Management of Chemotherapy      Complications          Elshami M. Elamin, MD            Medical Oncologist        Central ...
IntroductionChemotherapy: Affects the rapidly dividing cancer cells Also affects rapidly dividing normal cells   Hair   Mu...
Effect of chemo on blood countsBecause stem cells in BM do not reproducerapidly they are less likely to be affectsDuring h...
What is the chemo nadir?Lowest blood counts following chemoThe nadir time is usually about 10 days (7-14 days)after chemo ...
Why chemo given in Cycles (q3-4 wks?)  The nadir (7-14 days)  BM recovery (3-4 wks)   What if chemotherapy is given during...
10.0         8.0         6.0W.B.C.         4.0         2.0               Day 0               (Chemo    Day 7           Day...
Chemotherapy Side Effects   Immediate   Delayed     within days     Within weeks   Late
Immediate Side EffectsAllergic reactions:  Infusion-related    Rituximab  AnaphylacticBurning sensation or pain at the sit...
Immediate Side EffectsAcute emesis (Nausea/Vomiting):  Within few min – Hrs  Peaks after 5-6 hrs  Resolves within first 24...
Within daysDelayed-onset emesis:   > 24 hrs after chemo – 7 days   Related to types of chemo drugs (Platinum, Cytoxan, Dox...
Mucositis
MUCOSITIS
Within weeksHair loss (Alopecia)  Taxanes, Cisplatin, DoxoPeripheral neuropathy  Pacltaxel, Oxalipatin, CisplatinDry skin ...
Late Side effectsOtotoxicity  CisplatinMemory difficulties (chemo brain)Sexual dysfunctionAmenorrheaSterilityMDS, leukemia...
Delayed        Immediate                A.E.           A.E                                (days)                          ...
Management of a cancerpatient who is undergoing      chemotherapy
What is the patient status?SOAP: Subjective:   Fever, pain, S.O.B., cough, bleeding, diarrhea etc … Objective:   A/O x 3  ...
TREATMENT OF SIDE EFFECTS  AND COMPLICATIONS OF    CANCER THERAPIES
What do you need to know? When was the chemotherapy given?    Are you dealing with chemo NADIR Any supportive therapy foll...
EMESIS(Nausea/Vomiting)
23
Causes of N/V in cancer patients Chemo                    Uremia RT                       Opiates Bowel obstruction       ...
CINV• Acute  • Onset: minutes-hrs  • Resolves: first 24 hrs          It is easier to prevent                              ...
Which anti-emetic you should chose        for your patient?  Anti-emetic regimens should be chosen based on:    Chemo drug...
Categories of Emetogenic         ChemotherapyHigh emetic riskModerate emetic risk     *Don’t                       undertr...
PlatinumDoxorubicinCytoxanDacarbazine
Aprepitant   Lorazepam        5-HT3 Antagoist                                                Dexa                         ...
Management ofDelayed Emesis
Dopamine antagonists Metoclopramide (Reglan) and Domperidone (Motilium) Sensitize tissues to acetylcholine Stimulate upper...
Anxiolytics/Anti-psychoticsBenzodiazepine (Lorazepam)  May give the night before and after chemoPhenothiazine:  Prochlorpe...
Watch for Dystonic reaction Prochlorperazine Metoclopramide Domperidone
SteroidsDexamethasone  Improve efficacy of 5-HT3 antagonists   With Aloxi for moderate risk:        8 mg d1 enough        ...
SteroidsDexamethasone  Always keep in mind its side effects                 *Hyerglycemia                     *HTN        ...
Serotonin (5-HT3) Antagonists  5-HT3 antagonists (except aloxi/palonosetron) are less  effective for delayed emesis  A met...
MiscellaneousAntipsychotic :  Olanzapine (zyprexa)Cannabinol:  Dronabinol (marinol) 5-10 mg OR Nabilone 1-2 mgAnti-histami...
MANAGEMENT OFBREAKTHROUGH (REFRACTORY)    EMESIS
Breakthrough CINVThe most difficult to treatConsider routine (around the clock) rather thanPRNRectal or IV rather than POM...
Breakthrough Treatment for CIN/VFirst Step:  Add one agent from a different drug class PRN    Antipsychotic :       Olanza...
Breakthrough Treatment for CIN/VSecond Step:                Continue agent on                Schedule Not PRN   Agents    ...
Anticipatory N/V
Anticipatory N/VNegative bad experience with chemo18-57% of patients  N>VPrevention:  Optimal anti-emetic with each cycle ...
It is not always medication to do it …It is not always doctors and nurses todo it …It is most of the time the patient todo...
Non-Medical measures•Eating small frequent meals                                   Dietary•Choice of food                 ...
Behavioral therapyRelaxation/systematic desensitizationHypnosis with guided imageryMusic therapySpiritual
Radiation-Induced N/VR.T. - upper abdomin:   Pretreatment daily:     Granisetron 2 mg qd OR     Ondansetron 8 mg bid      ...
CANCER-RELATED INFECTIONS PREVENTION       TREATMENT
PREVENTION1. Neutropenic precaution2. Prophylactic antimicrobials3. G-CSF
Neutropenic precautionHand washGloves, Gowns, etcAccessing central venous lines:  Written policy  Training of medical staf...
Port-a-Cath
Prophylactic antimicrobials
RISK CATOGERIESOverall infection   Disease/Therapy       Fever/             Antimicrobial prophylaxixrisk                 ...
Fungal prophylaxisPts with hematologic malignancies and SCT not on antifungalprophylaxis:     Severe mucositis is a risk f...
Anti-viral ProphylaxisFor low risk pts:  None  Prior HSV: during neutropeniaIntermediate risk pts:  During neutropenia + 3...
CMV PreventionHigh risk groups and surveillance period :   1-6 m after SCT   GVHD   Minimum of 2 m after Alemtuzumzb      ...
PCP Prophylaxis      (Pneumocystis Jirovecii)  Recommended                           ConsideredAllo SC                    ...
PCP Prophylaxis          (Pneumocystis Jirovecii)Drugs of choice:TMP/SMX Preferred If allergic or intolerant:   Desensitiz...
G-CSF
10.0         8.0         6.0W.B.C.         4.0         2.0               Day 0               (Chemo    Day 7           Day...
TREATMENT
Neutropenic Fever                       Look for source of infection:                       *Catheter sites               ...
Choice of Initial AntibioticShould be based on:  Infection risk assessment:    High risk (inpt, co-morbid, prolonged neutr...
Choice of Initial Empiric AntibioticIV monotherapy:*Primaxin                                                 IV combinatio...
NOT-RESPONDING:                                      •FUO:                                          •Stable:              ...
Duration of therapy           Bacterial InfectionSkin/Soft tissue  7-14 dSimple bacteremia (no tissue site)  Gram-negative...
Duration of therapy          Fungal & Viral InfectionFungal:  Candida: minimum 2 wks after 1st negative blood cultue  Mold...
?? Catheter Removal ??                         Considered:                         •Bloodstream infection with:           ...
When to use Vancomycin as initial therapy?Serious infection associated with:  Clinically apparent, serious, catheter-relat...
Other agents for resistant Gram-positives                     Linezolid (Zyvox)*VRE                     Quinupristin/Dalfo...
Outpatient Therapy        (Low Risk Neutropenic Fever)Who is a low       Assessment:risk?                 Careful exam    ...
Outpatient Therapy        (Low Risk Neutropenic Fever)                      • Daily monitoring at leastDrugs of choice:   ...
Management of chemotherapy complications
Management of chemotherapy complications
Management of chemotherapy complications
Management of chemotherapy complications
Management of chemotherapy complications
Management of chemotherapy complications
Management of chemotherapy complications
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Management of chemotherapy complications

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Management of chemotherapy complications

  1. 1. Management of Chemotherapy Complications Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA
  2. 2. IntroductionChemotherapy: Affects the rapidly dividing cancer cells Also affects rapidly dividing normal cells Hair Mucous membranes Blood cells
  3. 3. Effect of chemo on blood countsBecause stem cells in BM do not reproducerapidly they are less likely to be affectsDuring hematopoiesis (differentiation) theblood cells are sensitive to chemo and mostlikely to be damagedAfter the mature cells (neutrophils, platelets)live out their life span, the blood count fall toTHE NADIR
  4. 4. What is the chemo nadir?Lowest blood counts following chemoThe nadir time is usually about 10 days (7-14 days)after chemo It varies depending on the drugs Risk of infection and bleedingThe next dose of chemotherapy is given only after: The nadir BM recovers (3-4 wks)
  5. 5. Why chemo given in Cycles (q3-4 wks?) The nadir (7-14 days) BM recovery (3-4 wks) What if chemotherapy is given during BM recovering period (increasing stem cell production)? It may cause: Prolonged myelosuppression Permanent BM damage
  6. 6. 10.0 8.0 6.0W.B.C. 4.0 2.0 Day 0 (Chemo Day 7 Day 21 Starts) Nadir
  7. 7. Chemotherapy Side Effects Immediate Delayed within days Within weeks Late
  8. 8. Immediate Side EffectsAllergic reactions: Infusion-related Rituximab AnaphylacticBurning sensation or pain at the site of infusion Irritant VesicantUrine discoloration Doxorubicin  Red Mitoxantrone  Blue
  9. 9. Immediate Side EffectsAcute emesis (Nausea/Vomiting): Within few min – Hrs Peaks after 5-6 hrs Resolves within first 24 hrs Related to: Age Gender Place History of alcoholism (reduce it) History of motion sickness Chemo drugs Anti-emetic used
  10. 10. Within daysDelayed-onset emesis: > 24 hrs after chemo – 7 days Related to types of chemo drugs (Platinum, Cytoxan, Doxo)FatigueMyelosuppression: During the nadir of chemo Mucositis Neuropenic fever +/- infectionDiarrhea or ConstipationReduced appetiteMetallic taste
  11. 11. Mucositis
  12. 12. MUCOSITIS
  13. 13. Within weeksHair loss (Alopecia) Taxanes, Cisplatin, DoxoPeripheral neuropathy Pacltaxel, Oxalipatin, CisplatinDry skin or pigmentaionNail changesFluid retention Docetaxel
  14. 14. Late Side effectsOtotoxicity CisplatinMemory difficulties (chemo brain)Sexual dysfunctionAmenorrheaSterilityMDS, leukemia Alkyl agent (2-5yrs), cytoxan (MDS 8-10 yrs) Topoiso ll inhibitor: usually M4, M5ALL (1-2 yrs) 11q23, 21q22, inv 16, t(15:17), t(9:22), t(4:11), t(3:21), t(16:21), t(8:16) Mitoxantrone (2-3 yrs)Cardiotoxicity AnthracyclinesPulmonary fibrosis Bleomycin
  15. 15. Delayed Immediate A.E. A.E (days) Delayed Chemo A.E. Starts (Wks) Late A.E.?
  16. 16. Management of a cancerpatient who is undergoing chemotherapy
  17. 17. What is the patient status?SOAP: Subjective: Fever, pain, S.O.B., cough, bleeding, diarrhea etc … Objective: A/O x 3 V.S.: BP, Pulse, Temp, RR, O2 Dehydration Mucositis Does the pt has a venous catheter Routine full system exam Assessment: Plan:
  18. 18. TREATMENT OF SIDE EFFECTS AND COMPLICATIONS OF CANCER THERAPIES
  19. 19. What do you need to know? When was the chemotherapy given? Are you dealing with chemo NADIR Any supportive therapy following the chemo was given? List of medication What kind of cancer? What kind of chemotherapy /regimen?
  20. 20. EMESIS(Nausea/Vomiting)
  21. 21. 23
  22. 22. Causes of N/V in cancer patients Chemo Uremia RT Opiates Bowel obstruction Gastroparesis Brain mets (Vincrestine) Electrolytes imbalance Psycophysiologic: Hypercalcemia, Anxiety Hyponatremia, Anticipating N/V Hyperglycemia
  23. 23. CINV• Acute • Onset: minutes-hrs • Resolves: first 24 hrs It is easier to prevent N/V• Delayed than to treat it • Platinum, Cytoxan, Doxo • Onset: >24 hrs • May last for 7 days• Anticipatory• Breakthrough/Refractory Always remember Dyspepsia may mimic nausea
  24. 24. Which anti-emetic you should chose for your patient? Anti-emetic regimens should be chosen based on: Chemo drugs and their sequence in the regimen Acute and delayed emesis may overlap Goal of chemo: Palliative vs Adj/curative Patient specific risk factors Smoker Alcoholic: less N/V Gender, Age (more CINV in young female) Hx of N/V or motion sickness Prior experience with anti-emetics
  25. 25. Categories of Emetogenic ChemotherapyHigh emetic riskModerate emetic risk *Don’t undertreatLow emetic riskMinimal emetic risk *Don’t underestimate
  26. 26. PlatinumDoxorubicinCytoxanDacarbazine
  27. 27. Aprepitant Lorazepam 5-HT3 Antagoist Dexa Dopamine PPI/H2-blocker antagonist
  28. 28. Management ofDelayed Emesis
  29. 29. Dopamine antagonists Metoclopramide (Reglan) and Domperidone (Motilium) Sensitize tissues to acetylcholine Stimulate upper GIT motility Facilitate gastric emptying Increase esophageal peristalsis Increase LES pressure Antagonize central and peripheral dopamine receptors Block dopamine receptors in chemoreceptor trigger zone in CNS2- Haloperidol
  30. 30. Anxiolytics/Anti-psychoticsBenzodiazepine (Lorazepam) May give the night before and after chemoPhenothiazine: Prochlorperazine (Compazine): Anti-dopaminergic effect Blocking dopamine receptors Blocking vagus nerve in GIT
  31. 31. Watch for Dystonic reaction Prochlorperazine Metoclopramide Domperidone
  32. 32. SteroidsDexamethasone Improve efficacy of 5-HT3 antagonists With Aloxi for moderate risk: 8 mg d1 enough No need on d 2-3 *Acute emesis: Do Not use if chemo include steroids PO/IV Prior to e.g. ESHAP mod-highly Contra-indicated with: emetogenic chemo IL-2 *Delayed emesis: IFN Days 2-3
  33. 33. SteroidsDexamethasone Always keep in mind its side effects *Hyerglycemia *HTN *Fluid retension *PU *Osteoporosis
  34. 34. Serotonin (5-HT3) Antagonists 5-HT3 antagonists (except aloxi/palonosetron) are less effective for delayed emesis A meta-analysis of randomized controlled trials: Adding 5-HT3 antagonist to Dexa did NOT improve antiemetic effect of Dexa for delayed emesis Another study: 5-HT3 antagonists (except Aloxi, not studied) NOT more effective than prochlorperazine for delayed emesis A Canadian meta-analysis: Ondansteron alone did help for delayed emesis Not cost-effective to use 5-HT3 antagonists on d 2-4
  35. 35. MiscellaneousAntipsychotic : Olanzapine (zyprexa)Cannabinol: Dronabinol (marinol) 5-10 mg OR Nabilone 1-2 mgAnti-histamine: Promethazine (phenergan)H2-Blocher or PPI
  36. 36. MANAGEMENT OFBREAKTHROUGH (REFRACTORY) EMESIS
  37. 37. Breakthrough CINVThe most difficult to treatConsider routine (around the clock) rather thanPRNRectal or IV rather than POMultiple, alternating agents and perhaps routesDo not forget: Hydration Electrolytes Brain mets GI tumors
  38. 38. Breakthrough Treatment for CIN/VFirst Step: Add one agent from a different drug class PRN Antipsychotic : Olanzapine (zyprexa) 2.5-5 mg po bid Caution: elderly, DM Benzodiazepine: Lorazepam 0.5-2 mg Cannabinol: Dronabinol 5-10 mg OR Nabilone 1-2 mg Dopamine antagonists: Metoclopromide , Domperidone, Haloperidol Phenothiazine: Prochlorperazine OR Promethazine Serotonin 5-HT3 antagonists Dexa
  39. 39. Breakthrough Treatment for CIN/VSecond Step: Continue agent on Schedule Not PRN Agents Consider from change different antiemetics drug class to higher PRN level for next cycle Re-eval, adjust dose and or new drug
  40. 40. Anticipatory N/V
  41. 41. Anticipatory N/VNegative bad experience with chemo18-57% of patients N>VPrevention: Optimal anti-emetic with each cycle AcupunctureAlprazolam 0.5-2 mg po tid beginning night beforeOrLorazepam 0.5-2 mg po night before and am
  42. 42. It is not always medication to do it …It is not always doctors and nurses todo it …It is most of the time the patient todo it …
  43. 43. Non-Medical measures•Eating small frequent meals Dietary•Choice of food consult • Easy on stomach•Eating food at room temperature
  44. 44. Behavioral therapyRelaxation/systematic desensitizationHypnosis with guided imageryMusic therapySpiritual
  45. 45. Radiation-Induced N/VR.T. - upper abdomin: Pretreatment daily: Granisetron 2 mg qd OR Ondansetron 8 mg bid +/- Dexa 4 mg qdTBI: Pretreatment: Granisetron 2 mg qd OR Ondansetron 8 mg bid-tid +/- Dexa 4 mg qdChemoRT: CIN/V protocol
  46. 46. CANCER-RELATED INFECTIONS PREVENTION TREATMENT
  47. 47. PREVENTION1. Neutropenic precaution2. Prophylactic antimicrobials3. G-CSF
  48. 48. Neutropenic precautionHand washGloves, Gowns, etcAccessing central venous lines: Written policy Training of medical staffIsolation
  49. 49. Port-a-Cath
  50. 50. Prophylactic antimicrobials
  51. 51. RISK CATOGERIESOverall infection Disease/Therapy Fever/ Antimicrobial prophylaxixrisk NeutropeniaLow Standard chemo for Low None solid tumor *Viral if prior HSV *Neutropenia < 7 dIntermediate ASCT High *Consider fluoroquinolone Lymphoma *Intermediate if (bactrim) MM single agent *Consider fluconazole during Purine analog Purine analog neutropenia, mucositis *Neutropenia 7-10 d *Antiviral during neutropenia and at least 30 days after SCTHigh Allo SCT High *Consider fluoroquinolone Acute leukemia (Bactrim) Alemtuzumab *Anti-fungal: I.D. consult: or GVHD on HD consider fluconazole, Ampho-B, steroids Voriconazole, Posaconazole, *Neutropenia >10 d Micafungin, Itraconazole, *Antiviral during neutropenia and at least 30 days after SCT *Consider PCN and TMP/SMX (GVHD)
  52. 52. Fungal prophylaxisPts with hematologic malignancies and SCT not on antifungalprophylaxis: Severe mucositis is a risk factor for candidemiaConsider for all GVHD patients on immunosuppressantsAcute leukemia receiving induction or re-inductionWhen selecting drugs: Take into account local susceptibility pattern Remember: Itraconazole, voriconazole, posaconazole are potent inhibitors of cytochrome P450 3A4 isoenzymes than floconazole May decrease clearance of some chemo drugsA lipid formulation is preferred based on less toxicity
  53. 53. Anti-viral ProphylaxisFor low risk pts: None Prior HSV: during neutropeniaIntermediate risk pts: During neutropenia + 30 days after SCTHigh risk: Acute leukemia: During neutropenia Alemtuzumab: During and minimum 2 m after Alemtuzumab and until CD4 > 200 ASCT: During neutropenia + 30 days after SCT Allo SCT: for the first yr
  54. 54. CMV PreventionHigh risk groups and surveillance period : 1-6 m after SCT GVHD Minimum of 2 m after Alemtuzumzb Surveillance done wkly by PCR or Ag testing Pre-emptive therapy: Ganciclovir, Foscarnet, Valganciclovir (PO) At least 2 wks and until CMV not detected
  55. 55. PCP Prophylaxis (Pneumocystis Jirovecii) Recommended ConsideredAllo SC Fludara, T-cell depleting agents For 6 m and while on Until CD4 > 200 immunosuppressants Prolonged steroids (e.g. Pred >ALL 20mg qd x > 4 wks0 Throughout anti-leukemic Temodar + RTAlemtuzumab ASCT For minimum of 2 m after it For 3-6 m after it
  56. 56. PCP Prophylaxis (Pneumocystis Jirovecii)Drugs of choice:TMP/SMX Preferred If allergic or intolerant: Desensitization or Dapsone, aerosolized Pentamidine, Atovaquone
  57. 57. G-CSF
  58. 58. 10.0 8.0 6.0W.B.C. 4.0 2.0 Day 0 (Chemo Day 7 Day 21 Starts) Nadir
  59. 59. TREATMENT
  60. 60. Neutropenic Fever Look for source of infection: *Catheter sites *Skin *Lungs/SinusTemp > 38⁰ C *GIT *ABCNeutropenia *GUT *Vitals Signs ANC < 500 *Venous Access OR *IVF Predicted *O2 Work-up: *Antibiotics decline to < 500 *CBC with diff *Renal and liver function *UA +/- C/S *C-x-ray *Blood C/S x2
  61. 61. Choice of Initial AntibioticShould be based on: Infection risk assessment: High risk (inpt, co-morbid, prolonged neutropenia, pneumonia) Low risk (outpt ) Potential VRE and ESBL (Extended Spectrum Beta-Lactamase) MRSA status Local susceptability Organ dysfunction Drug allergy Previous antibiotics Anti-pseudomonous Bactericidal
  62. 62. Choice of Initial Empiric AntibioticIV monotherapy:*Primaxin IV combination:*Meropenem *Aminoglycoside + Anti-pseudom*Zosyn *Cipro + Antipseudom*Cefepime*Ceftazidime Oral for low risk pts *Cipro+ Augmentin or Clinda Vanco, Linezolid, daptomycin , synercid should not be used routinely
  63. 63. NOT-RESPONDING: •FUO: •Stable: •Cont. same antibioticRESPONDING: •Consider•Continue same antifungal (highantibiotic until ANC > risk pts)500 and rising •Unstable: •FUO: *Daily F/U •Cover •DC *Eval anaerobes, gram antibiotic response neg/positive, •Documented infection +/- in 3-5 d Candida •Consider G-CSF bactremia: •ID consult •Duration •Documented infection: of therapy •Antibiotic/pathogen varies susceptibility •Consider G-CSF •Consider Granulocyte transfusion
  64. 64. Duration of therapy Bacterial InfectionSkin/Soft tissue 7-14 dSimple bacteremia (no tissue site) Gram-negative: 10-14 d Gram-positive: 7-14 d S. aureus: 2 wks after 1st negative blood culture & neg TEESinusitis: 10-21 dBacterial pneumonia: 10-21 d
  65. 65. Duration of therapy Fungal & Viral InfectionFungal: Candida: minimum 2 wks after 1st negative blood cultue Mold (e.g. Aspergillus): minimum of 12 wks Bloodstream Yeast: > 2 wks after 1st negative blood cultueViral: Localized HSV/VZV: 7-10 d (acyclovir, valacyclovir, famciclovir) Influenza: Tamiflu X 10 d and until symptoms resolution
  66. 66. ?? Catheter Removal ?? Considered: •Bloodstream infection with: •Candida •S. aureusRecommended: •P. aeruginosa•Septic phlebitis •Corynbacterium jeikeium•Tunnel infection •Acinetobacter•Port pocket infection •Bacillus •Atypical mycobacteria •Yeasts or molds •VRE •Stenotrophomonas maltophilia
  67. 67. When to use Vancomycin as initial therapy?Serious infection associated with: Clinically apparent, serious, catheter-related infection Blood culture  Gram positive (pending identification/susceptability) Known colonization with PCN/Cephalosporin-resistant pneumococci or MRSA Unstable pt (Hypotensive, septic shock) *DC Soft tissue infection Vanco in 2-3 Pt at risk for Strep viridans bacteremia: days if a Severe mucositis resistant Gram- positive not Quinolone or Bactrim prophylaxis identified Recent studies: Vanco unnecessary if beta-lactam agent is used
  68. 68. Other agents for resistant Gram-positives Linezolid (Zyvox)*VRE Quinupristin/Dalfopristin*Vano not (Synercid)an option Daptomycin (Cubicin)
  69. 69. Outpatient Therapy (Low Risk Neutropenic Fever)Who is a low Assessment:risk? Careful exam Plan: Fever at home Lab: No critical values 2-12 hrs Criteria for home therapy: No co- observation Consent for home care morbidities 24hr care giver Give 1st dose Anticipated Home phone and monitor short Access to ER within 1 Discharge hr neutropenia planning Assess for PO antibiotics: (<7d) No N/V Pt education Good P.S. PO tolerance Telephone F/U Creatinine <2 Not on within 12- fluoroquinolone LFTs < 3 X N 24hrs prophylaxi
  70. 70. Outpatient Therapy (Low Risk Neutropenic Fever) • Daily monitoring at leastDrugs of choice: for the first 3 days• Outpt IV long- • Return to clinic if: acting antibiotic • Positive culture• PO: Cipro 500mg • New symptoms/signs q8h + Augmentin • Persistent/recurrent or Clinda fever • Oral intolerance

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