as the bacterial infections discussed above, patients with meningitis are often quite ill, and knowledge of appropriate antibiotic coverage can speed time to therapy. The most common causes of community-acquired meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitidis, and, in older adults, Listeria monocytogenes48,49. Empiric treatment should be initiated as soon as meningitis is suspected. Empiric regimens should include ceftriaxone (2g every 12 hours) or cefotaxime (2g every 4-6 hours) for coverage of N. meningitidis and S. pneumoniae as well as vancomycin due to increasing rates of S. pneumoniae resistance to third-generation cephalosporins50,51. In patients >50 years of age or with immunocompromise, ampicillin (2g every 4 hours) should be added to provide coverage for L. monocytogenes49.

Adverse Effects of Antibiotic Use

A discussion of antibiotic use in the emergency department would be remiss without mention of the adverse effects of antibiotics commonly used in the ED. While the use of certain antibiotics may be unavoidable due to patient allergies or susceptibility patters, knowledge of the adverse effects of antibiotics may help guide therapeutic choices and inform or temper patient expectations.

Clostridium difficile infection should always be a consideration when starting antibiotics. Clindamycin is the most common culprit in antibiotic-associated C. difficile infection, but cephalosporins, penicillins, and fluoroquinolones are also common causes52–56. Aminoglycosides, tetracyclines, metronidazole, and vancomycin are rarely associated with C. difficile infection, though any antibiotic use increases the risk for C. difficile infection57. Other important adverse effects include QT prolongation with arrhythmia associated with macrolide and fluoroquinolone use and the risk of peripheral neuropathy and (the uncommon, but oft-cited) tendon rupture with fluoroquinolone use. Common or serious side effects of antibiotics used in the emergency department are summarized in Table 7 below.

Table 7: Common and serious adverse effects of commonly used antibiotics

Antibiotic Common Adverse Effects Serious Adverse Effects Comments
Beta-lactams C. diff infection, diarrhea Hypersensitivity reactions High risk of C. diff, especially with broader coverage and with ampicillin
Macrolides Diarrhea, nausea, vomiting, abdominal pain QT prolongation (especially with erythromycin)
Clindamycin C. diff infection, diarrhea Serious hypersensitivity reactions Most common cause of C. diff
Fluoroquinolones Anorexia, nausea, vomiting, abdominal pain Tendon rupture, peripheral neuropathy, QT prolongation High C. diff risk
Tetracyclines Nausea, diarrhea, photosensitivity Inhibition of bone growth and tooth discoloration (a concern in children) Low C. diff risk
Vancomycin Abdominal pain, nausea Nephrotoxicity, ototoxicity, Red man syndrome, hypotension Red man syndrome can be prevented with pretreatment with antihistamines
Aminoglycosides Nephrotoxicity, ototoxicity Need frequent monitoring of drug levels
Metronidazole Headache, dizziness, metallic taste Disulfiram-like reaction Low C. diff risk
  • Summary

Table 8: Common and serious bacterial infections and recommended empiric treatment

Infection Important organisms to cover Recommended Regimens
Community-acquired pneumonia S. pneumoniae CAP outpatient: doxycycline, macrolide +/- penicillin or cephalosporin

CAP inpatient, mild: respiratory fluoroquinolone, macrolide + penicillin or cephalosporin

S. pneumoniae, L. pneumophila, S. aureus CAP inpatient, severe: penicillin or cephalosporin+ fluoroquinolone OR azithromycin
Hospital-acquired pneumonia S. pneumoniae, MRSA, P. aeruginosa HAP inpatient: anti-pseudomonal penicillin or cephalosporin, or fluoroquinolone, or carbapenem + vancomycin/linezolid
Uncomplicated cystitis E. coli Nitrofurantoin or fosfomycin or TMP/SMX or ciprofloxacin

 

Complicated cystitis or uncomplicated pyelonephritis E. coli, Pseudomonas sp., Staphylococcus sp. Outpatient: Fluoroquinolone

Inpatient: Fluoroquinolone or aminoglycoside or third-generation cephalosporin or carbapenem

Complicated pyelonephritis E. coli, Pseudomonas sp., Staphylococcus sp. Inpatient, mild-moderate: third-generation cephalosporin or monobactam

Inpatient, severe: anti-pseudomonal penicillin or cephalosporin, carbapenem

Asymptomatic bacteriuria or simple cystitis in the pregnant patient E. coli Nitrofurantoin or TMP/SMX or fosfomycin, or penicillin or cephalosporin with gram-negative coverage
Nonpurulent cellulitis or abscess without MRSA risk factors, erysipelas Beta-hemolytic streptococcal species, MSSA Outpatient and inpatient: staphylococcal penicillin or cephalosporin
Purulent cellulitis, nonpurulent cellulitis or abscess with MRSA risk factors Beta-hemolytic streptococcal species, MSSA, MRSA Outpatient: Clindamycin or TMP/SMX or doxycycline

Inpatient: Vancomycin or clindamycin

Chlamydia C. trachomatis Azithromycin or doxycycline
Gonorrhea N. gonorrhea AND C. trachomatis Ceftriaxone plus azithromycin or doxycycline
Trichomonas Trichomonas vaginalis Metronidazole or tinidazole
Bacterial vaginosis Polymicrobial, anaerobic gram-negative rods Metronidazole oral or intravaginal gel or clindamycin
Candida Vulvovaginitis C. albicans, C. glabrata Fluconazole
Pelvic Inflammatory Disease N. gonorrhea, C. trachomatis Inpatient and outpatient: third generation cephalosporin plus doxycycline
Bacterial meningitis S. pneumoniae, N. meningitidis, L. monocytogenes (if >50 years or immunocompromised) Vancomycin plus third generation cephalosporin +/- ampicillin if age >50 or immunocompromised

 

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  57. Kelly, C. P., Pothoulakis, C. & LaMont, J. T. Clostridium difficile colitis. N. Engl. J. Med. 330, 257–62 (1994).

 

Evaluation of Fever in the Emergency Department

Authors: Sarah Dewitt, MD (EM Resident Physician, Virginia Tech-Carilion), Summer Chavez, DO/MPH (EM Resident Physician, Virginia Tech-Carilion), and Jack Perkins, MD (EM Assistant Program Director, Virginia Tech-Carilion) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case:  A 61 y/o male is brought to the Emergency Department (ED) by his family for complaints of dyspnea, subjective fever, and chest pain. He has no past medical history, and his VS include temperature 100.6°F, heart rate of 110, blood pressure 130/80, respiratory rate of 26, and pulse oxygenation 90% on room air.  His examination reveals a well-developed male who is in mild distress, but the cardiac and pulmonary examinations are non-contributory.  Your initial concerns focus around suspicion of pneumonia, although your resident quickly points out this could also be the presentation of a pulmonary embolus.  Does the fever help you differentiate between the two, or would have a lack of fever altered your clinical evaluation?  How does the presence of fever shape the differential diagnosis in the ED, and in those patients where an infectious etiology is suspected, should the absence of fever reassure the provider?

Introduction: The pathophysiology of fever

The hypothalamus controls body temperature by balancing inputs from the peripheral nerves that utilize warm/cold receptors in the skin and also analyze the temperature of blood in the surrounding area.1 Fever itself is typically caused by a pyrogen, simply defined as a chemical substance that provokes fever. One such example is exogenous pyrogens, such as those seen in gram-positive bacteria (Staphylococcus aureus enterotoxins) and the superantigens associated with Group A streptococcus and Group B streptococcus microbial infections.1 Many bacteria and fungi can trigger the production and release of cytokines, small proteins that trigger the inflammatory cascade. These cytokines lead to prostaglandin-2 release in peripheral tissues, raising the hypothalamic temperature set point through cAMP release. Central nervous system cytokines are responsible for the hyperpyrexia seen in neurologic trauma and infection.1

Table 1: Differential diagnosis of fever in the ED (note: table not inclusive of all possible causes of fever)

Infectious Causes of Fever   Non-Infectious Causes of Fever 
Bacterial Infections 

•      UTI 

•      Pneumonia 

•      Meningitis 

•      Intra-abdominal 

•      Skin/soft-tissue 

•      Osteomyelitis  

Malignancy (e.g. leukemia, lymphoma, pheochromocytoma)
Viral Infections 

•      URI, pharyngitis  

•      Gastroenteritis 

•      Aseptic meningitis  

•      HIV 

•      Influenza

Autoimmune (e.g. rheumatoid arthritis, systemic lupus erythematosus)
Parasitic Infection 

•      Malaria

•      Toxoplasmosis

•      Giardiasis

Drug Reaction

•      Allergic reaction to, or metabolic consequences of drug

Arthropod Infections 

•      Lyme

•      Rocky Mountain Spotted fever

•      Babesiosis

Seizure
Fungal Infections 

•      Candidiasis

•      Blastomycosis

•      Histoplasmosis

 

Environmental Fever

•      High external temperatures, or excess exercise

  Hyperthyroidism
  Neurologic

•      Subarachnoid hemorrhage

  Embolic vs. Thrombosis vs. Infarction

•      MI

•      Renal infarct

•      PE

  Blood Transfusion Reaction
  Factitious Fever

•      Munchausen’s vs. Munchausen’s by proxy

How do I proceed to determine if the fever in front of me is from an infectious vs. non-infectious source?

Fever is a common finding in patients presenting to the ED. The differential diagnosis of fever is broad and not limited to infectious etiologies. A key clinical question is deciding whether infection is likely enough to warrant antimicrobial administration. A detailed history and physical exam, the past medical history, current medications (e.g. chemotherapy, glucocorticoids), and recent use of antibiotics may help shape the pre-test probability of an infectious source of fever.  However, it is common to need adjunctive laboratory testing or radiographic imaging to further evaluate the source of the fever.  Basic testing in the ED often involves a complete blood count (CBC), urinalysis, and a Chest X-ray (CXR).  The emergency provider (EP) may deem it appropriate to send a urine culture, blood cultures, and add viral antigen testing in select cases.  For example, blood cultures may not be necessary in cases of UTI or pneumonia in patients being discharged; however, they would be useful in cases of severe sepsis or septic shock, as these patients will be admitted and the inpatient team will need this information.  It may also be necessary to look further through other serologic testing such as C-reactive protein (CRP), sedimentation rate (ESR), and Procalcitonin.

CRP is an acute phase reactant that becomes elevated in response to inflammatory stimuli. Serum CRP levels surge within 4-6 hours after stimulation, double every 8 hours, and peak after 35-60 hours. It is therefore going to be a more beneficial marker of infection after 12 hours of fever. However, in patients who present with fever at more than 12 hours after onset, it has been shown that serum CRP is elevated significantly in patients with bacterial infections.3  Initially, the measurement of CRP was quantitative and positive in almost all disease states, making it a poor test of choice for diagnosing.  Since then, labs have created a specific monoclonal antibody and immunological methods of measurement that have made the CRP test used today very accurate and reproducible.  It is quick, and its sensitivity is within 0.04mg/L.4  The value of a single CRP measurement in sepsis diagnosis has been investigated and has been found to be useful in the diagnosis of sepsis.4  In a review published in Intensive Care Med 2002, different studies found that CRP cutoffs between 40-100 mg/L had sensitivity for detecting sepsis between 71-100%, and specificity between 40-85.5%.4  CRP is non-specific, however, and may be elevated in numerous other conditions such as malignancy, rheumatologic disease, and chronic vascular disease among other conditions.  It is used most frequently when the provider needs adjunctive information in the search for more unusual sources of infection such as osteomyelitis.

Much like CRP, an ESR is occasionally sent in the ED often as an adjunctive piece of information when searching for more unusual causes of infection such as osteomyelitis or a septic prosthetic joint. It suffers from the same lack of specificity, especially in the older population with numerous comorbid conditions.

Procalcitonin (PCT) is a 116-amino acid peptide that is elevated mainly in response to infectious etiologies.  It is much more likely to be elevated in bacterial as opposed to viral infections.5, 6 Serum procalcitonin levels increase significantly in severe systemic infections.5 While PCT has been studied extensively in the inpatient setting to de-escalate antibiotic therapy and to determine utility of empiric antibiotics in COPD exacerbations, its role in the ED has yet to be defined.  Currently its use is not widespread, and it has not been well enough studied in the ED to support its use in determining antibiotic deployment in patients with severe sepsis or septic shock.

In sum, it may take a considerable amount of time to make a decision in the ED as to whether the febrile patient truly has an infectious etiology and what antibiotics are most appropriate.  In the sickest patient cohort (e.g. shock), empiric antibiotics are clearly indicated when sepsis is high on the differential. However, we are obligated to proceed cautiously in those stable febrile patients in whom infection is not readily apparent.  Indiscriminate use of antibiotics is fraught with consequences for the patient and the healthcare system.  Keep in mind it may still be unclear after a few hours in the ED as to whether the source of the patient fever is infectious, even after robust use of ancillary testing and a thorough history and physical examination.

How often does sepsis present without a fever?

The SIRS criteria embrace hyperthermia and hypothermia as part of the various parameters to help identify potential sepsis.  These criteria have come under scrutiny in recent years, and there is no better example as to the pitfalls of the SIRS criteria than the potential for the septic patient who is afebrile.  In the elderly and the immunocompromised patient (e.g. HIV/AIDS, cancer, cirrhosis, diabetes mellitus systemic corticosteroid use, organ transplant, use of immunosuppressant medications), the febrile response to infection might be absent. Some sources report that 20-30% of elderly patients may either remain afebrile or mount a blunted response to infection.8 In fact, some studies postulate that patients who do not mount a febrile response to infection often have more adverse clinical outcomes.  A study by Fernandes et al highlighted this risk in elderly patients with bacterial meningitis.9 They found that factors that were independently associated with adverse clinical outcome were older age, absence of fever at ICU admission, and lower GCS score.9

Caterino et al reported that only absence of fever on initial presentation to the ED and initial serum bicarbonate level were independently predictive of patient decompensation after admission to a floor bed as defined by a transfer to the ICU within 48 hours of admission.10 One potential conclusion from this study suggests that the diagnosis of sepsis, subsequent treatment, and assessment of severity of illness are all made more complex in the afebrile patient who truly has sepsis.11  The literature also supports atypical presentations (i.e. afebrile, non-specific complaints such as weakness) of the elderly patients who are bacteremic.12

In sum, do not dismiss the potential for sepsis simply because fever is not present.  The older patient and those who are immunocompromised should be expected to present in atypical fashion, and sepsis should be on many differentials regardless of whether fever is documented.

How accurate are oral temperatures compared to other core temperatures?

Oral temperatures are much more convenient that core temperatures in the ED. However, the evidence does not support the accuracy of oral temperatures. A 2015 meta-analysis determined that the accuracy of peripheral temperatures was unacceptable for making clinical decisions.1 Seventy-five studies were included that compared a gold standard core temperature to peripheral temperatures. The authors used ± 0.5 °C as the accepted limit of agreement.13 In patients with hyperthermia, the limits of agreement were -1.44 °C to 1.46 °C, and in hypothermia, -2.07 °C to 1.90 °C.13 The calculated sensitivity was only 64% [95% CI: 55-72%], but specificity performed better at 96% [95% CI: 93-97%].13

In conclusion, if the patient has a fever or is hypothermic by oral temperature, it does not need to be repeated. However, if the patient is normothermic by an oral temperature and the result would change provider management (e.g. sepsis is high on the differential), a core temperature is strongly recommended, either by a rectal thermometer or temperature sensing foley catheter.

Is there any harm in not treating a fever?

While some authors argue that fever places physiologic stress on patients, other data supports that fever enhances the immune system and curbs bacterial growth.14 Additional data from observational studies concluded that a higher early fever was linked to lower mortality rates in ICU patients admitted due to infectious causes.14  The results from a 2015 randomized controlled clinical trial that studied the benefit of treating fever in ICU patients were published in the New England Journal of Medicine.14 Seven hundred ICU patients with fever were randomized to receive either 1000 mg of acetaminophen or placebo.14 There was no statistical significance in number of ICU-free days, 28-day mortality, or 90-day mortality between either group.14 While this one RCT showed no true benefit to treating fever, clinical judgment is important as some patients may be distressed by the fever and appreciate anti-pyretic therapy.

Does the degree of fever help in narrowing the differential in terms of infectious vs. non-infectious etiology? 

Fever > 106.7° F is considered to be hyperpyrexia.1 While this can happen in septic patients, this is more common in those with intracranial hemorrhage, neuroleptic malignant syndrome, and heat stroke.1, 15 Additionally, there is a marked difference between hyperthermia and fever. Hyperthermia is treated differently and does not respond to typical anti-pyretics, as there are no pyrogenic molecules.1 Consider what the patient was doing immediately before presentation, such as long exposure in hot temperatures consistent with heat stroke.1 Even rarer are those patients who have pathology of their hypothalamus affecting their set point, such as tumor, trauma or hemorrhage—termed “hypothalamic fever.1

When you have a patient that presents with undifferentiated hyperpyrexia, think about the following differential to help guide your diagnostic evaluation.  A thorough review of the history and current medications is paramount, as serotonin syndrome, heat stroke, sepsis, and thyroid storm have specific treatments and high associated mortality.

Hyperpyrexia Differential in the ED
•      Sepsis
•      Heat Exposure (spectrum of illness)
•      Neuroleptic Malignant Syndrome
•      Medication Side Effects
•      Serotonin Syndrome
•      Thyroid Storm

Adapted from: McGugan EA. Hyperpyrexia in the emergency department. Emergency Medicine 2001;13(1):116.

In pediatric patients, it is often assumed that the degree of temperature elevation helps distinguish between a viral and bacterial etiology.  However, the literature does not support this assumption.16  In one study, neither maximum temperature, age, or leukocytosis was predictive of an underlying bacterial etiology.16

If I suspect sepsis, should I draw blood cultures in the ED each time the patient spikes a fever > 101?

It is incumbent upon emergency providers to try and obtain blood cultures on patients with severe sepsis or septic shock prior to initiation of antibiotics in a reasonable time frame. However, if the patient ends up in the ED for hours, is there utility in repeating blood cultures every time the patient is febrile?  Riedel et al did not find an increased likelihood of documenting bacteremia by employing this technique, and there is always the risk of false positive blood cultures.23 At this time it is recommended to only draw the initial set of blood cultures prior to antibiotic administration. Blood cultures are not recommended in patients who will be discharged, have uncomplicated infectious disease presentations (i.e. cellulitis admitted to a non-ICU setting), or in situations where the results of the cultures will not change management (i.e. community-acquired pneumonia admitted to a non-ICU setting).

How often does fever accompany a PE?

Two historical studies from the 1970’s reported fever in 50% (>37.5°C) and 57.1% (>38°C) of patients with pulmonary embolism respectively.16 The landmark Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study reported a much lower rate of fever in their patients with PE.  They found that 14% of patients with fever (≥ 100.0°F) had no identifiable source of that  fever other than pulmonary embolus.18 The incidence of pulmonary hemorrhage or infarction was not statistically significant higher in those with fever.18 Calvo-Romero et.al performed a retrospective review of 154 patients with acute pulmonary embolism and found 18.2% had fever (>37°C) without any other known causes.19

Fever is commonly seen in pulmonary embolism, especially low-grade fever, but any clinical significance remains to be determined. A high-grade fever (≥ 101°F) was present in only 6% of the study group in the PIOPED trial.18 In the Calvo-Romero study, 27 of 28 patients had a low-grade fever (temperature between 37°C and 39°C).1 In this study, compared to patients with PE without fever, EKG findings, mortality rates, and chest XR findings were similar.1 In the PIOPED study, 37% of patients who died with a pulmonary embolism had a low-grade fever.18 Higher-grade fevers were more likely to be associated with secondary pneumonitis or widespread pulmonary infarction in the PIOPED group.18 Unfortunately it is not uncommon for the EP to be faced with the dilemma of whether a febrile patient with respiratory complaints has a pulmonary embolus or is septic from pneumonia.  The clinician must vigorously examine the history, exam, past medical hisotry, and any ancillary testing (e.g. CXR) to help narrow the differential diagnosis. There are certianly circumstances when advanced imaging such as a CTA may be required to differentiate sepsis from pulmonary embolus, especially if the CXR is non-diagnostic.

Takeaways:

  • Not all fever is from an infectious source. Keep a broad differential and narrow based on a detailed history, a thorough physical exam, and lab/imaging results.
  • Blood cultures are not a routine part of the evaluation of fever and should be deployed in clinical scenarios which are evidence-based (e.g. septic shock) or when the results would affect patient care.
  • CRP, PCT, and ESR can be helpful in certain patient care scenarios as adjunctive information when trying to establish the source of a fever as infectious in etiology. Lack of specificity for each of these makes the clinical pre-test probability paramount prior to ordering these tests.
  • Not all septic patients have fever! Those without fever have been shown to have worse in-hospital outcomes.
  • Oral temperatures can be used for clinical decision making if a fever is documented. However, the poor sensitivity of oral temperatures mandates that a core temperature be obtained if the result would change management.  Bottom line: if you suspect sepsis and the patient is afebrile orally, get a core temperature.
  • Use your clinical judgment when deciding whether to treat a fever—not all fevers need to be treated with anti-pyretics.
  • Do not dismiss the diagnosis of pulmonary embolus because the patient is febrile.

 

References / Further Reading

  1. Dinarello CA, Porat R. Fever [Internet]. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill Education; 2015 [cited 2016 Oct 29]. Available from: http://mhmedical.com/content.aspx?aid=1120874671
  2. Morris F, Fletcher A. ABC Of Emergency Differential Diagnosis [Internet]. West Sussex, UK: Blackwell Publishing; [cited 2016 Nov 9]. Available from: https://www.google.com/search?client=safari&rls=en&q=Fletcher_C000.indd+-+ABC+Of+Emergency+Differential+Diagnosis+2009.pdf&ie=UTF-8&oe=UTF-8
  3. Lee C-C, Hong M-Y, Lee N-Y, Chen P-L, Chang C-M, Ko W-C. Pitfalls in using serum C-reactive protein to predict bacteremia in febrile adults in the ED. Am J Emerg Med 2012;30(4):562–9.
  4. Povoa P. C-reactive protein: a valuable marker of sepsis. Intensive Care Med 2002;28:235–43.
  5. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008;36(3):941–52.
  6. Mat-Nor MB, Ralib A, Abdulah NZ, Pickering JW. The diagnostic ability of procalcitonin and interleukin-6 to differentiate infectious from noninfectious systemic inflammatory response syndrome and to predict mortality. J Crit Care 2016;33:245–51.
  7. Puskarich MA, Jones AE. Sepsis [Internet]. In: Tintinalli JE, Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline DM, editors. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e. New York, NY: McGraw-Hill Education; 2016 [cited 2016 Nov 9]. Available from: http://mhmedical.com/content.aspx?aid=1121510693
  8. Moran D. Infections in the elderly. Top Emerg Med 2003;25(2):174–81.
  9. Fernandes D, Gonçalves-Pereira J, Janeiro S, Silvestre J, Bento L, Póvoa P. Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: retrospective study. J Crit Care 2014;29(3):347–50.
  10. Caterino JM, Jalbuena T, Bogucki B. Predictors of acute decompensation after admission in ED patients with sepsis. Am J Emerg Med 2010;28(5):631–6.
  11. Burlaud A, Mathieu D, Falissard B, Trivalle C. Mortality and bloodstream infections in geriatrics units. Arch Gerontol Geriatr 2010;51(3):e106–9.
  12. Wester AL, Dunlop O, Melby KK, Dahle UR, Wyller TB. Age-related differences in symptoms, diagnosis and prognosis of bacteremia. BMC Infect Dis 2013;13:346–346.
  13. Niven DJ, Gaudet JE, Laupland KB, Mrklas KJ, Roberts DJ, Stelfox HT. Accuracy of peripheral thermometers for estimating temperature: a systematic review and meta-analysis. Ann Intern Med 2015;163(10):768–77.
  14. Young P, Saxena M, Bellomo R, et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med 2015;373(23):2215–24.
  15. McGugan EA. Hyperpyrexia in the emergency department. Emerg Med 2001;13(1):116.
  16. Trautner BW, Caviness AC, Gerlacher GR, Demmler G, Macias CG. Prospective evaluation of the risk of serious bacterial infection in children who present to the emergency department with hyperpyrexia (temperature of 106 degrees F or higher). Pediatrics 2006;118(1):34–40.
  17. Nucifora G, Badano L, Hysko F, Allocca G, Gianfagna P, Fioretti P. Pulmonary Embolism and Fever. Circulation 2007;115(6):e173–6.
  18. Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute pulmonary embolism. Chest 2000;117(1):39–42.
  19. Calvo-Romero JM, Lima-Rodríguez EM, Pérez-Miranda M, Bureo-Dacal P. Low-grade and high-grade fever at presentation of acute pulmonary embolism. Blood Coagul Fibrinolysis Int J Haemost Thromb 2004;15(4):331–3.

Pneumonia Mimics: Pearls and Pitfalls

Authors: Drew A. Long, BS (@drew2232, Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021, Senior Staff Physician, Henry Ford Hospital)

It’s a busy day in the ED. You have a full waiting room and multiple patients who have been roomed but not seen. You force your exhaustion to the back of your mind as you see your next patient: a 52-year-old male with cough and shortness of breath for three days. He states he has felt warm at home, but he denies chest pain, abdominal pain, vomiting, and diarrhea. He has experienced several episodes of nausea.  His past medical history includes hypertension and hyperlipidemia.

His vital signs include HR 103, RR 24, BP 128/72, T 99.8, and SpO2 95% on room air. He has some crackles in the lower lung bases, but has an otherwise normal physical exam. You order a chest x-ray, which demonstrates a right lower lobe infiltrate. As you write the diagnosis of “pneumonia” on the discharge form and write a prescription for antibiotics, you pause. Is there something else you could be missing? Are there other diagnoses you should consider?

Background

Pneumonia is defined as an acute infection of the pulmonary alveoli.  Pneumonia can be life-threatening, most commonly in older patients with comorbidities or immunocompromised patients.  It is the 7th leading cause of death in the U.S. and the number one cause of death from infectious disease in the U.S.1   The annual incidence of community acquired pneumonia (CAP) ranges from 2 to 4 million, resulting in an estimated annual 500,000 hospitalizations.1  Pneumonia is broken into several categories: community-acquired (CAP), hospital-acquired, healthcare-associated (HCAP), and ventilator-associated (VAP) (Table 1).

Table 1.  Classification of Pneumonia (Adapted from Maloney G, Anderson E, Yealy DM.  Tintinalli’s Emergency Medicine:  A Comprehensive Study Guide.  Chapter 65:  Pneumonia and Pulmonary Infiltrates.  McGraw Hill Professional 2016.  8th ed.)

 

 

Community-acquired pneumonia

 

 

Acute pulmonary infection in a patient who is not hospitalized or residing in a long-term care facility 14 or more days before presentation

 

 

Hospital-acquired pneumonia

 

New infection occurring 48 hours or more after hospital admission

 

 

 

Healthcare-associated pneumonia

 

Patients hospitalized ≥ 2 days within past 90 days

Nursing home/long-term care residents

Patients receiving home IV therapy

Dialysis patients

Patients receiving chronic wound care

Patients receiving chemotherapy

Immunocompromised patients

 

 

Pneumonia can be caused by bacteria, viruses, or fungi.  However, it is often challenging to differentiate between these in the ED, and many patients will not have an etiologic agent identified even after inpatient evaluation.   It is estimated that a microbial agent cannot be identified in nearly half of cases of CAP.1 The “typical” pathogens in patients hospitalized with pneumonia include S. pneumoniae and H. influenza, with S. pneumoniae being the most common.  The “typical” pathogens are thought to account for about half of cases.1 “Atypical” pathogens include Legionella, Mycoplasma, and Chlamydia.  The most common identified viral causes of pneumonia are influenza and parainfluenza viruses.  Fungal pneumonia is often associated with patients who are immunocompromised or possess other risk factors.1,2

History and Physical Examination

The classic presentation of pneumonia is a cough productive of purulent sputum, shortness of breath, and fever.  The most common signs of pneumonia include cough (79%-91%), fever (up to 75%), increased sputum (up to 65%), pleuritic chest pain (up to 50%), and dyspnea (approximately 70%).3 There are many patterns of presentation with a variety of these symptoms and physical findings, making the diagnosis at times difficult. Elderly or debilitated patients in particular can present with non-specific complaints, such as altered mental status without the classic symptoms.1,2 In addition, pneumonia may cause lightheadedness, malaise, weakness, headache, nausea/vomiting, joint pain, and rash.  The examination may reveal bronchial or decreased breath sounds, dullness on percussion, rales, rhonchi, or wheezing. This wide variation in symptoms and presentation provides potential for misdiagnosis, especially if other conditions are not considered.

The chest x-ray in patients with pneumonia can vary greatly.  Radiologic findings in pneumonia are used in conjunction with the physical exam to identify any area of consolidation.  The most common cause of pneumonia, S. pneumoniae, classically presents with a lobar infiltrate visualized on chest x-ray.  Other organisms, such as Staphylococcus aureus pneumonia can be seen on chest x-ray as extensive infiltration and effusion or empyema.  Klebsiella may present with diffuse, patchy infiltrates.  Other findings on chest x-ray found in various organisms include pleural effusions, basilar infiltrates, interstitial infiltrates, or abscesses.1,2,4 However, each agent can present multiple ways on chest x-ray, and many patients may not demonstrate the classic radiographic findings, especially elderly and immunocompromised patients with weakened immune systems.

xray1
PA chest radiograph showing left upper lobe pneumonia.  (Image from Marx JA.  Rosen’s Emergency Medicine:  Concepts and Clinical Practice.  Saunders 2014.  8th ed.)

 While it is tempting to diagnose pneumonia in a patient with a classic presentation (fever, cough, shortness of breath) and a supportive chest x-ray, what else should be considered?  As Table 2 shows, many conditions can be confused for pneumonia based on the history, physical exam, and radiographic findings.

Table 2.  Mimics of Pneumonia (Adapted from Marx JA.  Rosen’s Emergency Medicine:  Concepts and Clinical Practice and Maloney G, Anderson E, Yealy DM.  Tintinalli’s Emergency Medicine:  A Comprehensive Study Guide.  Chapter 65:  Pneumonia and Pulmonary Infiltrates.)

Pulmonary Embolism
Endocarditis
Septic Emboli
Vasculitis
Atelectasis
Congestive Heart Failure
Tuberculosis
Cancer and leukemic infiltrates
Acute Respiratory Distress Syndrome
Bronchiolitis obliterans organizing pneumonia
Granulomatous disease
Drug induced pulmonary disease
Pulmonary fibrosis
Eosinophilic pneumonia
Allergic/hypersensitivity pneumonitis
Radiation pneumonitis
Foreign body obstruction

 

Unfortunately, many of these diagnoses are not even considered in a patient with a classic presentation for pneumonia until the patient fails to improve with initial antibiotic management.  Of the diagnoses listed in Table 2, several of these carry high potential for morbidity and mortality.  These include pulmonary embolism, endocarditis, vasculitis, acute decompensated heart failure, tuberculosis, primary lung cancer, and acute respiratory distress syndrome.  The remainder of this discussion will focus on differentiating each of these from pneumonia.

*Bonus: What can potentially assist providers? Ultrasound (US)!

US has demonstrated tremendous utility differentiating pneumonia from other conditions. X-ray has a sensitivity of 46-77% in diagnosing pneumonia. US findings with pneumonia include air bronchograms, b-lines, consolidations, pleural line abnormalities, and pleural effusions. Dynamic air bronchograms (those that move) are considered pathognomonic for pneumonia.  Positive likelihood ratios (LR) for these findings range from 15.6 to 16.8, with negative LR’s of 0.03 to 0.07.5,6  Please see a prior emDocs.net post on the use of US in pneumonia: http://www.emdocs.net/ultrasound-for-pneumonia-in-the-ed/

pic2
Air bronchograms in pneumonia (From http://www.emdocs.net/ultrasound-for-pneumonia-in-the-ed/)

Pulmonary Embolism

Pulmonary embolism (PE) occurs when a thrombus, most commonly from the venous system, embolizes to the pulmonary vasculature.7,8 Like pneumonia, the clinical presentation of a PE can vary greatly, ranging from an asymptomatic patient to an ill-appearing, dyspneic patient.  PE can be easily confused with pneumonia, as the most common presenting symptom is dyspnea followed by pleuritic chest pain and cough.8,9 Fever can also be present in pulmonary embolism. The most common symptoms and their frequency are shown in Table 3.

Table 3.  Signs and Symptoms Of Pulmonary Embolism (adapted from Stein PD, Beemath A, Matta F, et al.  Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med. 2007;120(10):871.)

Sign/Symptom Frequency
Dyspnea 73%
Tachypnea 70%
Pleuritic Chest Pain 66%
Rales 51%
Cough 37%
Tachycardia 30%
S4 heart sound 24%
Accentuated P2 23%
Hemoptysis 13%
Circulatory collapse 8%

 

A PE most commonly has non-specific chest x-ray findings (atelectasis, pleural effusion, peripheral infarct/consolidation, elevated hemidiaphragm) or is normal.2  That being said, while a normal chest x-ray is helpful in distinguishing PE from pneumonia, a normal chest x-ray does not definitively exclude pneumonia or pulmonary embolism.  Hampton’s Hump (peripheral wedge-shaped opacity with base against pleural surface) and Westermark’s Sign (focus of oligemia and vessel collapse distal to the PE) are classic findings in the PE radiograph, but they lack sensitivity.

The important aspect of not missing PE is first considering it. As the presentation of PE is nonspecific, clinical gestalt and risk stratification are useful. Evaluate the patient for signs/symptoms of PE including shortness of breath with pleuritic chest pain, tachypnea, and leg swelling in the setting of risk factors such as recent travel history, prior history of thrombosis, family history of thrombosis, or history of cancer.  If signs and/or symptoms are present and concerning, do not hesitate to begin the workup for PE.

In PE, US may reveal RV strain with dilated RV and free wall hypokinesis and normal RV apical contractility (McConnell Sign). On short axis view, the LV will appear “D” shaped, with RV bowing into the LV due to elevated right-sided pressures.10-12

pic3
Enlarged RV when compared to LV in setting of acute PE (from www.em.emory.edu)

Endocarditis

Endocarditis is most commonly caused by a bacterial agent, with a one-year mortality of 40%.13 The most common symptoms are intermittent fever (85%) and malaise (80%).1  Additionally, endocarditis can present with dyspnea, chest pain, cough, headache, weakness, and myalgias.  Infective endocarditis (IE) can easily be confused with pneumonia in a patient presenting with fever and dyspnea or chest pain.  Risk factors for IE are shown below in Table 4.  Diagnosis includes the Duke Criteria. A patient with flu-like symptoms (cough, myalgias, etc.) with the risk factors shown in Table 4, warrants further evaluation for IE. 13-17

Table 4.  Risk factors for IE

Age ≥ 60 (over half of cases occur in this population)
History of IV drug use
Poor dentition or dental infection
Structural heart disease (e.g. valvular or congenital)
Presence of prosthetic valve
Presence of intravascular device
Chronic hemodialysis
Immunosuppression

 

One of the most important aspects to not miss is the patient with multiple infiltrates on chest x-ray, as a dreaded complication of IE is septic emboli.  This has been described in 13 to 44% of patients with IE.18,19 Septic emboli can lead to damage in the systemic or pulmonary artery circulation, depending on left vs. right-sided disease.  Specifically, embolization can lead to stroke, paralysis, blindness, ischemia of the extremities, splenic or renal infarction, pulmonary emboli, or an acute myocardial infarction.18 In particular, septic emboli from the right heart to the pulmonary arteries can lead to a toxic-appearing patient with fever and shortness of breath.  Again, the chest x-ray may demonstrate multiple infarcts or consolidations. This patient may originally be worked up for pneumonia.  In the patient with IE risk factors described above and multiple consolidations/infarcts on chest x-ray, strongly consider IE and obtain multiple blood cultures and echocardiogram.  US may reveal valvular vegetation(s) and/or regurgitation.

pic4
Multiple emboli with consolidations from R sided IE (From https://www.roshreview.com/em.html)
pic5
Valvular Regurgitation with Vegetation in Endocarditis (From Journal of Medicine Cases, http://www.journalmc.org/index.php/JMC/article/view/286/212)

Vasculitis (Systemic Lupus Erythematosus)

A vasculitis that often manifests with pulmonary involvement is systemic lupus erythematosus (SLE).  SLE is an autoimmune disorder that leads to inflammation of multiple organ systems.  Pulmonary involvement is common and has been observed in up to 93% of patients with SLE.20,21 Lung involvement in SLE often manifests as pleurisy, coughing, and/or dyspnea.21-23 The most common respiratory condition among patients with SLE is pleuritis, thought to be due to autoantibodies damaging the pleura itself.1 Pneumonitis may also occur in the setting of SLE. Patients with acute lupus pneumonitis present with a rapid onset of fever, cough, and dyspnea, with elevation of serum antinuclear antibodies and anti-DNA antibodies.22,23

Patients with SLE (either diagnosed or undiagnosed) and lung involvement should be worked up for infection.  Since patients with SLE are often immunosuppressed due to immunomodulatory therapy and the disease itself, they are at a much higher risk of infection with both typical and opportunistic agents.  The patient with extrapulmonary features of SLE (e.g. malar rash, oral ulcers, polyserositis, renal insufficiency, cytopenia, thrombophilia, lymphadenopathy, splenomegaly, or arthritis) and signs of lung involvement warrants treatment for infection and worsening vasculitis. Consultation with rheumatology and the ICU is recommended due to the potential for rapid decompensation.

Diffuse alveolar hemorrhage (DAH) is one of the most life-threatening conditions in SLE. Diffuse alveolar damage is a more common presentation in patients who already have a documented history of lupus and rarely presents as the initial manifestation of lupus.  These patients present with severe shortness of breath, hemoptysis, and diffuse patchy infiltrates on chest x-ray. Patients often require intubation, ICU admission, and high dose steroids.24-26

Heart Failure Exacerbation

A patient with heart failure exacerbation can present similarly to a patient with pneumonia, particularly if a patient has undiagnosed heart failure.  Patients with acute decompensated heart failure most commonly present with cough, shortness of breath, fatigue, and/or peripheral edema.  The history and physical exam may be enough to differentiate a heart failure exacerbation from pneumonia.  A history of orthopnea and/or paroxysmal nocturnal dyspnea leading up to the patient’s presentation is sensitive and specific for heart failure.  Furthermore, many of these patients will have a cardiac history, history of cardiac procedures, and comorbid conditions for CHF (such as diabetes, hypertension, hyperlipidemia, or a history of smoking).  Physical exam may reveal an S3 or S4 heart sound, elevated jugular venous pressures, lower extremity edema, and crackles indicating interstitial pulmonary edema on auscultation of the lungs.  These patients often have nonspecific EKGs showing left-ventricular hypertrophy, bundle branch block, or signs of a previous MI such as prominent Q waves or T wave inversions.  BNP will more likely be elevated in CHF exacerbations, though sepsis from pneumonia can also increase BNP.1,27

The chest x-ray findings in CHF may include prominent interstitial markings, cardiomegaly, and pleural effusions.2

pic6
CXR in a patient with CHF depicting cardiomegaly, alveolar, and interstitial edema (From https://www.med-ed.virginia.edu/courses/rad/cxr/pathology2Bchest.html)

US in the setting of CHF will reveal b-lines in 3 or more lung fields bilaterally, which has a +LR of 20. The IVC will often reveal significant distension, with 2-2.5cm in size and < 50% collapse. Echocardiogram may reveal depressed contractility if systolic dysfunction is present.28

pic7
Multiple b-lines in the setting of acute CHF (From canadiem.org, http://canadiem.org/2015/01/19/us-world-ultrasound-differentiating-copd-chf/)

Tuberculosis

Tuberculosis (TB) is currently the world’s second leading infectious cause of death.1 The lungs are the major site for infection with Mycobacterium tuberculosis.  TB can occur in multiple forms, including primary TB, reactivation TB, laryngeal TB, endobronchial TB, lower lung field TB infection, and tuberculoma.29 As TB affects the lungs and can present with fever, cough, or dyspnea, it is often misdiagnosed as viral or bacteria pneumonia.  There are a wide array of nonspecific signs and symptoms associated with the multiple forms of TB, shown in Table 5.30

Table 5.  Symptoms and Signs of Tuberculosis (Adapted from Barnes PF, et al:  Chest roentgenogram in pulmonary TB: new data on an old test. Chest. 94:316, 1988.)

Symptom or Sign Frequency
Cough 78%
Weight loss 74%
Fatigue 68%
Tactile fever 60%
Night sweats 55%
Chills 51%
Anorexia 46%
Chest pain 40%
Dyspnea 37%
Hemoptysis 28%

 

In differentiating TB from pneumonia, it is important to assess the patient for risk factors for TB.  The most commonly reported behavioral risk factor among patients with TB in the U.S. is substance abuse (including drugs, tobacco, and alcohol).31 Other risk factors include malnutrition, systemic disease (silicosis, malignancy, diabetes, renal disease, celiac disease, or liver disease), or patients who are immunocompromised or homeless.32  Additionally, TB should be considered when a patient has a history of recent travel to an area where TB is endemic (Africa, the Middle East, Southeast and East Asia, and Central and South America).33

 As TB has many forms, the chest x-ray in TB can vary and may not be all that helpful in differentiating TB from pneumonia.  In summary, TB should be suspected in a patient with vague symptoms who possesses risk factors for TB, particularly in patients who are homeless, immunosuppressed, have a history of drug use, or have recently traveled to a TB endemic area.

Primary Lung cancer

In 2012, lung cancer worldwide was the most common cancer in men and the third most common cancer in women.34 In the U.S., lung cancer occurs in an estimated 225,000 patients every year and is responsible for over 160,000 deaths.35 There are many risk factors for cancer, the most notorious of which is smoking.

A patient with a primary lung cancer can easily be confused with pneumonia due to the similarity of symptoms (Table 6).  What is key in primary lung cancer is these symptoms have a more insidious onset than the relatively more acute onset of symptoms in pneumonia. Furthermore, these symptoms will progress over time and may include symptoms less commonly seen in pneumonia (weight loss, bone pain, or voice hoarseness).

Table 6.  Symptoms of lung cancer at presentation.  (Modified from: Hyde, L, Hyde, CI. Chest 1974; 65:299-306 and Chute CG, et al. Cancer 1985; 56:2107-2111).

Symptom Percent of Patients Affected
Cough 45-74%
Weight Loss 46-68%
Dyspnea 37-58%
Chest pain 27-49%
Hemoptysis 27-29%
Bone pain 20-21%
Hoarseness 8-18%

 

The chest x-ray in patients with lung cancer varies depending on the type and stage of cancer.  The chest x-ray in patients with a primary lung cancer may display a solitary nodule, an interstitial infiltrate, or may be normal.2

pic8
Non-small cell lung cancer.  (Image from http://emedicine.medscape.com/article/358433-overview)

 If considering a primary lung malignancy in a patient whose presentation is consistent with pneumonia, more definitive imaging including CT of the chest may be warranted. Discussion with the oncology service is advised.

Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) is acute, diffuse, inflammatory lung injury that carries high rates of morbidity, ranging from 26 to 58%.35,36 ARDS stems from diffuse alveolar damage and lung capillary endothelial injury, leading to increased capillary permeability and pulmonary edema.1 This disease manifests with respiratory distress, with patients often displaying tachycardia, tachypnea, hypoxemia, and dyspnea.37 Arterial blood gas analysis shows hypoxemia in addition to acute respiratory alkalosis and increased alveolar-arterial oxygen gradient (though ABG is usually not required in the ED).  A chest radiograph will typically reveal bilateral alveolar infiltrates, and classically, no cardiomegaly is seen.2

ards
Chest radiograph depicting bilateral lung opacities in a patient with ARDS.  (Image from http://emedicine.medscape.com/article/362571-overview#a2)

When considering ARDS, several factors come into play.  The diagnosis of ARDS is complicated, as the most common cause or ARDS is sepsis. Thus, ARDS may result from a prior pneumonia leading to sepsis. The patient with ARDS will appear sick and will likely require high levels of FiO2 or positive pressure ventilation if not intubated, while the severity of pneumonia varies greatly based on the patient and infectious microbe.  Risk factors such as sepsis, aspiration, and multiple transfusions are commonly seen with ARDS.38 Other risk factors for ARDS include alcohol abuse, trauma, and smoke inhalation.  On physical exam, patients with ARDS often have diffuse crackles on auscultation of the lungs.  The chest x-ray shows more diffuse involvement than would be expected in a patient with pneumonia.2 US will reveal b-lines in multiple lung fields.  If concerned for ARDS, be ready to intubate the patient for clinical course/oxygenation and admit to the ICU.

Case resolution

As you return to this 52-year-old gentleman’s room with his prescription for antibiotics, you notice that he remains tachycardic, tachypneic, and hypoxic (HR 105, RR 24, SpO2 93%).  You perform a more complete review of systems and find out this gentleman has been experiencing pain in his right calf over the past week after returning from an overseas business trip.  On exam, you notice that his right lower extremity is slightly edematous compared to the left.  In addition to pneumonia, you decide to begin to work up this gentleman for a possible deep venous thrombosis and pulmonary embolism.  A chest CT reveals a large right-sided segmental PE.

Summary

Many potentially deadly conditions can be confused for pneumonia.  Unfortunately, many of these conditions are not considered until the patient fails to improve after treatment with antibiotics.  The following should be considered in a patient presenting with signs of pneumonia:

  • Pulmonary embolism: suspect when a patient has signs/symptoms of PE including shortness of breath with pleuritic chest pain, tachypnea, and leg swelling in the setting of risk factors for DVT/PE.
  • Endocarditis/septic emboli: consider in febrile patients with risk factors including history of IV drug use, poor dentition, structural heart disease, or the presence of a prosthetic valve. Septic emboli leading to pulmonary infarction can present with multiple infiltrates on chest x-ray.
  • Systemic Lupus Erythematosus: pulmonary involvement is very common in lupus. Patients with SLE and lung involvement must always be evaluated for infection, and diffuse alveolar hemorrhage is a life-threatening complication.
  • Heart Failure exacerbation: suspect in a patient with cardiac history and signs/symptoms of heart failure (orthopnea, PND, peripheral edema, elevated jugular venous distension, etc.).
  • Tuberculosis: suspect in patients with risk factors for TB including substance abuse, malnutrition, systemic diseases, immunocompromise, or recent foreign travel.
  • Lung cancer: suspect in patients with insidious onset of symptoms and in patients complaining of constitutional symptoms such as weight loss or fatigue.
  • Acute Respiratory Distress Syndrome: suspect in toxic-appearing patients with white-out on chest x-ray who require high levels of FiO2 or positive pressure ventilation.

 

References/Further Reading

  1. Marx JA. Rosen’s Emergency Medicine:  Concepts and Clinical Practice.  Saunders 2014.  8th
  2. Maloney G, Anderson E, Yealy DM. Tintinalli’s Emergency Medicine:  A Comprehensive Study Guide.  Chapter 65:  Pneumonia and Pulmonary Infiltrates.  McGraw Hill Professional 2016.   8th
  3. Fine MJ, Stone RA, Singer DE et al. Processes and outcomes of care for patients with community-acquired pneumonia:  results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study.  Arch Intern Med 159:  970, 1999.
  4. Bartlett JG. Diagnostic approach to community-acquired pneumonia in adults.  UpToDate.  Jan 2016.
  5. Hu QJ, Shen YC, Jia LQ, et al. Diagnostic performance of lung ultrasound in the diagnosis of pneumonia: a bivariate meta-analysis. Int J Clin Exp Med. 2014;7(1):115-21. [pubmed]
  6. Chavez MA, Shams N, Ellington LE, et al. Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis. Respir Res. 2014;15:50. [pubmed]
  7. Thompson BT. Overview of acute pulmonary embolism in adults.  UpToDate.  Jan 2016.
  8. Thompson BT. Clinical presentation, evaluation, and diagnosis of the adult with suspected acute pulmonary embolism.  UpToDate.  Jan 2016.
  9. Stein PD, Beemath A, Matta F, et al. Clinical characteristics of patients with acute pulmonary embolism:  data from PIOPED II.  Am J Med.  2007;120(10):871.
  10. Perera, T. Mailhot, D. Riley, and D. Mandavia, “The RUSH exam: rapid ultrasound in Shock in the evaluation of the critically ill,” Emergency Medicine Clinics of North America, vol. 28, no. 1, pp. 29–56, 2010.
  11. P. Borloz, W. J. Frohna, C. A. Phillips, and M. S. Antonis, “Emergency department focused bedside echocardiography in massive pulmonary embolism,” Journal of Emergency Medicine, vol. 41, no. 6, pp. 658–660, 2011.
  12. Madan and C. Schwartz, “Echocardiographic visualization of acute pulmonary embolus and thrombolysis in the ED,” American Journal of Emergency Medicine, vol. 22, no. 4, pp. 294–300, 2004.
  13. Murdoch DR, Corey GR, Hoen B. Clinical Presentation, Etiology and Outcome of Infective Endocarditis in the 21st Century:  The International Collaboration on Endocarditis-Prospective Cohort Study.  Arch Intern Med.  2009 Mar 9;169(5):463-473.
  14. Sexton DJ. Epidemiology, risk factors, and microbiology of infective endocarditis.  UpToDate.  Jan 2016.
  15. Hill EE, Herijgers P, Claus P. Infective endocarditis:  changing epidemiology and predictors of 6-month mortality:  a prospective cohort study.  Eur Heart J.  2007;28(2):196.
  16. Cantrell M, Yoshikawa TT. Infective endocarditis in the aging patient.  Gerontology.  1984;30(5):316.
  17. Castillo FJ, Anguita M, Castillo JC, et al. Changes in the Clinical Profile, Epidemiology and Prognosis of Left-sided Native-valve Infective Endocarditis Without Predisposing Heart Conditions.  Rev Esp Cardiol (Engl Ed).  2015 May;68(5):445-8.  Epub 2015 Mar 16.
  18. Spelman D, Sexton DJ. Complications and outcome of infective endocarditis.  UpToDate.  Jan 2016.
  19. Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis:  the prognostic value of echocardiography.  Ann Intern Med.  1991;114(8):635.
  20. Dellaripa PF, Danoff Sonye. Pulmonary manifestations of systemic lupus erythematosus in adults.  UpToDate.  Jan 2016.
  21. King Jr. TE, Kim EJ, Kinder BW. Connective tissue diseases:  In:  Interstitial Lung Disease, 5th, Schwartz MI, King TE Jr. (Eds), People’s Medical Publishing House-USA, Shelton, CT 2011.
  22. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus:  review of twelve cases of acute lupus pneumonitis.  Medicine (Baltimore).  1975;54(5):397.
  23. Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus.  J Thorac Imaging.  1992;7(2):1.
  24. Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar hemorrhage and systemic lupus erythematosus.  Clinical presentation, histology, survival, and outcome.  Medicine (Baltimore).  1997;76(3):192. 
  25. Andrade C, Mendonca T, Farinha F, et al. Alveolar hemorrhage in systemic lupus erythematosus:  a cohort review.  Lupus.  2016 Jan;25(1):75-85.  Epub 2015 Sep 18.
  26. Collard HR, Schwarz MI. Diffuse alveolar hemorrhage. Clin Chest Med 2004;25:583–592, vii.
  27. Borlaug BA. Clinical manifestations and diagnosis of heart failure with preserved ejection fraction.  UpToDate.  Jan 2016.
  28. Ang S-H, Andrus P. Lung Ultrasound in the Management of Acute Decompensated Heart Failure. Current Cardiology Reviews. 2012;8(2):123-136.
  29. Pozniak A. Clinical manifestations and complications of pulmonary tuberculosis.  UpToDate.  Jan 2016.
  30. Barnes PF, et al: Chest roentgenogram in pulmonary TB:  new data on an old test.  94:316, 1988.
  31. Oeltmann JE, Kammerer JS, Pevzner ES, Moonan PK. Tuberculosis and substance abuse in the United States, 1997-2006.  Arch Intern Med.  2009;169(2):189.
  32. Horsburgh CR. Epidemiology of tuberculosis.  UpToDate.  Jan 2016.
  33. World Health Organization. Global Tuberculosis Report 2014. http://www.who.int.proxy.library.vanderbilt.edu/tb/publications/global_report/en/.
  34. World Cancer Research Fund International. Worldwide Data.  http://www.wcrf.org/int/cancer-facts-figures/worldwide-data.
  35. MacCallum NS, Evans TW. Epidemiology of acute lung injury.  Curr Opin Crit Care.  2005;11(1):43.
  36. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury.  N Engl J Med.  2005;353(16):1685.
  37. Hansen-Flaschen J, Siegel MD. Acute respiratory distress syndrome:  Clinical features and diagnosis in adults.  UpToDate.  Jan 2016.
  38. Siegel MD. Acute respiratory distress syndrome:  Epidemiology, pathophysiology, pathology, and etiology in adults.  UpToDate.  Jan 2016.