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The development of fevers in critically ill patients are a sign that the patient requires attention and management, as fevers are a common physiological response of a variety of infectious and non-infectious agents.
Table 1.2 Infectious and non-infectious causes of fever
Pangtey, G.S., Prasad, R. (2020). Fever in Intensive Care Unit. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
| Table 1.5 Medicines associated with drug fever | |
| Most common | Barbiturates, phenytoin, antihistaminic, methyldopa, penicillin, salicylates, sulfonamides, amphotericin-B, procainamide, bleomycin |
| Less common | Isoniazid, PAS, Streptomycin, rifampicin, propylthiouracil, streptokinase, vancomycin, nitrofurantoin, allopurinol, cephalosporin, hydralazine, azathioprine |
| Least common |
Insulins, tetracycline, digitalis, chloramphenicol |
Pangtey, G.S., Prasad, R. (2020). Fever in Intensive Care Unit. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
The systematic approach to patient with fever in critically illness in intensive care unit involves integration of following seven points:
Empiric Antibiotic Therapy
If the fever is suspected to be caused by an infectious agent, broad spectrum antibiotics should be started as soon as possible after taking cultures. Empirical antibiotics should only be started on patients in shock, neutropenic, or those with suspected infection of a VAD. Infected catheters should be removed immediately in blood stream infections.
Febrile neutropenia is defined by a single oral temperature of 101 °F or a temperature of more than 100.4 °F sustained over a period of 1 hour with ANC <500 cells/mm3 or an ANC which is expected to reduce to <500 cells/mm3 over the next 48 hours. Risk of infections secondary to neutropenia begins to rise with an absolute neutrophil count (ANC) of <1000 cells/mm3.
Figure 14.1:Risk assessment model for planning work-up and treatment, from Chakrabarti, P., Jitani, A.K. (2020). Approach and Management of Severe Infections in Neutropenic Patients. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Figure 14.2: Approach to diagnosis and monitoring, from Chakrabarti, P., Jitani, A.K. (2020). Approach and Management of Severe Infections in Neutropenic Patients. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Figure 14.3: Approach to management, from Chakrabarti, P., Jitani, A.K. (2020). Approach and Management of Severe Infections in Neutropenic Patients. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Sepsis is clinical clinical syndrome resulting from dysregulated physiologic, pathologic and biochemical response to an infection that can lead to multi-organ dysfunction and death. The definition has evolved over the years, with the most recent coming from the Sepsis-3 Consensus Document in 2016. Sepsis-3 defines sepsis as “a life-threatening organ dysfunction caused by a dysregulated host response to infection”. Organ dysfunction and mortality are prognosis are determined by Sequential Organ Failure Assessment (SOFA) scoring.
Since the current SOFA scoring can lead to misdiagnosis from non-infectious causes of organ dysfunction, its important to other other biomarkers to reliably differentiate infectious from non-infectious causes as well as bacterial from viral/fungal causes of sepsis.
There is no single symptom or sign or investigation that can reliably diagnose sepsis. It is usually an diagnosed based on the composite of history, examination and relevant investigations (laboratory, microbiological and radiological).
Figure 2.2: Overview of management of sepsis, from Mittal, A., Soneja, M. (2020). Clinical Approach to Sepsis. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Community-acquired pneumonia refers to an infection of the lung parenchyma acquired outside a healthcare setting. CAP forms a part of a larger group of diseases known as lower respiratory tract infections (LRTIs). The term severe CAP (SCAP) signifies a more serious form of community-acquired pneumonia that requires admission to the intensive care unit and has a high risk of mortality.
The pathogenesis of CAP involves establishment of an infection of the lung parenchyma by a virulent micro-organism by overwhelming the host defense. Cytokine levels (both pro-inflammatory and anti-inflammatory) in the plasma and the lungs are far higher in SCAP patients and are associated with both ICU admission and mortality. The reasons for this exaggerated response in some individuals are not well known. The administration of the first dose of antibiotics may also cause a massive surge in cytokine levels in some patients.
Around 11% of SCAP patients may have a polymicrobial etiology, especially when they present with ARDS or when they have underlying COPD.
Bacterial Pneumonia
The most common organism implicated in SCAP remains pneumococcus (Streptococcus pneumoniae), which is also the commonest organism isolated in any severity of CAP. The other common organisms causing SCAP include Hemophilus influenzae, atypical organisms, viruses, Staphylococcus aureus, Pseudomonas aeruginosa, other gram-negative bacilli (GNB), and anaerobes. About 6% of cases are caused by the so-called PES (Pseudomonas aeruginosa, extended-spectrum β-lactamase producing Enterobacteriaceae, and methicillin resistant Staphylococcus aureus) pathogens. Infections with atypical organisms such as Legionella, Mycoplasma, and Chlamydia species are also common and often co-exist with simultaneous typical bacterial infection in SCAP. Together, these pathogens may be responsible for 22% of cases of CAP.
Viral Pneumonia
Viruses also form a large group among microbes causing SCAP; the commonly implicated ones being influenza, rhinovirus, respiratory syncytial virus (RSV), metapneumovirus (HMPV), and the coronaviruses.
| Organism | Risk factors |
|---|---|
| Drug-resistant pneumococcus | Elderly β-lactam or macrolide therapy within 3 months Immunosuppression Alcoholism Day-care centers Medical co-morbidities |
| Gram-negative bacilli | Recent hospitalization/antibiotics Cardiopulmonary co-morbidities Smoking/alcoholism Underlying malignancy |
| Community-acquired methicillin resistant Staphylococcus aureus | Elderly End-stage renal disease/renal replacement therapy Prior MRSA infection/colonization Recent hospitalization/antibiotics (particularly fluoroquinolones) Contact sports Men who have sex with men Medical co-morbidities |
| Pseudomonas spp | Chronic obstructive pulmonary disease Structural lung disease like bronchiectasis Immunosuppression/recent steroid exposure Recent antibiotics/recent hospitalizatio |
Table 4.3 Risk factors for unusual pathogens and drug resistance, Saxena, P., Sehgal, I.S., Agarwal, R., Dhooria, S. (2020). Severe Community-Acquired Pneumonia. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Algorithm 4.1 Approach to Management of SCAP, Saxena, P., Sehgal, I.S., Agarwal, R., Dhooria, S. (2020). Severe Community-Acquired Pneumonia. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.\
Gram negative infections are responsible for causing both community and healthcare associated infections, however in recent years the number of infections caused by resistant gram negative species has increased, mostly in hospitalized patients. Drug resistant gram negative bacteria are some of the most difficult infections to treat in the ICU. Resistance to most commonly used drugs leads to delay in treatment, which increases the risk of morbidity and mortality in these patients. The often-indiscriminate use of broad spectrum antibiotics in intensive care further increases the prevalence of resistance in these organisms, creating a vicious circle.
| Clinical syndrome | Common microorganisms | Clinical features | Diagnosis | Treatment |
|---|---|---|---|---|
| Bacteremia | Community acquired—Escherichia coli (most common) Hospital acquired—Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli |
Fever, shaking chills, features of sepsis. Usually secondary to infection at other site (e.g. community acquired bacteremia is usually secondary to UTI) |
Blood culture (plus catheter tip in CLABSI) Rapid diagnostic tests such as MALDI-TOF and multiplex PCR can be used |
Sepsis/ septic shock + risk features of MDR—Two anti-pseudomonal agents Sepsis/ septic shock but no risk features of MDR—One anti-pseudomonal agentrisk factors of MDR but no sepsis/ septic shock—one anti-pseudomonal agent No sepsis/ no risk factors of MDR—Broad spectrum antibiotic (no anti-pseudomonal coverage required) Duration—7 to 14 days |
| Nosocomial pneumonia [hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP)] |
Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa |
New or progressive infiltrates on a chest radiograph with fever>100.4° F; leucocytosis (>12,000/μl) or leucopenia (<4000/ μl); altered mental status; new onset purulent sputum or change in sputum character; worsening gas exchange | HAP: Expectorated sputum: Culture growth is to be considered significant if ≥105 CFU/mL VAP: Endotracheal aspiration or mini bronchoalveolar lavage (BAL): Culture growth is considered to be significant if ≥105 CFU/mL for tracheal aspirate and ≥ 103 CFU/mL for BAL. |
Risk factors of MDR or shock—2 anti-pseudomonal No risk factors of MDR or shock—1 anti-pseudomonal Duration—7 days |
| Complicated urinary tract infection (catheter associated UTI/ pyelonephritis) | Escherichia coli, Klebsiella pneumoniae | Fever, urinary symptoms (dysuria, burning micturition, supra-pubic pain, urinary frequency and urgency), flank pain/ costovertebral angle tenderness, features of sepsis | Urine routine—for pyuria Urine culture from mid—stream urine Blood culture in pyelonephritis Abdominal/pelvic imaging |
Broad spectrum antimicrobial with ESBL coverage Duration—5–14 days |
Coverage of Newer Antimicrobials
| Newer antimicrobials | ESBL | KPC | NDM | OXA48 | MDR Pae | MDR Aba |
|---|---|---|---|---|---|---|
| Cefiderocol | Yes | Yes | Yes | Yes | Yes | Yes |
| Ceftolozane-Tazobactam (CWSI) | Yes | Yes | Yes | |||
| Ceftazidime-Avibactam (CWSI) | Yes | Yes | Yes | Yes | ||
| Aztreonam-Avibactam (CWSI) | Yes | Yes | Yes | Yes | Yes | |
| Imipenem-Relebactam (CWSI) | Yes | Yes | ||||
| Meropenem-Vaborbactam (CWSI) | Yes | Yes | ||||
| Plazomicin (aminoglycoside) | Yes | Yes | Yes | Yes | ||
| Eravacycline (Fluorocycline) | Yes | Yes | Yes | Yes |
Yes |
Table 21.4 Newer antimicrobials and their coverage, from Gupta, N., Soneja, M. (2020). Management of Gram Negative Multi-Drug Resistant Organisms in Intensive Care Units. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Methicillin-resistant Staphylococcus aureus (MRSA) was described by Barber M in 1961, soon after its introduction in October 1960, and outbreaks of MRSA were reported in the early 1960s). Methicillin resistance in S. aureus is defined as an oxacillin minimum inhibitory concentration (MIC) of ≥4 mcg/mL. Since that time, MRSA has spread worldwide, and the prevalence of MRSA has increased in both health care and community settings.
The prevalence of MRSA isolates in intensive care units in the USA is 60 percent, and more than 90,000 invasive infections due to MRSA occurred in the USA in 2005.
Methicillin resistance is mediated by PBP-2a, a penicillin-binding protein encoded by the mecA gene that permits the organism to grow and divide in the presence of methicillin and other beta-lactam antibiotics. The mecA gene is located on a mobile genetic element called staphylococcal chromosome cassette (SCCmec). A single clone probably accounted for most MRSA isolates recovered during the 1960s; by 2004, six major MRSA clones emerged worldwide, labeled as SCCmec I to VI.
| HA-MRSA | CA-MRSA |
|---|---|
| Recent hospitalization | HIV infection |
| Recent surgery | Infection drug use |
| Residence in long-term care facility | Prior antibiotic use |
| Hemodialysis | Incarceration |
| Indwelling catheters | Military services |
| Sharing needles, razors, and other sharp objects | |
| Men who have sex with men | |
| Sharing sports equipment |
Table 22.1 Risk Factors for HA- MRSA and CA-MRSA, Anand, R. (2020). Management of MRSA, VRE. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
| Drug | Group | Mechanism of action | Dose | Side effects | ||
|---|---|---|---|---|---|---|
| Vancomycin | Glycopeptide Bactericidal |
Inhibits cell wall synthesis | LD25–30 mg/kg IV (especially in septic shock) 15–20 mg/kgof actual BW IV q8–12 h | Red neck syndrome, DRESS, fever, thrombocytopenia, Neutropenia hearing lose, nephrotoxicity | ||
| Daptomycin | Lipopeptide | Depolarization of the bacterial cell membrane | 6 mg/kgTBW IV over 30 min q24 h | myopathy, peripheral neuropathy, and eosinophilic pneumonia. Serial measurements of serum creatine kinase should be monitored at least weekly, and daptomycin should be discontinued in patients with symptomatic myopathy and creatine phosphokinase (CPK) ≥5 times the upper limit of normal (ULN) or in asymptomatic patients With CPK ≥10 times the ULN |
||
| Teicoplanin | Glycopeptide Bacteriostatic |
Inhibits cell wall synthesis | LD 6 mg/kg IV 12 h for 3doses, then MD of 6 mg/kg IV 12 h. Severe Infection higher doses have been used LD 12 mg/kg iv 12 h 3 doses the MD 12 |
Hypersensitivity, fever, skin reaction marked thrombocytopenia, anemia and neutropenia Red neck syndrome and nephrotoxicity lesser than vancomycin |
||
| Linezolid |
|
Inhibits initiation of protein synthesis at the 50S ribosome | 600 mg/kg PO/IV q12h | Thrombocytopenia, anemia, lactic acidosis, peripheral neuropathy, serotonin toxicity, and ocular toxicity Can reversibly inhibit monoamine oxidase |
Table 22.2 Drugs used for MRSA infection,Anand, R. (2020). Management of MRSA, VRE. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Viral respiratory infections can have nonspecific clinical presentations which may be difficult to differentiate from bacterial or fungal infections. Even the severity and clinical course of viral respiratory infections is comparable to that of bacterial and fungal infections.
Immunocompromised patients have a more complicated course of illness as compared to immunocompetent. Whereas, an “atypical” pneumonia presentation may be seen in immunocompetent, severe lobar or bilateral pneumonia may be seen in immunocompromised hosts. These infections may be acquired either in community or nosocomial settings.
| Community acquired | Endogenous | HSV, CMV |
| Exogenous | Influenza, parainfluenza, adenovirus, rhinovirus, RSV, coronavirus, metapneumovirus | |
| Nosocomial | Endogenous | HSV, CMV |
| Endogenous | Mimivirus, CMV (transfusion), H1N1 pandemic influenza |
Table 15.2 Respiratory virus profile in community acquired and nosocomial settings, Gulati, S., Maheshwari, A. (2020). Management of Viral Infections in ICU. In: Soneja, M., Khanna, P. (eds) Infectious Diseases in the Intensive Care Unit. Springer, Singapore.
Corticosteroids have been used in influenza, SARS and VZV pneumonitis in order to decrease damage induced by inflammation in severe pneumonia. Dexamethasone is being currently used with evidence of benefit in COVID-19.
Among the immunotherapies palivizumab, IVIg, plasma exchange and combination ganciclovir-CMV immunoglobulins have been approved for high risk pediatric RSV infection, influenza, GBS, and CMV pneumonitis, respectively.