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Klebsiella species is one of the next most prevalent organisms causing blood borne infections after E.coli. Klebsiella infections are commonly found in healthcare settings and are linked to superior morbidity and mortality risks. The number of bacteremia cases specifically by Klebsiella species doubled from 1988 to 1993. The reasons may include patients with severe underlying disease tend to live longer, increased average age of hospitalised patients, widespread use of invasive medical equipments and advanced diagnosis tests for bacteraemia (e.g. better culture techniques) 2, 4.
Sepsis is grouped under systemic inflammatory response syndrome (SIRS)1, 6. Sepsis is one major cause of death amongst cancer patients (40%) which is due to the long term chemotherapy suppressing the levels of granulocytes, rendering the host exposed to infections, increasing the risk to a staggering 70-100%. It is estimated that 20-50% of septic death is caused by gram-negative bacilli (this includes Klebsiella species)3. Line sepsis or catheter-related infection refers to infection by the bacteria at the intravascular equipment and it is the top reason of hospital acquired infections 8. It is said that all type of invasive medical device carry the risk of introducing bacteria into the host system. The risk however, is highly dependent on the type of device used3. There are many clinical characteristics of line sepsis which may differ from normal septic patients as summarized in the (table 1)3. Majority of the symptoms of gram negative sepsis is triggered by the bacterial endotoxins4.
Non specific sepsis cases
Highly specific features for line sepsis
Source of bacteria invasion may not be conclusive
Low blood pressure, shock
IV device may be in place
Inflammation or pus secretion at IV site
Digestive system (abdominal pain, vomiting, diarrhoea)
Sudden onset might be related to shock. These will improve with administration of antibacterial therapy and removal of IV line
Neurological conditions (seizures and confusion)
Probable blood borne infections with Staph aureus, coagulase negative staph species, corynebacterium species, bacillus species, candida species.
Table 1: Features of catheter-related infections which may differ from other sepsis cases. However, these symptoms cannot validate the diagnosis of line sepsis. The presence of symptoms must be confirmed with cultures 3, 6.
When patients present with some of these symptoms, the severity of sepsis must be assessed. There are a number of score systems can be applied although the use of each of this score systems may vary in different areas. One of the score systems that are used for mild cases which may determine the need for hospital admission is the MASCC risk score system. Scoring systems in more severe cases of sepsis especially applied to patients in intensive care would be APACHE II and SAPS II risk score systems. Apart from these scoring systems, diagnosis should be accompanied by microbiological results in which samples from urine, stool or infection site being taken for examination to confirm the case of systemic bacterial infection1.
There are many different antibacterial agents that can be used in the treatment of sepsis caused by Klebsiella species since this species is susceptible to various antibacterials (table 2). However, the susceptibility pattern of different species may differ 2.
Klebsiella pneumonia (87%)
Klebsiella oxytoca (13%)
Table 2: Differences in the susceptibility pattern of two different Klebsiella species. Majority of Klebsiella species-related sepsis is caused by Klebsiella pneumonia (87%) and to a lesser extent, Klebsiella oxytoca (13%). It can be seen that both species are almost completely susceptible to imipenem 2.
These agents act through different mechanisms to act against bacteria. Some of them are described in Table 3.
Mode of actions
B-lactams penicillins (piperacillin, cephalosporins, carbapenems)
Inhibition of cell wall synthesis leading to cell death
Inhibition of cell wall synthesis
Aminoglycosides (gentamicin, amikacin)
Inhibition of protein synthesis
Inhibition of nucleic acid production
Table 3: Summarized mode of actions of antibacterial agents used in the treatment of severe infections. Most of them are used in combination because they act on different pathways which in combination have synergistic activity9.
Most infections caused by gram-negative bacteria will resolve in 10-14 days of appropriate antibiotic treatment3. There are cases in which longer treatment may be required due to patient reacting slower to the antibacterial or having haematological problems such as low neutrophil count6.
Figure 1: Flow chart of early management of patients with suspected nosocomial infections. These steps should be followed in every patient but review should be done on every phase to make sure patient gets the optimal treatment possible. Adapted from Koren, M.H. (2003) 5.
In patients who sepsis is suspected, especially when neutrophil is low, empiric therapy with antibacterials should be started urgently1, 4. A study confirmed that patient is more likely to survive if appropriate antibacterial therapy is initiated within the first hour of reported hypotension1, 5. Every following hour with the empiric therapy delayed will increase the risk of death by 7.6% 1. Since blood test and susceptibility results will not be available in the first 48-72 hours and half of the patients are not likely to survive the first two days of the infection, empiric therapy is vital4. Some of the agents used in empiric therapy would include meropenem or imipenem/cilastatin or piperacillin/tazobactam given individually. Other alternatives would be ceftazidime and cefepime 1, 3. However, the choice of drug will be affected by local microbiological information and prevalent organisms of the area as well as the infected organs1. There is a conflict of whether or not vancomycin should be included in the empiric treatment. Studies shown that by incorporating vancomycin into the treatment regimen, the mortality rate was not affected, therefore, there is no rationale in adding a drug that is not making a difference. But the addition of vancomycin is justified in the case of MRSA infections and if the patient is at high risk of endocarditis3.
To control the source of infection, infected fluids should be drained, infected equipments should be taken off, affected soft tissues should be removed and precautions to avoid another contamination should be taken6. In patients with intravascular device use, if the line is infected and patients display obvious signs of purulence at the insertion site, the catheter should be removed and samples taken from the insertion site should be sent for culture. Delay or failure to take away the catheter may bring about thrombus leading to vein inflammation or endocarditis. If there is a need for the catheter, a new line can be inserted at a different site. Studies has shown even without the removal of the line, antibiotic treatment given for 7-21 days have 60-91% of treatment success rates although this may greatly differ depending on infecting bacteria3, 8.
Figure 2: Overall management of sepsis cases. There are slight differences in the aims of the first line and second line treatment 6.
In patients with suspected gram negative sepsis, it is common to have a combination of two bactericidal antibacterial agents in their regimen. The logic in using combination therapy apart from the synergistic activity is to avoid the development of resistance strains 3, 4. The all time favourite agent for line sepsis is the aminoglycosides. Unfortunately, due to the fact that they are not effective against all organisms, they are used in combinations7. Most common combination therapy would be aminoglycoside paired with broad spectrum cephalosporin or semi-synthetic penicillins (amoxicillin or piperacillin) or an antipseudomonal agent 4, 7.
Conventional aminoglycosides used for this indication will be gentamicin and tobramycin but if there is resistance to both of these agents, amikacin and netilmicin are alternatives4. The plasma levels of gentamicin and tobramycin should be maintained at 6-10 mg/l while neltimicin should be maintained at 12-15 mg/l 4, 7. The trough concentration should not exceed 2 mg/l to reduce the risk of kidney toxicity as well as damage to the hearing apparatus 1, 4, 7. In cases where Klebsiella species is the infecting organism, combination with a broad spectrum cephalosporin is preferred. When susceptibility results are reviewed, drug regimens can be individualised to give the patient the most optimal treatment4, 6.
Semi-synthetic penicillins are broadly used in combination with aminoglycosides. Usual penicillins used would be amoxicillin, ampicillin, piperacillin and flucloxacillin. Amoxicillin is commonly chosen over ampicillin due to its lower proportion of protein binding plus lower risk of hypersensitivity effects and colitis. Unfortunately, many strains of E.coli and Klebsiella species have developed resistance to amoxicillin7.
Cephalosporins are agents that are widely used in infection treatment regimes due to the widespread activity and their nontoxic profile. Newer cephalosporins are of choice because they are not toxic to the kidney and do not cause hypersensitivity effects. A third generation cephalosporins, ceftazidime (2g three times daily) have excellent activity against a wide range of organisms however is not active against anaerobics. This agent nevertheless is effective when used alone or in combination with flucloxacillin or aminoglycosides7.
In cases where the bacteria are resistant to both cephalosporin and penicillins, a combination of imipenem with an aminoglycoside can be used4, 6. Imipenem/cilastatin (2g three time daily IV) are one of the most effective agent used alone or combination in the treatment of infections due to its excellent activity against aerobic and anaerobic bacteria. However, side effects may be a problem with this agent as it may cause nausea, vomiting, diarrhoea, hypersensitivity effects, confusion and seizures. The dosage of imipenem/cilastatin is affected by renal function and in patients with kidney problems, dose should be reduced. Other carbapenem such as meropenem may also be useful in severe infection7.
The emergence of resistance strains in gram negative bacteria is attributable to the elaboration of beta lactamase enzyme which may inactivate beta lactams. Therefore, the use of beta lactam/beta lactamase inhibitor agents is justified. Amoxicilin/clavulanic acid is rarely used in acute conditions but ticarcillin/clavulanic acid is safe and effective when used alone in the treatment of serious infections. Ciprofloxacin, a 4-fluoroquinolone, is an agent with activity against gram positive and gram negative bacteria. In patients with confirmed penicillin allergy, a monobactam beta lactam, aztreonam should be used7.
Although elimination of bacteria from the system is the main aim, there are many other vital factors that must be considered. Sepsis is always, if not in all cases, may cause organ failure and therefore accompanied by cardiovascular failure, respiratory depression, renal impairment as well as metabolic disorders. These problems must be tackled when therapy is started so that, patient can get relieve in the shortest period of time.
Widespread stimulation of the coagulation mechanism is the primary stage of sepsis causing accumulation of fibrin in microcirculation leading to organ failure. To avoid continuous trigger of the coagulation mechanism, many agents can be used to stop the coagulation process. In spite of this, it is crucial to note that any interruption to the coagulation process should be balanced with the risk of bleeding. HETRASE study revealed that there is no differences in survival rate with lose dose heparin. Other studies concluded that the dose of low dose heparin should be based on APACHE II scores. Antithrombin III (ATIII) is prevents thrombosis and inflammation. Unfortunately, recent studies showed ATIII to be ineffective in sepsis1. In patients with no reported thrombocytopenia, recombinant human activated protein C (APC) can be incorporated into their regimen but only in severe cases1, 7.
In sepsis, cytokines play a vital role in hyperinflammatory and anti-inflammatoy stages. Therefore, there is a consensus on the use of cytokines and cytokine inhibitors in the treatment regime of sepsis. Despite the fact that it might work theoretically, studies conducted on IL-1 receptor inhibitors, TNF antagonists and interferon gamma shows no improvement in patientsâ€™ condition. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) may boost the production of neutrophils and is therefore, added into the regimen of sepsis. Meta-analyses demonstrated that neutrophil levels are increased in short time and greatly reduce hospital stay although mortality rate is not improved. But due to its tendency to cause respiratory complication and side effects, it is not recommended to use these agents routinely in sepsis1.
Early objective of the treatment should be to protect the cardiovascular system from any damage and if this is successful within the first 6 hours, it can increase life expectancy of septic patients. Patients diagnosed with sepsis usually have low blood pressure as well as excessive lactic acid1. These conditions are mostly managed by volume substitution to preserve organ perfusion1, 6. Crystalloid fluids and colloids can be valuable for this indication. Although resuscitation using crystalloids may need more fluid, colloids are not preferable for use over crystalloids because trials found that there is a small but consistent elevation in the risk of renal impairment and increased fatality risk. Human serum albumin should not be used for volume substitution because there no evidence of better patient outcome from its use. It is essential that volume substitution is accompanied by haemodynamic monitoring. If the target blood pressure (below 65mmHg) is not achieved in a pre-set time period, a vasoconstricting agent (an alpha adrenergic agonist, norepinephrine 0.1-1.3 Âµg/kg/min) can be added which may help in improving kidney function by increasing blood pressure. There is no data supporting the use of higher dose in improving patient outcome and kidney function. Another different agent which is also used for this indication would be antidiuretic hormone (ADH). ADH is given 0.01-0.04 units/min to increase urine volume thus, improving creatinine clearance when compared with norepinephrine. A study reveals the poor therapeutic effects of ADH in sepsis1. In cases of sepsis-induced myocardial infarction, although appropriate volume substitution has been carried out, a combination therapy of vasoconstrictor and dobutamine should be started1, 4. However, epinephrine should not be combined with dobutamine due to toxic effects as well as poor patient outcome 1, 6. However, if these agents do not work, corticosteroids should be prescribed. Hydrocortisone is more favourable in comparison to dexamethasone due to risk of suppression of hypothalamic-pituitary gland functions6.
Acute lung damage and acute respiratory distress syndrome (ARDS) will occur in half of the patients diagnosed with severe sepsis1, 6. If the patient is conscious, patients with mild breathing difficulties (PaO2/FiO2 >200), intermittent continuous positive airway pressure (CPAP) can be started to help inhalation. In moderate and serious cases, endotracheal intubation and assisted ventilation may be required. However CPAP is preferred due to its non-invasive technique in patients with no reported hypotension and compromised mental health. CPAP is also preferred before the development of hypoxaemia and may help in making decisions whether invasive technique should be employed. However, half of the terminally ill haematologic patients started with non-invasive techniques experience treatment failure; therefore, in these patients especially in patients who have just undergone stem cell transplant, invasive mechanical breathing assistance is the first choice. In patients with foreign deposition in their lungs, if G-CSF was started, it is speculated that there is higher risk of pulmonary failure with acute lung damage and ARDS 1.
Another 23% of patients who are having severe sepsis and more than half of the patient with septic shock will have acute renal failure (ARF). The cumulative mortality rate of ARF and sepsis is 70%. The exact mechanism of ARF is not fully known but it is suggested that lack of blood flow to kidney, ischemia, acute tubular necrosis and vasodilatation may precipitate to ARF 1, 4. Kidney function in septic patient should be improved to maintain the fluid balance, to discard waste products and to regulate electrolytes levels. To do this, haemodialysis or continuous renal replacement therapies (CRRT) should be done. It is suggested that there is no benefit in using any of these methods. When any of these methods are used in patients, the dosage of antibacterial agents used should be monitored closely and adjusted accordingly1.
In cancer patients, extensive chemotherapy may cause adverse effects such as mucositis and may deter patients from eating. Furthermore, septic patients have higher demand of energy, higher catabolism rate as well as higher nitrogen balance. Patients of this sort should be given nutrients from external sources and oral formulation is preferred compared to parenteral formulations unless contraindicated 1, 6.
In conclusion, it is important that a systematic information portal to be created in healthcare settings to identify common organisms and guidelines to be updated regularly. It is also crucial for direct and indirect consequences of an illness to be considered by healthcare professionals. These will hopefully improve patient care.
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