The genus Providencia is composed of several species of gram negative bacilli that produce urease.[1] Organisms belonging to the genus Providencia are closely related to the genera Morganella and Proteus. With advances in genomics and sequencing, the taxonomy has undergone many changes. To date, five species (Providencia rettgeri [P rettgeri], P stuartii, P alcalifaciens, P rustigianii, and P heimbachae) have been identified in humans.[2] Of these, three species (P rettgeri, P stuartii, and P alcalifaciens) are capable of causing disease in humans. Two novel species have been identified in fruit flies but are not notable human pathogens.[3]
Providencia is a ubiquitous organism that can be found both in the environment and as a commensal organism of the human microbiome, primarily in the gastrointestinal tract.[4] As such, the isolation of Providencia from a clinical specimen does not always indicate clinical infection, and patients should be screened for an appropriate clinical syndrome. The most common clinical syndrome attributable to Providencia is urinary tract infections (UTIs) in patients with long-term indwelling urinary catheters (most commonly due to P stuartii and P rettgeri).[1, 2, 5] Other clinical syndromes include gastroenteritis in returning travelers (primarily P alcalifaciens), pneumonia (including hospital and ventilator associated), bacteremia, and wound infections.[1, 4, 6]
As discussed previously, Providencia spp are ubiquitous in the environment and can be isolated from water, soil, and sewage. Several species are known commensal organisms of the human gastrointestinal tract.[6, 7]
In humans, P stuartii and P rettgeri primarily have been implicated in catheter associated urinary tract infections (CAUTI).[1, 2, 5] Providencia’s predilection for colonizing long-term indwelling urinary catheters is felt to be mediated by an adhesin: mannose-resistant/Klebsiella-like (MR/K) hemagglutinin.[8] It is important to note that chronic indwelling urinary catheters often are colonized with bacteria, and growth of Providencia from the urine of a patient with a catheter not always indicates infection in the absence of symptoms suggesting an appropriate clinical syndrome. Other virulence factors include the production of urease, which can be associated with the formation of nephrolithiasis and then can place patients at risk for urinary tract obstruction and subsequent infections including pyelonephritis. Urease as a virulence factor is supported further by an increase in nephrolithiasis and bacteremia in patients with P stuartii and Proteus mirabilis co-infection.[9] Providencia species are also recognized as an etiology of “Purple Urine Bag Syndrome (PUBS)”, a syndrome characterized by purple appearing urine due to the metabolism of tryptophan to indole by colonizing/infecting bacteria in chronic indwelling catheters. If PUBS is observed, it is important to assess for signs and symptoms of urinary tract infection, while again noting that PUBS can occur in the setting of colonization and is not necessarily a sign of CAUTI.[10]
Providencia species have been isolated in the blood. Blood stream infections (BSI) due to Providencia most commonly are secondary to a urinary source. Manipulation of the urinary tract is a risk factor for Providencia BSI. Pulmonary source (pneumonia) and primary bacteremia have been documented but are less common. Interestingly, BSI with Providencia often are polymicrobial.[11, 12, 13]
Providencia alcalifaciens has been identified as a possible cause of traveler’s diarrhea/foodborne gastroenteritis, but the true scope is difficult to determine as the most commonly used diagnostic assays for TD/GE do not test for Providencia.[6, 7, 14, 15]
Pneumonia, especially ventilator associated pneumonia, has been reported.[16, 17] There have been few case reports documenting less common clinical syndromes secondary to Providencia infection including one case of infective endocarditis[18] and several cases of ocular infections (keratitis, conjunctivitis, and endophthalmitis).[19] Providencia has been isolated from wound infections, especially burns, but almost always as part of a polymicrobial infection with more virulent pathogens (ie, MRSA or Pseudomonas).[4, 20] Given Providencia’s pervasive presence in the nosocomial setting, any culture, especially a polymicrobial culture, with the growth of Providencia should be interpreted with caution.
Providencia is distributed worldwide. The epidemiology of Providencia is difficult to describe for several reasons including difficulty in distinguishing colonization from infection in the most at-risk patients and lack of inclusion of Providencia on molecular diagnostic panels (Gastrointestinal Pathogen Panel, Blood Culture Identification Panel).
Providencia infections previously were considered to be an uncommon pathogen;[21] however, the prevalence has been increasing. It is important to note that the prevalence of multi-drug resistant Providencia, especially extended spectrum beta-lactamase (ESBL) and carbapenemase producing isolates, also is increasing.[2, 16, 22, 23, 24, 25]
In terms of gastroenteritis, several countries, including Nigeria, India, and Bangladesh have published studies on the isolation of Providencia alcalifaciens from symptomatic patients with diarrhea.[7] Several other countries have reported foodborne outbreaks including Japan, Turkey, and Kenya.[26]
Race
All races appear to be equally susceptible to Providencia infection.
Sex
Sex does not appear to be a risk factor for Providencia infection. It is interesting to note that one study found a significant difference in Providencia bacteruria between men and women with long-term urinary catheters (more frequently isolated from women). This may be due to the higher frequency of condom catheter use in males.[8]
Age
Because older patients are more likely to have both chronic indwelling urinary catheters and frequent contact with the nosocomial environment, they are at increased risk for Providencia colonization and infection.
Reported mortality rates for Providencia infections range from 6-33%. One study from India reported a 20% mortality rate for Providencia CAUTI; however, the majority of these patients were critically ill, and it is not evident whether mortality in these cases was completely attributable to Providencia.[21]
Another review reported a mortality rate of 6-33% for Providencia BSI with the highest risk of mortality in polymicrobial BSI.[27]
Polymicrobial co-infections and relative antimicrobial resistance are likely major contributors to mortality in Providencia BSI.
The clinical history of Providencia infections depends on the syndrome of infection.
CAUTI: Patients with Providencia (primarily P stuartii and P rettgeri) catheter-associated urinary tract infections typically present with fever/chills, suprapubic pain/bladder cramping, and dysuria. Flank pain also may be present.
Gastroenteritis: P alcalifaciens gastroenteritis typically presents with watery, non-bloody diarrhea. Associated symptoms may include abdominal pain and fever in some cases.[6, 7] Of note, vomiting is a prominent symptom of Providencia gastroenteritis.[26]
A careful travel history (specifically travel to Southeast Asia and Africa) should be taken if there is concern for traveler’s diarrhea. As multiple foodborne outbreaks have been documented in the literature, it is critical to ask the patient about any sick contacts. Incubation period for gastroenteritis ranges from 1-4 days.[6]
Bacteremia: Symptoms of Providencia BSI are identical to those seen with other gram negative rod BSIs including fever/chills, rigors, and possibly hemodynamic instability.
Pneumonia: Pneumonia, primarily hospital acquired or ventilator associated, is a less common syndrome associated with Providencia.[16, 17] When present, symptoms may include fever/chills, productive cough, respiratory distress, and need for increased ventilatory support.
Wound infections: Burn wounds have been reported to be at higher risk for Providencia infection.[4, 28, 29] It is important to assess for signs and symptoms of wound infections including erythema, induration, warmth, swelling, purulent drainage, and graft failure. As previously mentioned, Providencia is ubiquitous in the nosocomial environment and its presence in an open wound (especially in the presence of polymicrobial co-infection), may not indicate true infection, but simply colonization in a critically ill patient.
CAUTI: Typical physical exam findings may include abdominal tenderness to palpation (especially suprapubic), costovertebral angle tenderness, and fever.
Gastroenteritis: Physical exam findings in Providencia gastroenteritis primarily are due to volume loss via diarrhea and vomiting. Findings may include poor skin turgor, dry mucus membranes, and tachycardia. Abdominal tenderness frequently is present.[6, 7]
Bacteremia: Physical exam findings in Providencia BSI are non-specific, but may include fever, tachycardia, and hemodynamic instability.
Pneumonia: Typical exam findings of pneumonia include respiratory distress, acute respiratory failure, tachypnea, decreased breath sounds on auscultation, and increased ventilatory support.
Wound infections: Indications of wound infections include erythema, swelling, warmth, induration, purulent drainage, fluctuance, and graft failure.
Providencia urinary tract infections (UTIs), blood stream infections (BSIs), pneumonia, and wound infections primarily are nosocomial. Risk factors for UTIs include chronic indwelling catheters and frequent exposure to healthcare, including residence in a long-term care facility.[1, 21]
The most common source of Providencia BSI is the urinary tract, followed by pneumonia and primary bacteremia.[1, 11]
P alcalifaciens gastroenteritis may develop after travel to certain countries (primarily in Southeast Asia and Africa).[7]
Primary infection with P stuartii and P rettgeri (CAUTI, pneumonia) can be complicated by bacteremia. Bacteremia leading to circulatory collapse is associated with multi-organ dysfunction including renal failure and Acute Respiratory Distress Syndrome (ARDS).
P alcalifaciens gastroenteritis can be complicated by dehydration.[6, 7, 26]
CAUTI: Obtain urinalysis and urine culture. Urine should be collected after catheter exchange in patients with indwelling urinary catheters. Assessing renal function is important, especially if there is a concern for urinary obstruction.
Gastroenteritis: Commonly used PCR platforms (ie, gastrointestinal pathogen panel) do not include Providencia targets. Stool cultures should be obtained for isolation of the pathogen to aid in diagnosis. Consider assessing renal function in the setting of high volume diarrhea given the risk for dehydration.
Bacteremia: At least two blood culture sets from two separate peripheral sites should be obtained if bacteremia is a concern. It is important to note that PCR platforms for the rapid identification of positive blood cultures (ie, blood culture identification panel) do not include Providencia.
Pneumonia: Obtain sputum culture if able if concerned for pneumonia.
Wound infections: Intraoperative cultures should be obtained if there is a concern for wound infection. Superficial cultures should be avoided.
If Providencia is isolated, antimicrobial susceptibility should be performed to guide therapy.
CAUTI: Imaging (CT or US) of the renal and urinary tract should be obtained if there is a concern for obstruction.
Pneumonia: Chest imaging (CXR or CT) should be obtained if there is a concern for pneumonia.
Organisms belonging to the genus Providencia exhibit intrinsic resistance to several antibiotics including ampicillin, amoxicillin-clavulanate, first generation cephalosporins, tetracycline, tigecycline, nitrofurantoin, and polymyxin B/colistin. Providencia spp may have elevated MICs to imipenem, which can be mediated by mechanisms other than carbapenemase production; if the isolate tests as susceptible it should be considered susceptible. P stuartii is considered intrinsically resistant to most aminoglycosides (gentamicin, tobramycin) with the exception of amikacin.[30, 31, 32]
Historically, Providencia spp were felt to be at risk for inducible AmpC expression, meaning that although they initially may test susceptible to third generation cephalosporins, they may develop resistance in the presence of therapy due to derepression of the AmpC beta-lactamase. However, based on more recent studies, Providencia spp along with Morganella morganii and Serratia marcescens are felt to have a significantly lower chance of clinically significant inducible AmpC expression, estimated by one study to be less than 5% of these organisms. As such, based upon the most up to date guidance from the Infectious Disease Society of America (IDSA), the authors recommend treatment based upon antimicrobial susceptibility testing except for patients who are felt to have a high bacterial burden or in whom source control may be difficult to attain, in which case it is suggested that cefepime instead of ceftriaxone may be reasonable.[33]
In addition to intrinsic resistance, extended spectrum beta lactamase (ESBL) and carbapenemase (especially New Delhi metallo-beta-lactamase) production among Providencia spp is an emerging problem.[16, 17, 24, 28, 29, 34]
Antimicrobial therapy should be guided by the IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections, local ESBL patterns, and severity of disease.[33] Definitive therapy should be guided by antimicrobial susceptibility testing.
For empiric therapy, piperacillin-tazobactam, ceftriaxone*, cefepime, or ciprofloxacin would be reasonable options if the local ESBL rate is < 10-15% and the infection is not severe/life threatening. If the local ESBL rate is >15%, meropenem is recommended (with extended infusion recommended for severe/life threatening infections). Once antimicrobial susceptibility testing (AST) is available, therapy should be de-escalated as able. Piperacillin/tazobactam, cefepime, ciprofloxacin, and ceftriaxone* remain reasonable options if susceptible.
*Caution should be exercised when using ceftriaxone given the presence of inducible AmpC when the patient is felt to have a high bacterial burden or difficult to control source of infection; resistance can develop with prolonged exposure to third generation cephalosporins even if the isolate is reported as susceptible.
Carbapenems including meropenem and ertapenem are recommended for the treatment of EBSL producing Providencia. Fluoroquinolones can be considered for step down therapy when the patient is improving if susceptibility is documented.
If the isolate is resistant to carbapenems, expert infectious disease consultation is recommended. Antibiotic regimens would include ceftazidime-avibactam or meropenem-vaborbactam (in the setting of serine-based carbapenemase) versus ceftazidime-avibactam plus aztreonam or cefiderocol (in the setting of metallo-beta-lactamase carbapenemase).
Simple cystitis secondary to Providencia spp is rare (chronic urinary catheters are important risk factors); however, if present, oral fosfomycin potentially could be considered with appropriate antimicrobial susceptibility testing. Infectious disease consultation should be sought if this option is pursued, as antimicrobial susceptibility data for fosfomycin against Providencia spp is limited, and there are some studies that suggest higher rates of resistance.[35]
Optimal duration of antimicrobial treatment depends on the clinical syndrome and has not been clearly defined given rarity of the infection and lack of large clinical trials. The authors propose approaching treatment duration similarly to other Enterobacterales infections. Consider 7 days of therapy for uncomplicated BSI[36] and pneumonia, 7-14 days for urinary tract infection depending on presence of complicating factors, and 5-10 days for wound infection.
In the setting of CAUTI, urinary catheters should be removed. Necessity of the catheter should be evaluated and it only should be replaced if deemed absolutely necessary.
CAUTI: Surgical correction of obstruction should be considered if indicated.
Wound infection: Surgical debridement with obtainment of intraoperative cultures should be considered.
Consult an infectious diseases specialist to choose the optimum antibiotic treatment plan.
Consider consultation with a urologist if a suspected structural genitourinary pathology is the underlying etiology of the infection.
Indication for chronic urinary catheter should be readdressed frequently. If a catheter no longer is indicated, it should be discontinued to help mitigate the risk for CAUTI.
Given the nosocomial nature and the extensive intrinsic and acquired resistance of Providencia spp, adherence to infection prevention and control (IPaC) tenants is paramount in preventing infections with this organism. IPaC measures to help prevent infections secondary to Providencia include hand hygiene, implementation and compliance with device-related bundle protocols, isolation of patients with ESBL or carbapenemase production, and proper PPE (gowns and gloves) for patients with ESBL or carbapenemase production.[21]
Monitor the patient for resolution of clinical manifestations and potential toxicities of antibiotics.
Infection may recur, particularly if an indwelling device remains in place. If repeat cultures after treatment continue to demonstrate the organism, clinical evidence of infection should be sought. The urine may continue to be colonized after a course of antibiotic treatment, especially in the presence of an indwelling device (eg, urinary catheter, condom catheter).
If infection is associated with an indwelling device, such as a urinary catheter, carefully re-evaluate the continued need for this device.
The patient should be transferred if they require treatment modalities (intensive care, mechanical ventilation, hemodialysis, expert consultation) that the initial treating facility cannot accommodate.
Resistance patterns, if known, should be communicated to accepting facilities to ensure proper infection prevention and control precautions are implanted if indicated.
Medical therapy is directed at eradication of the infecting Providencia organism with an antimicrobial agent to which the organism is susceptible.
Please note that antimicrobial therapy should be guided by the IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections, local ESBL patterns, and severity of disease. Definitive therapy should be guided by antimicrobial susceptibility testing. Selection of final antimicrobial therapy, once the susceptibility of the infecting organism is known, should favor the safest and most cost-effective agent with the narrowest spectrum of activity to which the infecting pathogen is susceptible.
Clinical Context: Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria. Has slightly increased activity against gram-negatives and slightly decreased activity against staphylococci and streptococci compared with imipenem.
Clinical Context: For treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to potential for toxicity.
Providencia spp. can exhibit higher MICs for imipenem/cilastatin. As such, this agent should not be used for empiric therapy. It is reasonable to de-escalate to imipenem/cilastatin if the organism is found to be susceptible by AST.
Clinical Context: Providencia spp. were felt to be at risk for inducible ampC expression, meaning that while they may initially test susceptible to third generation cephalosporins, they may develop resistance in the presence of therapy due to derepression of the ampC beta-lactamase. However, based on more recent studies Providencia spp. along with Morganella morganii and Serratia marcescens are felt to have a significantly less likely chance of clinically significant inducible ampC expression, estimated by one study to be less than 5% of these organisms. As such, based upon the most up to date guidance from the Infectious Disease Society of America, we recommend treatment based upon antimicrobial susceptibility testing except for patients who are felt to have a high bacterial burden or in whom source control may be difficult to attain, in which case it is suggested that cefepime instead of ceftriaxone may be reasonable.
Clinical Context:
Clinical Context: Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.
Clinical Context: Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin.
Use patient's IBW for dosage calculation. The same principles of drug monitoring for gentamicin apply to amikacin. Please note that there is variable susceptibility of Providencia organisms to aminoglycosides other than amikacin.
Clinical Context: A monobactam (a monocyclic beta-lactam) antibiotic that inhibits cell wall synthesis during bacterial growth. Active against gram-negative bacilli but very limited gram-positive activity and not useful for anaerobes. Lacks cross-sensitivity with beta-lactam antibiotics. May be used in patients allergic to penicillins or cephalosporins.
Duration of therapy depends on severity of infection and should be continued for at least 48 h after symptom resolution or evidence of bacterial eradication is obtained. Doses smaller than indicated should not be used.
Transient or persistent renal insufficiency may prolong serum levels. After initial loading dose of 1 or 2 g, reduce dose by one half for estimated ClCr of 10-30 mL/min/1.73 m2. When only serum creatinine concentration available, the following formula (based on sex, weight, and age) can approximate ClCr. Serum creatinine should represent a steady state of renal function.
Males: ClCr = [(weight in kg)(140 - age)] / (72 X serum creatinine level in mg/dL)
Females: 0.85 X above value
In patients with severe renal failure (ClCr < 10 mL/min/1.73 m2), those supported by hemodialysis, usual dose of 500 mg, 1 g, or 2 g, is given initially.
Maintenance dose is one fourth of usual initial dose given at usual fixed interval of 6, 8, or 12 h.
For serious or life-threatening infections, supplement maintenance doses with one-eighth of initial dose after each hemodialysis session.
Elderly persons may have diminished renal function. Renal status is a major determinant of dosage in these patients. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by kidneys, obtain estimates of ClCr and make appropriate dosage modifications. Insufficient data are available regarding IM administration to pediatric patients or dosing in pediatric patients with renal impairment. Administer IV only to pediatric patients with normal renal function.