Hospital Medicine

Gram Negative Rod Infections

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Gram Negative Rod Infections

I. Problem/Condition.

Gram negative rod (GNR) infections cause a significant amount of morbidity and mortality amongst hospitalized patients. Patients with poor underlying medical status are most at risk, especially the immunosuppressed, elderly, and patients with malignancies.

Infections with this class of bacteria often arise from the genitourinary system, hepatobiliary tract, gastrointestinal tract, and lungs. Less commonly, but also important for hospitalized patients, infections can be found in IV access sites, surgical wounds and drains, and soft tissue/skins infections.

A. What is the differential diagnosis for gram negative rod infections?

Specific bacteria can be grouped into those that cause acute infectious diarrhea as their primary symptom versus those that do not.

Infectious diarrhea

1. Shigella

2. Salmonella (nontyphoidal)

3. Campylobacter jejuni

4. E Coli

a. Enterotoxigenic E Coli (ETEC)

b. Enteroinvasive E Coli (EIEC)

c. Enterohemorrhagic E Coli (EHEC)

- E Coli O157:H7

d. Enteroaggregative (EAEC)

e. Enteropathogenic (EPEC)

Non-diarrheal

1. Klebsiella pneumoniae

2. E Coli (extraintestinal pathogenic)

3. Proteus

4. Pseudomonas aeruginosa

5. Yersinia pestis

6. Salmonella

a. Typhi

b. Paratyphi

B. Describe a diagnostic approach/method to the patient with gram negative rod infections

Gram negative sepsis/bacteremia, in general, will present abruptly with fever and chills. However, a sizable percentage of patients (15%) will be hypothermic and up to 5% never exhibit fever. Hyperventilation and alterations in sensorium can develop as the disease state worsens.

To classify disease processes further, it will be important, and easier, to classify one's thinking into gram negative bacteria that cause infectious diarrhea and those that do not.

For the most part, the infectious diarrheal presentations are all very similar and all bacteria are considered likely in etiology until further proof (i.e., culture) is obtained. Classifying the diarrhea as either inflammatory/bloody versus non-inflammatory/watery is the first step in narrowing down a specific organism.

Non-enteric infections can occur at almost any site in the body. Most common sites of infection include genitourinary system, hepatobiliary tract, lungs, intravenous lines, infusion fluids, surgical drains, skin/soft tissue infections. Infections at any of these sites could have a gram negative organism etiology. Hospitalized patients and those with significant immunocompromised states should be considered at the highest risk.

1. Historical information important in the diagnosis of gram negative rod infections.

Infectious diarrhea

Shigella

This is the classic etiology for dysentery; fever, abdominal cramps, and frequent, small volume stool with blood and mucous. Transmission is via the fecal-oral route. Once infected, there is an incubation period of 1-4 days. Subsequently, patients will enter the "watery diarrheal" phase, which is characterized by fever, malaise and watery diarrhea, which does not lead to significant dehydration. In developed countries, especially, this might be the extent of the illness.

If the illness progresses, though, frank dysentery follows, with bloody, mucopurulent, small volume bowel movements with increasing abdominal pain and possibly tenesmus. Most of the severe complications and extraintestinal manifestations occur in young children, typically below 5 years of age and in developing countries.

Salmonella

Is most commonly transmitted to people via animal products such as eggs, poultry, undercooked meat, dairy products and fresh fruits/vegetables. In addition, up to 6% of cases in the U.S. are linked to contact with amphibians and reptiles.

The incubation period is from 6 hours up to 2 days. Symptoms are primarily a non-specific gastroenteritis, producing a moderate severity diarrhea, with loose non-bloody stool in addition to fever and abdominal cramps. In more severe cases, patients can report large volume or bloody stools. In rare occasions, the illness can even mimic inflammatory bowel disease or appendicitis. Symptoms should resolve by one week.

Up to 5% of patients develop bacteremia, of those 5-10% develop metastatic infections. Endovascular infections are a concern for patients with valvular/atheroscrelotic disease. Additional sites of infection include: intraabdominal (hepatic/splenic abscesses or cholecystitis), CNS (meningitis/abscess), pulmonic (lobar pneumonia), GU tract (cystitis/pyelonephritis), and musculoskeletal (osteomyelitis/septic arthritis).

Campylobacter jejuni

Is most commonly transmitted via ingestion of contaminated poultry (30-70% of cases) and causes a prodrome of fever, headache, myalgia which begin about 12-48 hours before the onset of the diarrheal illness. When diarrhea begins, stool can vary between loose and watery to grossly bloody. Cramping abdominal pain is also common.

While similar to other bacterial diarrheal infections, in that the course is often self-limited, symptoms can also persist for over a week in a significant percentage of patients and clinical relapses are not unheard of. Multiple sites of distant infection are possible, but all are extremely rare.

The most well known and somewhat more common complication of infection is the Guillain-Barre syndrome (1 out of 1000-2000 cases). Because of Camplobacter's ubiquitousness though, it is thought that up to 40% of cases of Guillain-Barre syndrome (GBS) are caused by this infection.

Escherichia Coli (intestinal pathogenic strains)

  • Enterohemorrhagic (EHEC): Consumption of undercooked ground beef and fresh produce are the common sources of transmission. 0157:H7 is the most common, and most notorious, of the numerous serotypes as it has drawn much media attention from outbreaks at fast food restaurants. In addition, person to person spread has been noted. The peak incidence of disease is in the summer, similar to most of the intestinal infections. An incubation period of 3-4 days is followed by an initial secretory diarrhea, which subsequently leads to the classic presentation of grossly bloody diarrhea. This hallmark symptom is found in over 90% of cases. While abdominal pain is also common, fever surprisingly not. Similar to other causes of bacterial diarrhea, the course is self-limited and should resolve by 5-10 days. Hemolytic Uremic Syndrome (HUS) is commonly discussed as the classiccomplication but only occurs in approximately 5% of the cases. Of biggest concern for HUS are the very young and very elderly. As a review, HUS produces a syndrome similar to TTP, with thrombocytopenia and micro-angiopathic hemolytic anemia, but more commonly with renal failure (in contrast to TTP which more often has neurological complications).

  • Enterotoxigenic (ETEC): This is the most common etiology (~50%) of traveler's diarrhea. It is found mostly in tropical or developing countries. In contrast to EHEC, this strain causes a non-inflammatory diarrhea; mostly watery without blood or mucous. Abdominal cramps and lack of fever are similar, though. In general, symptoms are self-limited, and will resolve in approximately 3 days.

  • Enteropathogenic (EPEC): Primarily a disease of young children.

  • Enteroinvasive (EIEC): This strain is rarely seen in the US. Disease produces an initial watery diarrhea, followed by a colitis picture of abdominal pain, bloody/mucopurulent stool, with fever. Symptoms are self-limiting and resolve by 10 days.

  • Enteroaggregative and diffusely adherent (EAEC/DAEC): Another cause for traveler's diarrhea. Mostly watery stools.

Extra-intestinal infections

Escherichia Coli (extraintestinal pathogenic strains)

This is the most common gram negative bacilli (GNB) to cause extraintestinal disease in all settings (inpatient, outpatient, and nursing homes). Multiple different sites of infection can occur, with the genitourinary tract and intra-abdominal being the top two.

Infection in additional sites has been known to cause pneumonia (much more common in the form of Health-Care Associated Pneumonia or Hospital Associated Pneumonia), and soft tissue/muscle/bone infections. Meningitis has also been seen, but this is mostly a pediatric problem.

Klebsiella

This pneumoniae strain is by far the most common and most relevant to this review. Currently, Klebsiella is most often found causing Hospital Acquired Pneumonia. Similar to E Coli, Klebsiella causes disease primarily in the lungs and GU system but unlike E Coli, pneumonia is more common than UTIs.

Klebsiella Pneumoniae can also be community acquired, most classically known to cause disease in alcoholics producing a "current jelly" sputum. Infection can also occur in the abdomen/pelvis and soft tissue/bone/muscle, as is seen with E Coli.

Proteus

The mirabilis strain is by far the most common cause for disease throughout all patient care areas. The main site of infection is the urinary tract, but other sites similar to those listed for E Coli/Klebsiella can occur. There is an association between urinary tract disease and the development of nephrolithiasis, which can lead to staghorn calculi and obstruction.

Yersinia pestis (plague)

Transmitted to humans mainly by flea bite; less commonly by direct contact with infected animal tissues or by airborne droplet. Rodents are the usual host species and disease is often centered around areas where rodent infestation is high and sanitation is poor.

In the U.S., it is endemic to the Southwest states, including California, New Mexico, Arizona, and Nevada. Diseases can be divided up into bubonic plague, which accounts for the majority (80-90%) of the cases, septicemic plague, and pneumonic plague. The incubation period is typically 2-8 days following an exposure.

  • Bubonic plague: Patients will often experience the sudden onset of fever, chills, weakness and headache. Subsequently, a localized swollen and intensely painful lymph node (bubo) will appear followed by more generalized lymphadenopathy. Classically, this bubo will be located in the inguinal region, but axillary and cervical areas have been described as well.

  • Septicemic plague: Patients are febrile and very ill appearing, but do not exhibit the classic bubos as described above. Gastrointestinal symptoms can be present, including nausea, vomiting, diarrhea and abdominal pain.

  • Pneumonic plague: Often is secondary to bubonic or septicemic plague, but can occur as a primary infection. Inhalation of the aerosolized bacteria caused symptoms within a few hours to a few days. Typical symptoms include rapid onset of dyspnea, pleuritic chest pain, fever, cough (often bloody).

Salmonella typhi/paratyphi

These bacterium produce a spectrum of symptoms classically known as Typhoid Fever (Enteric Fever). Infection is transmitted from contaminated food and water; thus relatively uncommon in developed countries. Infection is endemic to most developing nations, though, with major pockets of disease in the Indian subcontinent, Central/South America, Asia/Eastern Europe.

Symptomatology are largely non-specific and thus requires a high level of clinical suspicion, especially in a recent traveller. Incubation period can be as long as 3 weeks or as short as 3 days. Fever is present in up to 75% of cases and abdominal pain in 20-40%.

Often a prodrome of additional nonspecific symptoms will precede the fever; chills, anorexia, headache, weakness, cough, sore throat, dizziness and muscle pains are just some of these symptoms. A faint rash ("rose spots") located mostly on the chest and trunk develops in approximately 30% of patients at the end of the first week and will resolve after about 2-5 days.

Later, and more severe manifestations include neuropsychiatric symptoms, intestinal perforation/hemorrhage. Less common manifestations are pancreatitis, hepatic/splenic abscess, endo-/peri-/myocarditis, hepatitis, orchitis, arthritis, parotitis, osteomyelitis, nephritis, meningitis, nephritis and pneumonia.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of gram negative rod infections.

Shigella

There are no specific exam findings. Commonly, there will be fever and non-specific abdominal tenderness.

Salmonella (nontyphoidal)

There are no specific exam findings to the gastroenteritis presentation. Commonly, there will be fever and non-specific abdominal tenderness. All other findings would be specific to the site of infection, as listed above.

Camplobacter

There are no specific exam findings to the gastroenteritis presentation. Commonly, there will be fever and non-specific abdominal tenderness.

E. Coli (intestinal strains)

The main physical finding that helps differentiate the strains are presence or lack of fever. Fever is present in enteroinvasive strains, but absent in the rest. All strains will likely produce some amount of abdominal tenderness.

E. Coli (extraintestinal strains), Klebsiella, Proteus

Exam findings would be specific to the site of infection, as listed above.

Yersinia pestis

The most specific physical finding would be the bubos, as described above.

Salmonella typhi/paratyphi

A rash, as described above, can occur early in the disease course, located primarily on the trunk and chest. The lesions are described as faint, salmon-colored, blanching and maculopapular. There may be as many as 2-3 crops of lesions. Other exam findings can include hepatosplenomegaly, epistaxis, and relative bradycardia (heart rate lower than expected for the fever elevation).

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of gram negative rod infections.

Shigella

The gold standard for diagnosis is in isolation of the organism via stool culture. Ideally, one should sample stool that contains blood and/or mucous, as this leads to the highest yield. Blood cultures are not recommended, unless the patient is in sever sepsis, as the yield is under 5%.

Salmonella (nontyphoidal)

Diagnosis is made by isolating the organism from the stool or additional sterile fluid.

Campylobacter

Unlike other the gastroenteritis etiologies, failure to identify the organism from stool does not rule out disease, as it is often difficult to isolate on typical medias. If there is high suspicion for disease, the lab can be asked to use direct microscopic examination or dark-field microscopy.

Stool can be checked for fecal leukocytes or red blood cells (RBCs) as they should be present when Camplobacter is the etiology of infection.

E. Coli (intestinal infections)

The only strain for which testing is readily available is for EHEC and most specifically, 0157. This can be diagnosed through stool culture. The other strains are not easily diagnosed. The two main invasive strains, EHEC & EHIC, will both have a positive test for fecal leukocytes.

E. Coli (extraintestinal), Klebsiella, Proteus

Cultures from blood or sterile fluid from the site of the primary infection will be diagnostic.

Proteus

Can be associated with an alkaline urine and microscopic hematuria secondary to stone development. An elevated urinary pH in the setting of a UTI is enough to make a presumptive diagnosis of Proteus infection.

Yersinia pestis

A high index of clinical suspicion is necessary in all cases of plague. Peripheral leukocytosis is common and values as high as 100,000/L have been seen. Thrombocytopenia and DIC can also be present.

Tests need to be conducted by trained personnel and specimens should be sent from peripheral blood, lymph node aspirates in patients with bubos and sputum aspirates in patients with pulmonic signs.

Salmonella typhi/paratypi

Diagnosis is made by a positive culture, mostly from the blood or bone marrow. While the sensitivity of a blood culture is as high as 90% early on, this rate drops to 50% later in the disease course. A bone marrow sample may be warranted, especially in the setting of unexplained leukopenia/neutropenia, which can occur in up to 25% of cases.

While obviously more invasive, a bone marrow sample continues to have a high sensitivity for detection even during later stages of the illness.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

There is no formal criteria for diagnosing any of the gram negative infections. For the most part, a positive culture from a sterile fluid source is considered diagnostic.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Cultures taken from areas known for chronic colonization (most commonly local wound cultures, simple respiratory cultures and cultures from chronic indwelling urinary catheters) can often yield positive culture results yet not truly indicate active infection. One should be very cautious in making decisions based solely on positive cultures taken from these sites without additional clinical evidence of active infection.

A. Management of gram negative rod infections.

Generally, the management of gram negative sepsis is nonspecific and similar to sepsis in general. The physician must make every effort to identify the source of the infection and either remove it (in the case of an infected catheter) and drain it (in the case of a localized abscess).

Intravenous fluids and pressors, if needed are, important to maintaining adequate blood pressure in the setting of impending or full blown shock. Antibiotics should be initiated as soon as possible and should cover broadly, with a plan to narrow the spectrum once an organism is identified and the patient has stabilized.

Common first line agents include a third generation cephalosporin, ticarcillin-clavulante, and imipenem. Empiric anti-pseudomonal therapy is warranted in patients with 2 or more of the following:

  • severe immunodeficiency, aged over 90

  • antimicrobial therapy in the last 30 days

  • presence of central venous catheter or urinary catheter.

There is debate over when and if to initiate treatment with 2 agents "double cover". This will be discussed further in the pseudomonas section.

In addition, gram negative bacteria are becoming increasingly resistant to traditionally useful antibiotics. This is most obvious in the setting of extended-spectrum ß-lactamases (ESBL), which confer resistance to third-generation cephalosporins, aztreonam, and even at times, fourth-generation cephalosporins. Klebsiella pneumonia and E. Coli are two of the most affected bacteria by ESBLs.

The resistance profiles will vary by geographic location, regional antibiotic use, and hospital site (ICU vs wards). Knowing your own hospital's resistance patterns can help immensely in deciding what empiric therapy to start, especially in the sickest of patients.

Shigella

Ciprofloxacin is recommended as the first line agent of choice. Ceftriaxone and azithromycin have also been shown to be effective. Treatment should generally be for 5 days in immunocompetent hosts and 7-10 days in those who are immunocompromised.

Salmonella (nontyphoidal)

Antibiotic treatment is generally not needed and has actually been associated with increased rates of illness and prolonged carriage of the organism. In select patients, the immunocompromised and those with significant joint or valvular/endovascular disease, one can consider a short 2-3 course of oral ciprofloxacin. More aggressive treatments are specific to the site of disseminated infection and is outside the scope of this review.

Camplobacter

Antibiotics are typically not needed as the disease is mild and self limited. In cases of prolonged duration (>7 days), high fever, bloody diarrhea, or significant diarrhea, antibiotics are reasonable though. Typical regimens include erythromycin or ciprofloxacin for 5-7 days. Anti-motility agents should be avoided.

E. Coli (intestinal infections)

Antibiotics are reasonable for traveller's diarrhea, as they decrease the duration of illness. The 2 main drugs used are ciprofloxacin or azithromycin. It is important to note that if EHEC (0157:H7) is suspected on the grounds of bloody diarrhea without fever, antibiotics should not be given as there is a concern for increasing one's risk for HUS.

E. Coli (extraintestinal)

After initial empiric therapy, definitive treatment will likely be guided by the results of your culture's sensitivity profile. Making the choice for your initial empiric therapy however is becoming increasingly difficult in the setting of increasing resistance. Trimethoprim-sulfamethoxazole, previously thought of as first-line treatment for UTIs, has been associated with resistance in up to 40%.

Fluoroquinolones, also a common UTI treatment, are noted to have resistance in up to 20% of cases. As noted above, ESBLs are making this problem even more difficult.

Klebsiella

Treatment recommendations are similar to that of E. Coli. ESBLs are making treating hospital/health care associated infections increasingly difficult. As it stands now, the lowest resistance rates are for tigecycline, the carbapenems, and amikacin.

Proteus

This bacteria seems less affected by resistance issues for now. ESBLs, especially, do not seem to play a major role.

Yersinia pestis

Untreated, plague is fatal in over 50% of bubonic cases and essentially 100% of septic/pneumonic cases. The overall mortality rate in the U.S. is 14%. The main treatment is intravenous gentamicin.

Salmonella typhi/paratyphi

The most prudent empiric therapy is with a 3rd generation cephalosporin or azithromycin. If cultures reveal the isolate to be fully susceptible, then change your treatment to ciprofloxacin (the most effective treatment), for a total of 14 days.

In addition, it is important to note that there are two readily available vaccines. The first is a one-time intramuscular injection of a polysaccharide from the bacterial capsule. The other is an oral, live attenuated vaccine that must be taken every other day for the first 7 days.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

The main pitfall in the management of GNR infections is the increased risk for clostridium difficile infection. This is not specific to GNR infections, though, and is an issue relevant to anyone who has recently or is currently receiving antibiotics for any infection, especially for a protracted length of time in a hospital setting.

There is also the general concern for allergic/anaphylactic reactions, often associated with penicillins. Other concerning antibiotic side-effects are acute interstitial nephritis, thrombocytopenia, and a myriad of liver panel abnormalities.

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