Using gentamicin in the management of sepsis

Using gentamicin in the management of sepsis Sepsis is defined as the inflammatory response toward an infection (1). It is either simple or severe sepsis depending on the organ dysfunction involved as a result of the infection and other factors (2). In terms of the pathophysiology of severe sepsis, a cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis causes changes in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death (3). In terms of definitions of other sepsis-associated symptoms, it was generally agreed at the International Sepsis Definitions Conference which was convened in 2001 and the following definitions of sepsis syndromes were published in order to clarify the terminology used to describe the spectrum of disease that results from severe infection. Sepsis is the presence of infection in association with meeting the Systemic inflammatory response syndrome (SIRS) criteria (Box 1 (2)). The clinical significance of meeting SIRS criteria in the absence of organ dysfunction or shock is still unclear. Severe sepsis is defined as evidence of end-organ dysfunction such as altered mental status, episode of hypotension, elevated creatinine, or evidence of disseminated intravascular coagulopathy. Septic shock is defined as persistent hypotension despite adequate fluid resuscitation or tissue hypoperfusion manifested by a lactate greater than 4 mg/dL. Bacteremia is defined as the presence of viable bacteri a within the liquid component of blood (1). Acute pyelonephritis is defined as an acute infection of one or both kidneys; usually, the lower urinary tract is also involved (4). Antibiotic regimen of choice for Sepsis that is associated with urinary tract infection is Co-amoxiclav 1.2g 8 hourly intravenously together with Gentamicin IV dose of 5mg/kg once daily (5). Although that is controversial whether to use the ideal body weight (IBW) or to obtain blood samples indicating Gentamicin level to get the optimal dosing regimen for Gentamicin in obese patient due to risk of accumulation with Aminoglycoside and the fear of oto- and nephrotoxicity (6). Other supportive measures depend on the patients status; table 1 (1) contains helpful measures that indicate markers of organ dysfunction. Case Summary Our patient, C.M., is a 56 years old female who was admitted to the Accident and Emergency department (AE) due to an increased urinary frequency and a high temperature of 40.5 °C. Other complaints were back pain and shortness of breath (SOB). Also, the patient had reported a fall the night before admission. Moreover, the patient had vomited the night before and in the morning of admission. C.M. is a previous smoker who had stopped smoking several years ago and she lives with a partner. She is clinically obese weighing 100kg and her height is 152.4cm. Giving this, her ideal body weight (IBW) comes to 49kg. The only known allergy for this patient is microspores tapes. The patients past medical history (PMH) included asthma, non-insulin dependent diabetes mellitus (NIDDM) and fibromyalgia. She was on one puff daily of each Symbicort Turbohaler 200/6  µg and Ventolin Accuhaler for the management of her stage 3 asthma. Metformin 1g daily was prescribed for her diabetes control; however, its formulation was not mentioned (whether it is a sustained release tablet or a normal release one!). For her fibromyalgia, she was taking 300mg of Quinine sulphate daily together with 150mg of Amitriptyline daily (which is a very high dose; low dose of tricyclic antidepressant (T CA) is recommended i.e. 20-30mg of Amitriptyline). For her pain, the patient was on Co-codamol tablet as required (strength, dose and frequency were not mentioned). Having that she is a diabetic patient over 40 years old, a dose of Simvastatin 40mg daily was prescribed as a primary cardiovascular disease (CVD) protection measure. In addition, Omeprazole 20mg daily was one of her regular m edications with unclear indication. Investigations On admission, an Electrocardiography (ECG) was performed and indicated sinus tachycardia; which could be related to the high temperature, pain or sepsis. The patients vital signs were abnormal having a respiratory rate (RR) of 22 breaths per minute (normal is ~ 12bpm), a heart rate (HR) of 117 beat per minute (normal is ~ 70bpm) and a blood pressure (BP) of 142/65 mmHg (target for diabetic patients is Her laboratory investigations were almost normal except for some parameters. The Sodium level was a bit low which could be a result of the frequent urination or an Amitriptyline hyponatremic effect. Glucose and C-reactive protein (CRP) levels were high which might indicate the presence of infection. Thrombocytopenia may be caused by Quinine or Simvastatin administration! Impression and related Management Plan The patient was diagnosed as a pyelonephritis and sepsis case; so empirical antibiotic regimen was initiated with 1g Amoxicillin intravenously six hourly and 500mg ciprofloxacin orally once daily. Also, 1g Paracetamol intravenously six hourly and one liter Normal Saline intravenously over 24hours was started. Urinalysis on the first day indicated the presence of leucocytes, nitrites, glucose, ketones and blood which means a presence of infection. On the second day, blood culture showed a growth of E. coli which is sensitive to Gentamicin, therefore, 400mg Gentamicin intravenously every 24 hour was prescribed and ciprofloxacin was discontinued. Gentamicin plasma level was requested 6-14 hours after administration of the first dose. In addition to the patients regular medications, 50 mg of Cyclizine eight hourly and 20mg of Citalopram once daily were added, paracetamol IV was switched to orally in the second day and 30mg of oral codeine as required was prescribed ; but the patients Salbutamol Inhaler had been stopped for unclear reason. Discussion Revising the management plan for this patient and in comparison to the local guidelines for the management of pyelonephritis and sepsis patients, we would notice that 1.2g intravenous Co-Amoxiclav is the first-line choice of Penicillins, not Amoxicillin, together with Gentamicin. However, if the ideal body weight is required to obtain the appropriate dosing of Gentamicin for obese patients, so in this case, 245mg of Gentamicin supposed to be prescribed instead of 400mg which is the maximum daily dose (Although that some infectious diseases specialist would recommend going to the maximum dose to make sure that we get the maximum benefit; but we must consider patient status and severity of infection!). Also, it is essential to check the optimal timing for monitoring each drug plasma level, in our case, Gentamicin therapeutic drug monitoring (TDM) has not deviated from the local guidelines recommendation for the once daily dosing of Gentamicin i.e 6-14 hours after giving first dose. Having a patient with increased urination and vomiting, we must consider fluid replacement. Replacing with one liter Normal Saline (NS) might have not met the patients requirement! So it is recommended to check patients need to ensure appropriate replacement i.e. at least 2.5-3 liter daily. We could have recommended giving 2 liter NS each over 8 hours plus the addition of 500ml 5% Dextrose to ensure calories intake if the patient cannot tolerate oral intake. Considering the patients asthma control, we must confirm that Salbutamol inhaler was not mistakenly missed after admission. Since that SOB was one of the patients complaints, we must ensure that it was relieved, if not, consider 5mg of Salbutamol nebulizer four times daily to be added to the regimen and if nebulizer is not necessary, ask for Salbutamol inhaler to be charted as if required basis (6). Also, blood gases were not mentioned so it is probably safer to ask for the oxygen and carbon dioxide saturations to consider if oxygen therapy is needed! Confirm that the patient and nursing staff are aware of inhalers techniques. The patient is on Amitriptyline 150mg orally daily which is considered an old practice for the treatment of fibromyalgia (high dose TCA) and the current recommendation states 20-30mg of Amitriptyline daily for 8 weeks (6) so it is better to re-consider dosing or to change regimen. Low dose Sertraline or high dose Venlafaxine therapy may be effective (6) so consider changing if no further benefit of the use of Amitriptyline. For the associated pain, Paracetamol with Tramadol has better efficacy than Co-codamol. Pregabalin (150-300mg every 12 hours) may improve pain especially if combined with Tramadol; it also improves sleep and morning stiffness (6). So, knowing the patients control with the current medication would be helpful to consider treatment change or modeling to get the most of pharmacologic treatment. Suggesting alternative ways to manage symptoms is also recommended, e.g. spa therapy, physiotherapy, stress management, acupuncture or diet (6). NICE guidelines for the management of type II diabetes mellitus state that Metformin is the first line choice for obese patients. Choosing appropriate formulation that suits the patients lifestyle is essential to ensure patients compliance. Once daily dosing of sustained release formula could provide 24 hour control over glucose, but in this case the present of infection interfered with having accurate reading so it is logical to check the HbA1c to check the glycemic control over the last 8 weeks to consider any therapy modification. Also, pre- and post-prandial glucose level monitoring is required to avoid both hyper- and hypoglycemia using the current regimen. Statins must be prescribed for all diabetic patients who are over 40 years old (6) and having any risk factor of Coronary Vascular Diseases (CVD). The patient was on Simvastatin 40mg daily but no Cholesterol level obtained (consider Ezetimibe if high Cholesterol). Monitoring liver function tests (LFTs) and any muscular side effect is important. Also, having a high BP on admission, checking that BP is normal after sepsis reveals is vital. If persistent high BP, consider adding ACE inhibitors, having the benefit of BP control and protecting the heart in patients susceptible to Vascular Diseases. Weight loss in this patient is advisable so consider dietitian and physiotherapist review to consider going on diet and exercise. Also, annual eye check is recommended to control retinopathy due to DM. Cyclizine was prescribed on regular basis, so we better check if the patient is really on need of a regular anti-emetic, otherwise, consider changing it to as required basis. Regarding Paracetamol, it was prescribed on as needed basis but it was not put clear not to exceed the maximum daily dose, so it is recommended to clarify that to not give the patient more than 4g per day. It is safer to contact the patients GP to confirm the indication of Omeprazole and to consider discontinuation if no clear indication was obtained. Additionally, the patient was thrombocytopenic, which could be a side effect of administration either Quinine or Simvastatin, so monitoring the platelets count is highly recommended to prevent any complication, although DVT prophylaxis is not needed as long as the patient is mobile. Conclusion In conclusion, the overall patient management had no much deviation from the current guidelines recommendation except for some practice that need to be reviewed considering the current patients status. Therapeutic monitoring should be carried on because the patient is under risk of many complications or side effects. Lastly, patients awareness of her clinical condition and treatment requirement for each problem is helpful to prevent or reduce future health problems. Appendix 1: PATIENT MEDICATION PROFILE Patient details Name C.M. Consultant General Practitioner Address Gender Female Weight 100 kg Height 152.4 cm Community Pharmacist Date of Birth (Age) 56 y.o. Known Sensitivities Micropores tapes Social History Previous smoker, lives with partner Patient hospital stay Presenting complaint in primary care / reason for admission Admission date 2008 Increased urinary frequency Back pain Shortness of breath Vomiting Fall (the night before) Fever (40.5 °C) Discharge Date Discharged to Relevant medical history Relevant drug history Date Problem Description Date Medication Comments Asthma Symbicort 200/6 Turbohaler 1 puff daily Ventolin Accuhaler 1 puff daily Non-insulin dependent diabetes mellitus Metformin 1g daily Formulation? Fibromyalgia Co-codamol PRN Strength? Amitriptyline 150mg daily Too high! Quinine sulphate 300mg daily Duration? Simvastatin 40mg daily 1ry CVD prevention Omeprazole 20mg daily Indication? Relevant non drug treatment Prescribed Medication Start Stop Clinical/Laboratory Tests Result 1 Paracetamol 1g IV 6 hourly Day 1 Day 2 ECG Sinus tachycardia 2 0.9% sodium chloride 1000ml IV over 24 hours Day 1 HR 117 bpm 3 Amoxicillin 1g IV 6 hourly Day 1 BP 142/65 4 Ciprofloxacin 500mg PO OD Day 1 Day 2 RR 22 bpm 5 Metformin 1g PO OD Day 1 Urine analysis Leucocytes, nitrites. Glucose, ketones, blood +ve 6 Omeprazole 20mg PO OD Day 1 Blood culture E. coli 7 Quinine sulphate 300mg PO OD Day 1 Na 134 (135-145) 8 Simvastatin 40mg PO OD Day 1 CrCl 145.3 (78-120) 9 Amitriptyline 150mg PO OD Day 1 Glucose 8.9 (3.9-5) 10 Symbicort 200/6 inhaler 1 puff daily Day 1 CRP 180 ( 11 Codeine phosphate 30mg PO PRN Day 1 Bilirubin 35 (3-16) 12 Citalopram 20mg PO OD Day 1 PT 17 (12-15) 13 Cyclizine 50mg PO 8 hourly Day 1 APTT 39 (20-30) 14 Gentamicin 400mg IV 24 hourly Day 2 Platelets 70 (150-400) 15 Paracetamol 1g PO PRN Day 2 Clinical management Diagnosis Pharmaceutical Need Pyelonephritis Evidence-based treatment Sepsis Treatment according to guidelines Care Issue/Desired Output Action Output Confirm drug history + reconcile drug history Ask patient how and when she takes her medication and the indication for each medicine. Compare with GPs DHx + Phone GP for indications for amitrip., omep. and quinine, and when they were initiated. All regular meds have been charted except prn salbutamol. Patient is SOB; advise Dr to chart it prn. Confirm antibiotic regimen for pyelonephritis/sepsis in addition to TDM Check the local guidelines that amoxicillin is first-line for the indication (culture sens. to gent.).Calc. her ideal body weight and CrCl.Calc. gent. dose based on ideal body weight and compare to 400mg iv od (max dose).Check local guidelines whether 6-14 post dose gent. level is correct procedure. Chase level. Monitor BP, Temp, Pulse, RR for signs of resolving sepsis whilst on current regimen. Co-amox 1.2g iv tds is first-line with gent 5mg/kg (max 400mg, ideal body wt 49kg, CrCl 71ml/min). Recommend switch to co-amox because she needs 7/7 iv + oral. Recommend 245mg gent iv od Obtain level before 2nd dose is given+TDM for gent is correct. Review need for gent in 48h Fluid requirements possibly not being met by 1L N. saline in 24hours Request a running fluid balance chart due to vomiting + increased urinary frequency. Ask patient if she can tolerate oral liq. or if feels thirsty. Assess if iv is necessary (2.5L daily + replace losses) Advise doctor to amend first bag to 8 hours and chart 1L N.saline over 8hours + 500ml glucose 5% over 8 hours if patient cant tolerate oral liq. Is her current SOB being treated appropriately? If patient is still wheezy, ask for PaCO2 + PaO2. Request salbutamol nebs 5mg qds + O2 60% to be charted. If not currently SOB, ask for accuhaler to be charted prn. Assess inhaler technique for both inhalers when breathing ok Is her fibromyalgia regimen in-line with current evidence? Check Brit. Soc. Rheum for current guidance on fibromyalgia. Check that citalopram is the SSRI of choice in fibromyalgia since it has been started on admin. Review quinine; if has been in use for 3 months with no benefit consider stopping it High dose TCA is an old practice; current evidence states 25mg/day for 8 weeks. Advise a review of Amitrip. Low dose sertraline has better evidence for use in Fibro. Advise switch + show evidence to prescriber. Tramadol with paracetamol has better efficacy than co-codamol. Suggest trial switch and monitor for dizziness due to recent unexplained fall. Consider pregabalin. Lifestyle advice: stress management, diet, physiotherapy/massage, etc. Is her type II diabetes under control? Check SIGN guidelines on diabetes for current management. Request HbA1c test to determine control over last 2-3/12 Monitor glucose pre/post-prandial and random. Ask patient how she takes the metformin and how regularly Metformin is first-line in obese type II. From lab results, assist endocrinologist in determining whether metformin dose should be increased + which preparation suits patients lifestyle. Is her CVD primary prevention needs being met? Check SIGN guidelines on CVD primary prevention. Check BP + Cholesterol. Next UEs ask for urine albumin + protein levels. Ask patient about current diet and exercise plan (obese) + last eye test. Simvastatin 40mg charted. Check cholesterol. If it is high, may need ezetimibe 10mg od. LFTs ok BP 142/65, upon resolving sepsis recheck BP and initiate ACEi if appropriate. Advise dietician review (obese) + physiotherapy review (or GP) for plan (30mins exercise 5/7). Advise eye test once a year Regular cyclizine may be unnecessary Endorse chart for paracetamols maximum daily dose Reassess patients need for a regular anti-emetic and re-chart cyclizine as prn instead of regular if required Max 4g in 24 hours (e.g. 1g QDS) Highlight patients thrombocytopenia No need for DVT prophylaxis if patient is mobile. Mention that quinine or simvastatin could be the cause of low platelets. Suggest trial withdrawal of quinine if not planning on stopping anyway. Monitor Platelets level if continued. Indication for omeprazole Determine indication from GP and patient. Consider trial withdrawal if indication unknown. Appendix 2: Box 1. Consensus Conference of the American College of Chest Physicians and Society of Critical Care Medicine definitions for the various manifestations of infection.   Ãƒ ¢Ã¢â€š ¬Ã‚ ¢ Systemic Inflammatory Response Syndrome (SIRS): Manifest by two or more of the following conditions: 1. A temperature >38oC or 2. A heart rate >90 beats per minute 3. A respiratory rate >20 breaths per minute or a PaCO2 4. A white blood cell count >12,000/mm3 or 10% immature forms. à ¢Ã¢â€š ¬Ã‚ ¢ Infection:Microbial phenomenon characterised by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by these organisms. à ¢Ã¢â€š ¬Ã‚ ¢ Bacteraemia: The presence of viable bacteria in the blood. à ¢Ã¢â€š ¬Ã‚ ¢ Sepsis (Simple): The systemic response to infection, manifested by two or more of the SIRS criteria pus an infection. à ¢Ã¢â€š ¬Ã‚ ¢ Sepsis (Severe): Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria or an acute alteration in mental status. à ¢Ã¢â€š ¬Ã‚ ¢ Septic shock: Sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that the perfusion abnormalities are measured. This is a subset of severe sepsis. à ¢Ã¢â€š ¬Ã‚ ¢ Sepsis-induced hypotension: A systolic blood pressure 40 mmHg from baseline in the absence of other causes for hypotension. Adapted from Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644-1655. Appendix 3: Table 1. Clinical and laboratory markers of organ dysfunction. Organ System Clinical Laboratory Cardiovascular Tachycardia Hypotension Cardiac arrest Arrhythmias Haemodynamic support Altered CVP, PCWP Reduced cardiac output Endocrine Weight loss Hyperglycaemia Hypoalbuminaemia Haematological Bleeding Thrombocytopenia Increased D-dimers Abnormal white cell count Abnormal clotting profile Gastrointestinal Ileus GI bleeding Acute pancreatitis Acalculous cholecystitis Decreased intestinal pH Elevated amylase Hepatic Jaundice Hyperbilirubinaemia Increased PT Elevated LFTs Hypoalbuminaemia Neurological Delirium Confusion Altered consciousness Altered EEG Renal Oliguria Anuria Renal replacement therapy Elevated creatinine Elevated urea Respiratory Tachypnoea Cyanosis Mechanical ventilation PaO2 SaO2 PaO2/FiO2 Immune Pyrexia Nosocomial infection Altered white cell count Impaired white cell function Adapted from Balk RA. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit Care Clin 2000; 16: 337-352.