Beta-lactams and tetracyclines

C H A P T E R

23 Beta-lactams and tetracyclines Rebecca A. Buckler, PharmD, BCPS1, Meghan T. Mitchell, PharmD, BCIDP, Samantha R. Phillips, PharmD Thomas Jefferson University Hospital, Philadelphia, PA, United States 1 Corresponding author: [email protected]

CARBAPENEMS Ertapenem Organs and systems NERVOUS SYSTEM

Carbapenems, including ertapenem, have good penetration to the central nervous system and as a result have been reported to cause neurologic side effects including seizures and encephalopathy. A 74-year-old male with end stage liver disease, a history of an orthotopic liver transplant, and end stage renal disease requiring dialysis secondary to hepatorenal syndrome presented to the hospital with weakness and chills. Blood cultures subsequently grew an extended spectrum beta-lactamase Klebsiella oxytoca and the patient was started on intravenous (IV) ertapenem 0.5 g dosed with dialysis on Monday, Wednesday and Friday. After a week of therapy the patient developed a tremor in his voice, weakness, confusion, forgetfulness and a change in personality. This adverse effect was initially thought to be due to the tacrolimus he was taking, but upon evaluation the tacrolimus level was within normal limits (5.3 ng/mL). Ertapenem was then implicated in causing the reaction and was discontinued. The patient returned to his baseline mental status immediately upon ertapenem discontinuation. The authors advise that ertapenem is capable of producing unusual neurologic adverse effects besides the more commonly reported seizures [1A].

Meropenem Organs and systems LIVER

Several antibiotics have been implicated in causing hepatotoxicity, but this has rarely been reported in patients receiving meropenem. A 63-year-old male was Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.07.015

admitted to the hospital for fever and confusion 6 days after an endoscopic resection of a sinonasal adenocarcinoma. Imaging revealed a left frontal lobe abscess and the patient was initiated on empiric vancomycin and meropenem 2 g IV every 8 h. The abscess was biopsied and cultures grew Streptococcus constellatus. Antibiotic therapy was then changed to ceftriaxone and metronidazole on hospital day 2. On hospital day 3 labs revealed elevated liver enzymes (alkaline phosphatase (ALP) 297 U/L, gamma-glutamyltransferase (GGT) 252 U/L, alanine aminotransferase (ALT) 168 U/L and aspartate aminotransferase (AST) 383 U/L). His liver enzymes continued to rise and reached a peak on hospital day 5. The patient remained asymptomatic and denied abdominal pain, nausea or vomiting and remained hemodynamically stable. Drug-induced liver injury was suspected and as a result ceftriaxone and metronidazole were discontinued. Meropenem was restarted on hospital day 22 after additional tissue cultures revealed Gram negative bacilli. Liver function enzymes were again markedly elevated on hospital day 25 after restarting meropenem (ALP 498, GGT 864, ALT 2030 and AST 2660 U/L). All antibiotics were then stopped and moxifloxacin was started on day 26. All liver enzymes significantly improved on day 27. Vancomycin was restarted again on day 28 and liver enzymes continued to decrease. Other causes of acute liver injury were ruled out, and drug induced liver injury was suspected based on the temporal relationship between drug exposure and liver injury, as well as the normalization of liver enzymes after discontinuation of the meropenem. It was also known that the previous year the patient had another episode of elevated liver enzymes that developed 48–72 h after receiving cefazolin. The authors take interest in the fact that the patient developed liver injury following exposure to multiple beta-lactam antibiotics, suggesting possible immunologic cross-reactivity [2A].

257

© 2019 Elsevier B.V. All rights reserved.

258

23. BETA-LACTAMS AND TETRACYCLINES

Meropenem/vaborbactam General adverse drug reactions A phase 3, multicenter, randomized controlled trial was conducted to evaluate the efficacy and adverse effects of meropenem–vaborbactam in patients with complicated urinary tract infections including acute pyelonephritis. Patients were randomized to receive either meropenem–vaborbactam (2 g/2 g IV over 3 h every 8 h, n ¼ 274) or piperacillin–tazobactam (4 g/0.5 g IV over 30 min every 8 h, n ¼ 276). Patients could be transitioned to oral levofloxacin after 15 or more doses if they met prespecified criteria, and all patients were treated for 10 days total of antibiotics. Thirty-nine percent of patients receiving meropenem–vaborbactam experienced an adverse event compared to 35.5% of patients receiving piperacillin–tazobactam. For patients receiving meropenem–vaborbactam, 15.1% experienced a study related adverse event and 2.6% experienced a severe event. The most common adverse events reported were headache (n ¼ 24, 8.8%), diarrhea (n ¼ 9, 3.3%) and nausea (n ¼ 5, 1.8%) [3C]. Another phase 3, open-label, randomized controlled trial evaluated the efficacy and safety of meropenem– vaborbactam monotherapy compared to the best available therapy for patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Patients with confirmed or suspected CRE infections (bacteremia, pneumonia, complicated intra-abdominal infection, complicated urinary tract infection or acute pyelonephritis) were randomized to receive meropenem–vaborbactam (2 g/2 g IV over 3 h every 8 h for 7–14 days, n ¼ 50) or best available therapy (n ¼ 19). Eighty-four percent of patients receiving meropenem–vaborbactam experienced treatment emergent adverse events. Adverse events occurring in at least 10% of patients treated with meropenem– vaborbactam included diarrhea (12%), anemia (10%) and hypokalemia (10%) [4c].

PENICILLINS Amoxicillin/clavulanic acid Organs and systems PANCREAS

Drug-induced pancreatitis (DIP) cases are underreported in literature. A previously healthy 58-year-old male with a past medical history of hypothyroidism presented with acute abdominal pain. The patient’s prescription medications only included levothyroxine and amoxicillin/clavulanic acid 875 mg twice daily for 10 days as prophylaxis for a dental procedure. The patient noted that he had similar abdominal pain when taking amoxicillin/clavulanic acid several years ago

that resolved after refraining from food intake. On admission, his vital signs were stable. On physical examination, he had epigastric tenderness. Labs revealed an increased white blood cell count of 13.5  109/L, increased serum lipase >600 U/L, amylase 1220 U/L, and C-reactive protein 19.6 mg/dL. Abdominal CT was notable for acute pancreatitis with no pseudocyst formation. The patient was diagnosed with mild acute pancreatitis and managed with aggressive IV hydration and pain management with bowel rest. The patient had significant improvement within 72 h. DIP was suspected after all other possible causes of pancreatitis were eliminated. It was concluded that the patient’s acute pancreatitis was attributed to amoxicillin/clavulanic acid therapy. The authors hope to increase awareness of drug-induced acute pancreatitis and promote to reporting of cases of DIP [5A].

Nafcillin Organs and systems ELECTROLYTE BALANCE

Drug-induced hypokalemia after administration of beta-lactam antibiotics is rare. A middle-aged man with a past medical history of hypertension presented with a 1-day onset of right-sided weakness and bilateral shoulder pain. MRI of the cervical spine revealed an epidural abscess from mid C5 through mid C7. Emergent cord decompression and abscess drainage occurred. Broadspectrum antibiotic coverage with vancomycin, ceftriaxone, and metronidazole was initiated. Both blood and abscess cultures revealed methicillin-susceptible Staphylococcus aureus, and antibiotics were narrowed to nafcillin. Additionally, the patient received a short course of polymyxin and meropenem for carbapenemase producing Klebsiella pneumoniae bacteremia. Baseline potassium level was 4.3 mEq/L. After the initiation of nafcillin, potassium levels decreased to less than 3.5 mEq/L despite repeated IV repletion of potassium chloride 80 mEq per day. Urine potassium was 63.9 mEq/L. Nephrology was consulted and suggested his hypokalemia was induced by nafcillin. The patient continued on IV and oral potassium supplementation while on nafcillin therapy. Upon completion of his treatment course of nafcillin, the patient’s potassium levels returned within normal limits without further need of supplementation. The authors cite the Naranjo Adverse Drug Reaction Probability Scale score of 6, indicating a probable adverse drug reaction. The authors reviewed literature, and confirmed drug-induced hypokalemia after administration of nafcillin is known but infrequent. Awareness of this complication and strategies for potassium replacement should be discussed when hypokalemia occurs during therapy [6A].

PENICILLINS

Piperacillin/tazobactam Organs and systems HEMATOLOGIC

Hematologic events such as eosinophilia, thrombocytosis, thrombocytopenia, leukopenia, and neutropenia have been reported in clinical studies for patients receiving piperacillin–tazobactam. Benli and colleagues conducted a study to evaluate the incidence and risk factors of hematologic adverse effects of piperacillin– tazobactam. Patients were included in the study if piperacillin–tazobactam therapy was greater than 10 days. Patients were excluded if they had HIV infection and hematologic malignancy, leukopenia and neutropenia, and steroid or chemotherapy use within the last 3 months. One hundred and two patients were included with 110 piperacillin-therapy treatment courses. The incidence of leukopenia, neutropenia, and eosinophilia was found to be 16.3%, 10%, and 10%, respectively. The authors concluded that a longer duration of therapy, combination with other antibiotics, younger age with fewer comorbidities, and initial higher eosinophil count increased the risk of hematologic adverse effects with piperacillin– tazobactam therapy [7C]. Alzahrani and colleagues detail two cases of severe and rapid thrombocytopenia after administration of piperacillin–tazobactam with a recent exposure to the antimicrobial. An 81-year-old man with multiple comorbidities including type II diabetes, hypertension, depression, chronic obstructive pulmonary disease, and dementia presented to a local hospital with shortness of breath and cough. On imaging, he was found to have a left lower lobe pneumonia and was initiated on piperacillin– tazobactam and moxifloxacin. The patient’s clinic status began to deteriorate requiring transfer to the different hospital, mechanical ventilation, and vasopressor support. Laboratory results upon transfer showed a white blood count (WBC) of 14  109/L, hemoglobin of 139 g/L, platelet of 230  109/L, prothrombin time of 14.7 s, international normalized ratio (INR) of 1.16, and activated partial thromboplastin time (aPTT) of 29 s. Moxifloxacin therapy was stopped after 5 days, and he was extubated on day 7 of admission. Piperacillin–tazobactam therapy continued at this time. On day 9, his platelet count dropped to 25  109/L after receiving piperacillin–tazobactam therapy for 12 days. Heparin-induced thrombocytopenia immunologic testing was negative and coagulation profile remained within normal limits. A new right middle lobe infiltrate was found on imaging with increased WBC to 24  109/L and increased oxygen requirements. Piperacillin–tazobactam therapy was switched to imipenem on day 12, with improvement of platelet count to 160  109/L. He then completed 7 days of imipenem. On day 20, he became febrile, septic, and hypoxic. Piperacillin–tazobactam was started empirically for sepsis.

259

Platelet count prior to the piperacillin-tazobactam dose was 470  109/L at 4 pm. After the dose, platelet count decreased to 3  109/L at 7 pm. A third platelet count was repeated to confirm severe thrombocytopenia. Disseminated intravascular coagulation was ruled out. A Hematology consult led to the diagnosis of druginduced thrombocytopenia. Piperacillin–tazobactam was switched to imipenem and the patient was treated with intravenous immunoglobulin (IVIG) 1 g per kg for 2 days and methylprednisolone 80 mg IV daily for 6 days. After 7 days, his platelet count recovered to 143 109/L. The second case described was of a 77-year-old man with a history of type II diabetes, metastatic colon cancer, and nonischemic cardiomyopathy who was admitted due to low oral intake, abdominal pain, vomiting, and constipation. Enoxaparin was initiated for deep vein thromboprophylaxis. During the admission, piperacillin–tazobactam was given empirically for 2 days for an infective process of the right parotid gland. Later in the admission, piperacillin– tazobactam was started for a Pseudomonas aeruginosa urinary tract infection (UTI). His initial CBC showed WBC 10.4  109/L, hemoglobin 15 g/L, and platelet count of 274  109. A CBC after 5 days of piperacillin–tazobactam revealed a platelet count of 7  109/L. Coagulation labs were normal, and his 4Ts score was low for heparin-induced thrombocytopenia. Drug-induced thrombocytopenia secondary to piperacillin–tazobactam was assumed. UTI therapy was switched to ciprofloxacin. In addition, the patient was treated with dexamethasone 40 mg daily for 2 days plus IVIG 60 g daily for 2 days. Immune thrombocytopenia (ITP) was confirmed when the platelet count improved to 95  109/L the next day. Unfortunately, the patient deteriorated clinically and the decision for comfort care was made by family given his comorbidities and advanced malignancy. The authors reviewed literature on immune and non-immune mechanisms of piperacillin–tazobactam induced thrombocytopenia. Non-immune thrombocytopenia cases are rarely reported. The authors concluded that, while uncommon, thrombocytopenia could be associated with use of piperacillin–tazobactam. They note that recent use of the drug followed by re-exposure can lead to a quick drop in platelet count, and recognition is critical in management of this adverse effect. It was displayed that stopping piperacillin–tazobactam therapy and initiation of steroids plus IVIG improved platelet count [8A]. Cases have described piperacillin-induced bleeding and thrombocytopenia, but direct abnormalities in platelet function have not been implied. Bower and colleagues describe a 55-year-old man with history of hypertension and intracerebral hemorrhage (ICH) who presented as a transfer for new left basal ganglia ICH. At the time of external ventricular drain (EVD) and quad-lumen bolt placement, the patient’s platelet function assays (PFAs) were normal and imaging showed no hemorrhage. Empiric piperacillin–tazobactam was

260

23. BETA-LACTAMS AND TETRACYCLINES

then started for aspiration pneumonia. CT scans after removal of the quad-lumen bolt and EVD showed new hematomas and hemorrhage in the device tracts. Repeat PFAs at this time were abnormally prolonged. The transfusion medicine team suggested piperacillin– tazobactam induced platelet dysfunction, and cite a Naranjo Adverse Drug Reaction Probability Scale score of 5. Therefore, piperacillin–tazobactam was discontinued, and PFAs trended to normal. The authors were the first to describe a case of intracranial hemorrhage potentially related to piperacillin–tazobactam. They attributed the significant bleeding to platelet dysfunction rather than thrombocytopenia. The authors urge further research in the causal relationship [9A]. SKIN

Fixed drug eruption (FDE) is an adverse drug reaction that is described as well-circumscribed, round, dusky erythematous macules and plaques on cutaneous or mucosal surfaces often accompanied by burning or pruritus. When more than one lesion is present, it is referred to as generalized eruption. FDE with piperacillin–tazobactam administration has been reported. A 31-year-old male with a history of patent foramen ovale, cystic fibrosis, type II diabetes, and pancreatic insufficiency presented with a cystic fibrosis flare. Piperacillin–tazobactam was initiated, and the patient developed several non-pruritic dusky, grey two-toned macules and patches less than 3 cm in size on his hands, arms, legs, and abdomen. The patient recalled the same development 2 months prior when treated with piperacillin–tazobactam. Biopsy with presence of melanophages around superficial vessels supported the diagnosis of generalized FDE. Piperacillin–tazobactam was continued and the patient was treated with triamcinolone 0.1% with improvement. Upon review of literature, the authors found antibiotics were common pharmacologic agents linked to FDE and generalized FDE. They noted that the number of sites affected might increase with re-exposure to an agent, meaning FDE can progress to generalized FDE when re-exposed to the offending agent. The authors conclude that this is the first report of generalized FDE associated with piperacillin–tazobactam [10A]. URINARY TRACT

There continues to be mounting literature evaluating the potential nephrotoxicity of co-administering IV vancomycin with piperacillin–tazobactam when compared with the co-administration of IV vancomycin and alternative beta-lactams. Balci and colleagues present a retrospective cohort study evaluating the nephrotoxic effect of piperacillin–tazobactam and vancomycin in comparison to piperacillin–tazobactam monotherapy, vancomycin monotherapy, and vancomycin combined with meropenem in 402 patients. Patients were included if they had received a minimum of 48 h of antibiotic

treatment and a measured baseline serum creatinine. Patients were excluded if their baseline serum creatinine was greater than 2 mg/dL, on hemodialysis or peritoneal dialysis, pregnant, admitted to the intensive care unit, or were in septic shock. The incidence of AKI was significantly higher in the piperacillin–tazobactam plus vancomycin group (43%) compared with piperacillin– tazobactam monotherapy (16.0%), vancomycin monotherapy (15.7%), and vancomycin plus meropenem (10.1%) groups (P < 0.001). The risk of AKI increased 3.5-fold in patients treated with piperacillin–tazobactam plus vancomycin. The authors state the combined used of piperacillin–tazobactam and vancomycin should be used cautiously in patients with high likelihood of developing AKI [11C]. Luther and colleagues published a systematic review and meta-analysis assessing AKI with combination therapy of vancomycin and piperacillin–tazobactam. Randomized and observational reports were eligible for inclusion if the reports included adult patients on concomitant vancomycin and piperacillin–tazobactam and either vancomycin alone, vancomycin plus another beta-lactam, or piperacillin–tazobactam alone. Fifteen published studies and 17 conference abstracts were included with 24 799 total patients. Overall AKI was 16.7%, with 22.2% for vancomycin plus piperacillin– tazobactam and 12.9% for comparators. Overall the number needed to harm was 11. The odds of AKI with vancomycin plus piperacillin–tazobactam were increased vs vancomycin monotherapy (OR 3.40; 95% CI 2.57–4.50), vs vancomycin plus cefepime or carbapenem (OR 2.68; 95% CI 1.83–3.91), and vs piperacillin–tazobactam monotherapy (OR 2.70; 95% CI 1.97–3.69). In a subset of 968 critically ill patients, the odds of AKI were increased vs vancomycin monotherapy (OR 9.62; 95% CI 4.48–20.68), but not significantly different for vancomycin plus cefepime or carbapenem (OR 1.43; 95% CI 0.83–2.47) or piperacillin monotherapy (OR 1.35; 95% CI 0.86–2.11). The authors conclude the combination of vancomycin and piperacillin–tazobactam increased the odds of AKI over vancomycin or piperacillin monotherapy and vancomycin plus cefepime or carbapenem. They recommend further research in the critically ill population [12M]. Susceptibility factors AGE

Combination therapy with vancomycin and piperacillin– tazobactam is a common empiric regimen for broad Gram-positive and Gram-negative bacterial coverage. As previously mentioned, greater AKI risk with the combination of the two agents compared to monotherapy has been reported in adults. In pediatrics, similar reports are sparse. Abouelkheir and colleagues performed a retrospective chart review of pediatric patients (age 0–14 years) who developed AKI after receiving vancomycin and

CEPHALOSPORINS

piperacillin–tazobactam concomitantly for greater than 48 h. AKI was diagnosed as greater than a 50% reduction in renal function based on eGFR. Eight of 38 patients who received concomitant vancomycin plus piperacillin–tazobactam developed AKI. All patients had normal baseline renal function prior to therapy. Therapeutic drug monitoring was performed for vancomycin once steady state was achieved, and doses were adjusted accordingly. The median onset of AKI was 3 days, and percent reduction in eGFR ranged from 56% to 84%. None of the patients had vancomycin trough concentrations greater than 15 mcg/mL prior to AKI onset. Two patients required renal replacement therapy, while the rest recovered after discontinuation of vancomycin and /or piperacillin–tazobactam. Drug Interaction Probability Scale (DIPS) score for causation assessment was 9 in all cases, giving high probability that the AKI was secondary to the use of combination therapy. The authors promote caution and close monitoring of renal function when utilizing combination of vancomycin and piperacillin–tazobactam in pediatric patients [13c].

CEPHALOSPORINS Cefazolin General adverse drug reactions In recent years extensive analysis has been conducted to evaluate the comparative safety and efficacy of cefazolin vs anti-staphylococcal penicillins (ASPs) for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In 2018 alone, 4 meta-analyses and 2 retrospective studies were published on the topic. In regard to efficacy, all trials found cefazolin to be noninferior to ASPs, with some further demonstrating a mortality benefit. Safety outcomes analyzed ranged from evaluating overall discontinuation rates due to adverse effects to evaluating specific rates of nephrotoxicity and hepatotoxicity between therapies. Bidell and colleagues performed a systematic review and meta-analysis to identify differences in clinical outcomes between treatments. They included 7 trials with a total of 4391 patients. The authors note that only 3 of the studies included evaluated the tolerability of either treatment. They found that the odds of discontinuation due to adverse events (AEs) were significantly lower in patients receiving cefazolin (OR 0.25; 95% CI 0.11–0.56) [14M]. Similarly, Shi et al. performed a meta-analysis including 10 observational studies. Secondary outcomes evaluated included hematotoxicity, hepatotoxicity and nephrotoxicity. There were no significant differences found between cefazolin and ASPs in regard for hematotoxicity; however, hepatotoxicity (OR 0.12; 95% CI 0.04–0.41; I2 ¼ 0%) and nephrotoxicity (OR 0.36; 95% CI 0.16–0.81; I2 ¼ 0%)

261

were significantly lower in patients treated with cefazolin. There was also a lower probability of discontinuation due to AEs in the cefazolin group (OR 0.24; 95% CI 0.12–0.48; I2 ¼ 18%) [15M]. Rindone and colleagues performed a meta-analysis including 9 retrospective and 1 prospective trial evaluating 4728 patients. Their analysis demonstrated significantly more discontinuations due to AEs in the cefazolin group (RR 0.27; 95% CI 0.16–0.47; P < 0.00001) as well [16M]. Monogue et al. performed a retrospective, noninferiority, cohort study to evaluate treatment failure between nafcillin and cefazolin in patients with MSSA bacteremia due to a non-meningitis source. Their secondary outcome analysis found that rates of AEs were higher in the nafcillin group overall (19.7% vs 7%; P ¼ 0.046), and that nafcillin was associated with significantly higher rates of nephrotoxicity (adjusted odds ratio (OR) ¼ 5.4; 95% CI 1.1–26.8) [17C]. Furthermore, a single center retrospective study evaluated patients with MSSA bacteremia who were treated with either nafcillin or cefazolin. A total of 130 patients were included in the evaluation and those treated with nafcillin (n ¼ 79) experienced a higher incidence of nephrotoxicity (25% vs 2%, RR 1.31; 95% CI 1.15–1.5; P < 0.001) as well as a higher incidence of hepatotoxicity (11.4% vs 0%, P ¼ 0.01) [18C]. Eljaaly and colleagues performed a meta-analysis with the intent of evaluating the safety profile of ASPs in comparison to cefazolin. This analysis was unique in that it addressed both inpatient and outpatient populations. The authors reviewed 11 retrospective studies of inpatient therapy and 3 retrospective studies of outpatient therapy. In regard to the inpatient evaluation, authors found lower rates of nephrotoxicity (Peto OR 0.225; 95% CI 0.127–0.513), acute interstitial nephritis (Peto OR 0.189; 95% CI 0.053–0.675), hepatotoxicity (Peto OR 0.160; 95% CI 0.066–0.387), and drug discontinuation due to adverse reactions (Peto OR 0.192; 95% CI 0.089–0.414) in patients treated with cefazolin. For the outpatient evaluation, cefazolin was associated with lower rates of nephrotoxicity (Peto OR 0.372; 95% CI 0.192–0.722) and hepatotoxicity (Peto OR 0.313; 95% CI 0.156–0.627) [19M]. These evaluations add to the growing body of literature suggesting that cefazolin is not only non-inferior to ASPs for the treatment of MSSA bacteremia, but result in fewer AEs and AE-related drug discontinuations.

Cefepime Organs and systems NERVOUS SYSTEM

Cefepime-induced encephalopathy is a relatively rare adverse event occurring in approximately 3% of patients treated. Prior literature has suggested that patients with underlying neurologic conditions may be at an increased

262

23. BETA-LACTAMS AND TETRACYCLINES

risk for this complication. Kenzaka and colleagues present a case report of a 61-year-old man with a past medical history of cerebral palsy, but no documented history of epilepsy, who is believed to have suffered from this adverse effect. The patient was hospitalized for a primary diagnosis of community-acquired pneumonia. Providers initiated treatment with cefcapene 100 mg three times daily by mouth. When the patient did not improve, repeat imaging was conducted which revealed abscess formation. Empiric ceftriaxone 2 g IV every 24 h was started pending the result of sputum cultures. Sputum cultures grew Pseudomonas aeruginosa and antibiotics were broadened to cefepime 2 g IV daily (dosed for renal function). On the fourth day of cefepime therapy the patient had not improved, and began to suffer myoclonic movements of the face, upper limbs and trunk. Cefepime was then discontinued and changed to ceftazidime. Three days following the discontinuation of cefepime the myoclonic movements stopped without recurrence. The patient was followed for recurrence for 4 weeks following discharge from the hospital without event. The authors believe that a history of cerebral palsy may have placed this patient at increased risk for cefepime-induced encephalopathy. They conclude that physicians should exercise caution when prescribing cefepime in patients with underlying neurological disorders [20A]. Susceptibility factor AGE

Cefepime is an important antimicrobial agent for use as empiric therapy against nosocomial pathogens in the neonatal population. Currently there is limited data available regarding its safety and efficacy in this vulnerable population. Knoderer and colleagues performed a retrospective cohort study evaluating cefepime use in the neonatal intensive care unit (NICU). They reviewed all full-term patients (at 40 weeks gestational age), preterm patients (up to 48 weeks postmenstrual age) and patients up to 2 months of age who received at least 48 h of cefepime. The evaluation found that adverse effects occurred in 14.9% (11 of 74) of cefepime courses. The authors describe that 12 of the noted AEs could potentially be attributed to cefepime. The most common AE was hypophosphatemia occurring in 12.2% of overall courses (9 of 74). Acute kidney injury developed in 16.2% (12 of 74) of the patients treated; however, it is worth noting that all of those patients had received a concomitant nephrotoxin. Other adverse effects documented included hyponatremia (n ¼ 1) and seizures (n ¼ 2). The authors conclude that their analysis suggests that cefepime can be used safely in the neonatal population but requires further data to assess clinical efficacy. This evaluation created evidence to support the safe use of cefepime as empirical therapy for hospital-acquired infections in the NICU [21c].

Cefoperazone/tazobactam Interactions DRUG–DRUG INTERACTIONS

An 83-year-old male with a past medical history significant for cerebral infarction, COPD, diabetes type II, chronic renal insufficiency and recurrent urinary tract infections presented to a hospital with a chief complaint of cough. His maintenance medications included vinpocetine, alprostadil, amlodipine, irbesartan, acarbose, cefotiam, ambroxol, haloperidol and tiapride. He was diagnosed with pneumonia and started on etimicin sulphate 0.2 g IV daily. On day 4 sputum cultures were positive for Pseudomonas aeruginosa. On day 8 he continued to worsen and therapy was changed to cefoperazone– tazobactam (2 g IV every 8 h). His baseline PT, aPTT and PT/INR values were within normal limits. Etimicin was discontinued on day 10 due to a worsening in renal function. On day 12 doxycycline 0.2 g IV daily was added given the lack of clinical improvement. Following the initiation of doxycycline, PT, aPTT and PT/INR began to steadily increase. The PT and PT/INR peaked on day 18 (13.3 s and 1.22, respectively). Of note, the patient’s renal function had worsened throughout his hospitalization [207 μmol/L (day 10) to 263 μmol/L (day 21)]. The authors calculated the Naranjo ADR score to be 4, suggesting that concomitant administration of the two antibiotics in the setting of severe pneumonia, chronic renal insufficiency and malnutrition was possibly associated with an elevated PT, aPPT and PT/INR. Unfortunately, the patient expired due to complications of severe pneumonia. The authors conclude this is the first case report describing an elevation of PT, aPPT and PT/INR secondary to doxycycline and cefoperazone co-administration. They highlight that the changes in hematologic values only began following the initiation of the doxycycline. They offer a theoretical mechanism for the drug interaction. Cefoperazone is associated with an increased risk of bleeding due to its N-methyl-thio-tetrazole (NMTT) side chain which is known to prevent vitamin K-dependent carboxylation. As cefoperazone is nearly 90% protein bound, the authors discuss that hypothetically there may be a drug interaction preventing cefoperazone binding, resulting in an increase in free drug and therefore NMTT presence. The authors recommend being vigilant for hematologic abnormalities in patients prescribed concomitant cefoperazone and doxycycline [22A].

Cefoperazone/sulbactam General information Clinical practice guidelines recommend monotherapy with an anti-pseudomonal beta-lactam as first-line empirical antimicrobial coverage for febrile neutropenia (FN).

CEPHALOSPORINS

There is limited data evaluating the efficacy and safety of cefoperazone–sulbactam (CS) for febrile neutropenia. Ponraj and colleagues published a prospective, singlecenter study comparing cefepime (2 g IV q8h for adults and 50 mg/kg IV q8h for children) to CS (2 g IV q8h for adults and 50 mg/kg IV q8h for children) plus amikacin (15 mg/kg IV daily) for FN. Efficacy was defined as resolution of fever at 72 h following antibiotic initiation and remaining afebrile for more than 48 h without requiring initiation or second-line antimicrobials or antifungals. The authors assessed 365 episodes of FN (168 cefepime, 168 CS + amikacin). There was no difference found between the agents in regard to clinical efficacy. Overall 24 patients experienced adverse events. The CS + amikacin group had significantly higher rates of nephrotoxicity compared to the cefepime group (7 events vs 1 event, respectively; P < 0.05), otherwise there were no significant differences in AEs. Fourteen patients (8%) treated with CS + amikacin experienced adverse events. Beyond nephrotoxicity, other adverse reactions included febrile reaction (within 1 h of drug infusion), rash, neurotoxicity, myopathy, ototoxicity, respiratory distress and idiopathic thrombocytopenic purpura. This study demonstrated that cefepime and CS + amikacin performed similarly as first-line therapy for FN in regard to both efficacy and safety [23C].

Cefotetan, cefoxitin Susceptibility factors WEIGHT

There is limited literature devoted to outcomes of larger antimicrobial doses in the obese population. Clinical practice guidelines for surgical site prophylaxis recommend 2 g IV doses of cefotetan or cefoxitin in patients undergoing intra-abdominal procedures. Pharmacokinetic modeling suggests that obese patients may require larger doses to attain desired antimicrobial exposure. Banoub and colleagues performed a retrospective review of 169 patients undergoing 175 intra-abdominal procedures to assess whether surgical site infection rate would differ between patients receiving 2 g vs 3 g of cefotetan or cefoxitin as prophylaxis in patients greater than 120 kg. The median body mass index of evaluated patients was 42 kg/m2. The higher 3 g dose was used in 20% of cases and more often in patients who weighed greater than 130 kg (RR 1.36, 1.01–1.76; P ¼ 0.04). Surgical site infections were not statistically different between the 2 and 3 g groups (20.7% vs 22.9%, respectively, RR 1.10; 95% CI 0.55–2.20; P ¼ 0.78). One secondary outcome evaluated in this study was the rate of study drug related adverse effects. The authors found no difference in adverse effect rates between those given 2 g and those given 3 g prophylactic doses.

263

Five patients overall experienced drug-related adverse effects. Three patients experienced penicillin reactions (1 in the 2 g group and 2 in the 3 g group) and 2 patients developed Clostridium difficile diarrhea within 30 days of procedure (one from each study group). The authors conclude that there was no difference in regard to both efficacy and safety in obese patients given higher doses of prophylactic cefotetan or cefoxitin prior to undergoing intra-abdominal surgery [24C].

Ceftaroline General information There is currently limited evidence supporting the use of ceftaroline for the treatment of spinal infections. In an effort to better characterize the safety and efficacy of ceftaroline use in these patients, Watkins and colleagues performed a multicenter, retrospective, cohort evaluation of spinal infections treated with ceftaroline. They included 74 patients, half of which were given ceftaroline and half of whom were treated with standard of care. The most common pathogen isolated from culture was methicillinresistant Staphylococcus aureus (MRSA). Multivariate regression demonstrated no difference in clinical success between the groups. The authors state that adverse reactions were rare and did not differ significantly between the control and treatment populations. The only described adverse reactions in patients treated with ceftaroline included eosinophilic pneumonia, drug fever and thrombocytopenia. This study demonstrates that ceftaroline is both safe and efficacious for a variety of spinal infections including discitis, vertebral osteomyelitis and epidural abscess [25c].

Ceftriaxone Organs and systems HEMATOLOGIC

Acute splenic sequestration crisis is a common complication of sickle cell disease found in young children. A 9-year-old female with a past medical history of sickle cell disease presented to an outpatient hematology clinic with fever. Of note, 9 days prior to presentation she had been admitted to the hospital for an Escherichia coli urinary tract infection. At that time she was treated for 4 days with ceftriaxone and then discharged on oral cefdinir to complete therapy. Upon presentation to the outpatient clinic she was administered a 2 g dose of ceftriaxone IV. Twenty minutes into the infusion the patient became unresponsive. She was found to have a rapid decrease in pulse oxygenation and hypotension. The patient went into bradycardic cardiac arrest and despite all measures expired. The baseline laboratory values drawn prior to the ceftriaxone infusion demonstrated

264

23. BETA-LACTAMS AND TETRACYCLINES

a hemoglobin (Hb) level of 9.3 g/dL, white blood count (WBC) of 11.9  109/L, and platelet (PLT) count of 380  109/L. Following the initiation of the code blue, repeat labs demonstrated a marked decrease in Hb, falling to 2.3 g/dL. Repeat laboratory specimens confirmed no hemolysis had occurred. Post-ceftriaxone blood samples submitted for review had ceftriaxone-dependent RBC antibodies associated with a strong agglutination reaction. Her direct antiglobulin test (DAT) was positive with polyspecific (2 +), anti-C3 (2 +), and anti-C3d (2 +), but was negative for anti-immunoglobulin (Ig)G suggesting the presence of IgM antibodies. Splenic and hepatic enlargement with sinusoidal congestion was found on autopsy. The authors describe 9 prior published cases detailing ceftriaxone-induced drug reactions in pediatric patients with sickle cell disease. They state that this is the first case of an immune agglutination reaction leading to a fatal outcome. They advise prescribers to be aware that this reaction may present similarly to acute splenic sequestration crisis [26A].

Organs and systems BILIARY TRACT

Biliary excretion of ceftriaxone causes an increase in the biliary concentration of ionized calcium. The combination can result in precipitation and biliary sludge. The resulting biliary pseudolithiasis (BPL) is a well described event in the pediatric patient population, but there is limited data in adults. Renal dysfunction is theorized to be risk factor for BPL as decreases in renal clearance result in slight elevations in biliary clearance of ceftriaxone. There is currently no literature assessing the impact of renal dysfunction on BPL. Imafuku and colleagues present a retrospective analysis of 478 patients treated with ceftriaxone to define the incidence of and risk factors for BPL in the adult population. Overall 12 patients experienced biliary complications during treatment (2.5%). The median time from ceftriaxone initiation to complication was 12 days. Ten patients (7.7%) exhibited BPL, 2 patients (16.7%) developed only biliary sludge, and 5 patients (41.7%) had a common bile duct stone. Half of the patients with biliary complications expressed no symptoms while the other 6 patients suffered fever, abdominal pain and vomiting. Eleven of the 12 patients had renal dysfunction at baseline (defined as a CrCl < 60 mL/min). Bile could only be analyzed in 1 patient; however, there were confirmed ceftriaxone–calcium complexes found in that analysis. Two of the 12 patients underwent endoscopic retrograde cholangiopancreatography. Of the 10 remaining patients, 9 improved with discontinuation of ceftriaxone and 1 was lost to follow-up. The authors state that this evaluation demonstrates that renal dysfunction is a risk factor

for BPL in the adult population and they encourage providers to be aware of the risks of ceftriaxone administration in this population [27C]. Interactions DRUG–DRUG INTERACTIONS

It is well described that some medications can inhibit aldehyde dehydrogenase preventing the proper conversion of acetaldehyde to acetate. In the presence of ethanol-containing substances this can result in a disulfiram-like reaction due to the noxious effects of excess acetaldehyde. Most often cephalosporins containing a methylthiotetrazole (MTT) substituent are associated with this interaction. Ceftriaxone does not contain a MTT side chain; however, it does contain a methylthiodioxotriazine (MTDT) side-chain making a reaction hypothetically possible. To the author’s knowledge there is very little literature describing a disulfiram-like reaction from ceftriaxone, and no literature in the pediatric population. Small and colleagues describe a case in which an 8-year-old male presented to an outpatient clinic for cough, sore throat and fever. The patient had a past medical history of moderate persistent asthma. In the clinic he was administered a 40 mg dose of oral prednisolone elixir (5% ethanol, v/v) in addition to alcohol-free acetaminophen and ibuprofen elixir, and nebulized albuterol–ipratropium. Two and a half hours following the steroid dose the patient was administered a 1000 mg dose of ceftriaxone IV. Thirty minutes following completion of the infusion the child began experiencing facial flushing without other systemic symptoms of allergic reaction (urticaria, swelling or difficulty breathing). The provider administered a 25 mg dose of diphenhydramine IV and flushing improved. The patient was admitted for inpatient care and further treated for atypical pneumonia. During care he experienced no further flushing. The authors conclude that this case highlights that disulfiram-like reactions may present similarly to hypersensitivity reactions. They recommend that providers be vigilant when using alcohol based preparations in combination with this class of medications [28A].

Cefuroxime Organs and systems NERVOUS SYSTEM

De novo absence status epilepticus of late onset (DNASLO) is a non-convulsive form of seizure that can be medication-induced in patients without a past medical history of epilepsy. It has been theorized that cephalosporins can precipitate DNASLO by crossing the brain–blood barrier and competing for binding at gamma-aminobutyric acid (GABA) receptors. A 79-yearold woman with no past medical history of epilepsy

TETRACYCLINES AND GLYCYLCYCLINES

was admitted to the hospital for altered mental status, poor spontaneous speech and mild tremor. The patient had been taking cefuroxime (dose not noted) the week prior to presentation for acute otitis media. Her maintenance medications included omeprazole, tolterodine tartrate, telmisartan, torasemide, calcifediol, and iron. Routine laboratory tests and imaging were normal. On presentation to the hospital, video-electroencephalograhy revealed frequent, intermittent paroxysms of spike–wave complexes consistent with DNASLO. Cefuroxime was discontinued and the patient was initiated on levetiracetam (1000 mg/day). Seizure activity resolved within 24 h. The authors describe that DNASLO caused by nonpsychotropic medications often occur in patients with severe comorbidities (most often renal dysfunction) and deteriorating clinical status. The authors note that prior literature has described this complication arising from cefepime, ceftazidime and ceftriaxone exposure. This is the first case report to their knowledge to describe DNASLO from oral cefuroxime. They recommend considering DNASLO for adult patients presenting with unexplained confusion who are currently exposed to cephalosporin therapy [29A].

TETRACYCLINES AND GLYCYLCYCLINES Doxycycline Organs and systems SKIN

Phototoxicity is a known adverse event associated with doxycycline use. Randhawa and colleagues report two cases of doxycycline-induced phototoxicity. The first patient, a 64-year-old female, traveled to Majorca following the start of doxycycline 100 mg by mouth daily for rosacea. After a few hours of sun exposure, a florid eruption developed on her exposed face, neck, and lower limbs. In addition, the patient developed photo-oncholysis. Eruption resolved over 2 months. The second patient, an 87-year-old female, developed a unilateral eruption on her face and forearm shortly after completion of a course of doxycycline for hospitalacquired pneumonia while admitted to a medical ward. The affected areas of her body were facing an adjacent window. After moving her bed and treatment with topical steroids, the eruption improved. The authors discuss the importance of ultraviolet A (UVA) wavelengths in inciting phototoxicity to doxycycline. While ultraviolet B (UVB) is blocked by physical barriers, UVA can be transmitted through window glass and a human nail as seen in the aforementioned cases. The authors emphasize the importance of informing patients of this common adverse effect and methods for sun protection [30A].

265

Minocycline Organs and systems MUSCULOSKELETAL

Tetracycline incorporation into bone has been described in literature. Most reports describe an effect in the mandible or alveolar bone of the maxilla. Judge and colleagues present two cases of minocycline-induced bone discoloration of the foot and ankle. A 19-year-old female presented with a black-brown discoloration over her ankle occurring 9 months after open reduction and internal fixation (ORIF) for ankle fracture dislocation. Her only medical history included chronic acne for which she took minocycline. The appearance of discoloration over the ankle was associated with progressive morning stiffness. Radiograph imaging did not show degenerative change, periostitis, osseous insufficiency, or fracture. Internal fixation removal was requested by the patient, and the intraoperative view revealed green discoloration of bone affecting the distal fibula throughout. Photographs taken during her initial procedure did not show visible discoloration. After hardware removal, the patient had fading of pigmentation and was able to regain normal function. A second patient, a 20-year-old female with a past medical history of chronic acne treated with both minocycline and spironolactone, presented to an outpatient office with a painful bunion. Examination of the first metatarsophalangeal joint revealed a hallux valgus deformity with an abnormal interphalangeus. Surgical intervention was indicated. Intraoperatively, visible appearance of the first metatarsal head showed a deep green-blue discoloration. The procedure was completed without complication, and she returned to normal activity. The authors want to emphasize this manifestation of minocycline-induced hyperpigmentation that is rarely described in foot and ankle [31A]. Another report by Toffoli and colleagues detail a 28-year-old male who experienced black pigmentation of both forearms. He was originally involved in a motorcycle-car collision resulting in traumatic brain injury, chest wall trauma, fracture of 4 ribs, and an open right diaphyseal forearm fracture. The forearm fracture was debrided, irrigated, and titanium intramedullary nailing was performed. He then developed a surgical site infection requiring revision. Isolation of Enterobacter cloacae, Bacillus cereus, and Coagulase-negative Staphylococci was revealed. The patient received a 3 month course of levofloxacin, minocycline, and rifadin. A second procedure was indicated for a mid-shaft forearm non-union. During the procedure, radius and ulna bones were black in appearance. Surgical debridement was done until bleeding of bone extremities, causing a 5 cm deficit in both bones that was filled with a gentamicin cement spacer. Another course of levofloxacin and rifadin was given for 3 months given the microbiologic results of

266

23. BETA-LACTAMS AND TETRACYCLINES

the second procedure. After the completion of antibiotics, surgical reconstruction was performed and complete bone healing was attained at 6 months. Because the black bone showed normal histological structure, minocycline-related pigmentation was presumed. Again, the authors want to bring awareness to secondary black bone disease from minocycline use, as surgery can still be performed at sites with change in color pigmentation [32A]. SENSORY SYSTEMS

Arshad and colleagues describe a brief case of a 70-year-old man with a history of inflammatory arthritis taking minocycline 100 mg daily for more than 15 years. He presented with a 1 year history of bluish scleral discoloration of both eyes. He was diagnosed with minocycline-induced pigmentation. The authors highlight that scleral pigmentation was still present 1 year after discontinuation of minocycline [33A]. NEUROMUSCULAR FUNCTION

Minocycline is known to cause autoimmune syndromes such as drug-induced lupus, autoimmune hepatitis, and systemic vasculitis. Kang and colleagues describe two cases of biopsy-proven vasculitis secondary to minocycline. First, a 47-year-old women, on minocycline for Propionibacterium acne infection, presented with migratory attacks of pain and altered sensation in extremities for 1 month. Minocycline was initiated 3 months prior to her onset of symptoms. Family history included polymyalgia rheumatica on the paternal side, and thrombocytopenia and neuropathy of unknown cause in her sister. Laboratory testing revealed C-reactive protein (CRP) elevated at 150, complete blood count showed mild anemia, and lupus-anticoagulant antibody was positive. The following laboratory results were within normal limits: basic metabolic panel, liver function tests, creatine kinase, autoimmune panel, urine and serum electrophoresis, cryoglobulin, HIV, Hepatitis B and C, rapid plasma regain (RPR), Lyme titer, ehrlichiosis, anaplasmosis, folate, vitamin B12, and thyroid function tests. Nothing abnormal was revealed on imaging and malignancy was ruled out. Evidence of early axonal multifocal neuropathy affecting the left ulnar nerve and left peroneal nerve was discovered via nerve conduction study and electromyography. Nerve and muscle biopsies were consistent with vasculitic neuropathy. Minocycline was discontinued and she was started on a prednisone taper starting at 60 mg by mouth daily. Following discontinuation of minocycline, her symptoms improved with resolution in CRP level. Second, a 37-year-old male on minocycline for acne treatment for several years presented with a right foot drop. The initial onset included

a rash in his toes, which progressed to the middle of his calves over a month. Bilateral hyperpigmentation in the dorsum of the feet was found on physical examination. His neurological examination revealed decreased strength in several areas and sensory examination revealed decrease pain, vibratory and light touch sensation in extremities. His laboratory results showed positive double-stranded DNA, CRP elevated to 33, and antinuclear antibody positive to 1:15. Right peroneal, right tibial, left musculocutaneous and left sural sensory neuropathies were discovered from nerve conduction study and electromyography. His nerve biopsy showed decreased density of myelinated fibers with increased rate of axonal degeneration and number of empty nerve strands and perivascular mononuclear cells of varying sizes with vessel wall invasion and destruction. His CRP normalized after discontinuation of minocycline and initiation of prednisone. Despite this, residual symptoms were present with new right foot drop. Monthly therapy with cyclophosamide was started and slowly improved symptoms. The authors conclude the autoimmune response to minocycline may involve many different immune mechanisms, and these cases emphasize the importance of recognizing this rare clinical syndrome [34A].

Tigecycline Organs and systems LIVER

Tigecycline is a glycylcycline antibiotic, structurally similar to tetracyclines. Numerous adverse events have been reported. Duran and colleagues detail a case of hypofibrinogenemia associated with tigecycline use. A 90-year-old female with a history of asthma and chronic renal failure presented with nausea and vomiting. She progressed to respiratory failure and unconsciousness. CT of the thorax displayed bilateral effusion, consolidation, and diaphragm hernia requiring intubation and transfer to the ICU. Her initial antimicrobials were piperacillin–tazobactam plus ciprofloxacin. However, therapy was switched to tigecycline on day 15 due to lack of response to initial therapy. Ten days after switching to tigecycline, hyperbilirubinemia and decreased hemoglobin level were noted. Imaging was unrevealing. Additionally, fibrinogen was decreased. Tigecycline was discontinued. Fibrinogen levels improved after day 8 of discontinuation. Unfortunately, the patient died on day 40 of admission. The authors suggest routine coagulation monitoring during tigecycline therapy and consider discontinuation if hypofibrinogenemia is developed [35A]. Additional case studies on the same topic can be found in another published review [36R].

REFERENCES

References [1] Hanna RM, Sun S, Gaynor P. A case of ertapenem neurotoxicity resulting in vocal tremor and altered mentation in a dialysis dependent liver transplant patient. Antibiotics (Basel). 2018;8(1):1–3 [A]. [2] Tattersall T, Wright H, Redmond A. Meropenem-induced liver injury and beta-lactam cross-reactivity. BMJ Case Rep. 2018;11(1):1–3 [A]. [3] Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenemvaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection. The TANGO I randomized clinical trial. JAMA. 2018;319(8):790–9 [C]. [4] Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther. 2018;439-55:7 [c]. [5] Chams S, El Sayegh S, Hamdon M, et al. Amoxicillin/clavulanic acid-induced pancreatitis: case report. BMC Gastroenterol. 2018;18(1):122 [A]. [6] Casado F, Mudunuru SA, Nasr R. A case of hypokalemia possibly induced by nafcillin. Antibiotics (Basel). 2018;7(4):1–5 [A]. [7] Benli A, Simsek-Yavuz S, Basaran S, et al. Hematologic adverse effects of prolonged piperacillin-tazobactam use in adults. Turk J Hematol. 2018;35(4):290–5 [C]. [8] Alzahrani M, Alrumaih I, Alhamad F, et al. Rapid onset severe thrombocytopenia following reexposure to piperacillintazobactam: report of two cases and review of literature. Platelets. 2018;29(6):628–31 [A]. [9] Bower M, Borders C, Schnure A, et al. Platelet dysfunction in intracerebral hemorrhage in patient treated with empiric piperacillin-tazobactam in the neurocritical care unit. World Neurosurg. 2018;11:204–10 [A]. [10] Kornmehl H, Gorouhi R, Konia T, et al. Generalized fixed drug eruption to piperacillin/tazobactam and review of literature. Dermatol Online J. 2018;24(4):14 [A]. [11] Balci C, Uzun O, Arici M, et al. Nephrotoxicity of piperacillin/ tazobactam combined with vancomycin: should it be a concern? Int J Antimicrob Agents. 2018;52(2):180–4 [C]. [12] Luther M, Timbrook T, Caffrey A, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. Crit Care Med. 2018;46(1):12–20 [M]. [13] Abouelkheir M, Alsubaie S. Pediatric acute kidney injury induced by concomitant vancomycin and piperacillin-tazobactam. Pediatr Int. 2018;60(2):136–41 [c]. [14] Bidell MR, Patel N, O’donnell JN. Optimal treatment of MSSA bacteremia: a meta-analysis of cefazolin versus antistaphylococcal penicillins. J Antimicrob Chemother. 2018;73:2643–51 [M]. [15] Shi C, Xiao Y, Zhang Q, et al. Efficacy and safety of cefazolin versus antistaphylococcal penicillins for the treatment of methicillinsusceptible Staphylococcus aureus bacteremia: a systematic review and meta-analysis. BMC Infect Dis. 2018;18(508):1–9 [M]. [16] Rindone J, Mellen CK. Meta-analysis of trials comparing cefazolin to antistaphylococcal penicillins in the treatment of methicillinsensitive Staphylococcus aureus bacteraemia. Br J Clin Pharmacol. 2018;84:1258–66 [M]. [17] Monogue ML, Ortwine JK, Wei W, et al. Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia. J Infect Public Health. 2018;11:727–31 [C]. [18] Miler MA, Fish DN, Barber GR, et al. A comparison of safety and outcomes with cefazolin versus nafcillin for methicillin-susceptible

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30] [31]

[32]

[33] [34]

[35]

[36]

267 Staphylococcus aureus bloodstream infections, J Microbiol Immunol Infect. 2018. [ePub ahead of print]. https://doi.org/10. 1016/j.jmii.2018.07.006 [C]. Eljaaly K, Alshehri S, Erstad B. Systematic review and meta-analysis of the safety of antistaphylococcal penicillins compared to cefazolin. Antimicrob Agents Chemother. 2018;62(4)e01816-17 [M]. Kenzaka T, Matsumoto M. Cefepime-induced encephalopathy. BMJ Case Rep. 2018;2018. https://doi.org/10.1136/bcr-2017223954 [A]. Knoderer CA, Kaylor DM, Toth ME, et al. Characterization of the clinical outcomes with cefepime in a neonatal intensive care unit: a retrospective cohort study. J Pediatr Pharmacol Ther. 2018;23(3):209–14 [c]. Zhu XQ, Guo CF, Wen YG, et al. Elevated PT, APPT and PT/ INR possibly associated with doxycycline and cefoperazone co-administration: a case report. J Clin Pharm Ther. 2018; 43:141–4 [A]. Ponraj M, Dubashi B, Harish BH, et al. Cefepime vs. cefoperazone/ sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia. Support Care Cancer. 2018;26:3899–908 [C]. Banoub M, Curless M, Smith J, et al. Higher versus lower dose of cefotetan or cefoxitin for surgical prophylaxis in patients weighing one hundred twenty kilograms or more. Surg Infect (Larchmt). 2018;19(5):504–9 [C]. Watkins RR, Yendewa G, Burdette SD, et al. DISC: describing infections of the spine treated with ceftaroline. J Glob Antimicrob Resist. 2018;13:146–51 [c]. Van Buren NL, Gorlin JB, Reed RC, et al. Ceftriaxone-induced drug reaction mimicking acute splenic sequestration crisis in a child with hemoglobin SC disease. Transfusion. 2018;58:879–83 [A]. Imafuku A, Sawa N, Sekine A, et al. Risk factors of ceftriaxoneassociated biliary pseudolithiasis in adults: influence of renal dysfunction. Clin Exp Nephrol. 2018;22:613–9 [C]. Small SM, Bacher RS, Jost SA. Disulfiram-like reaction involving ceftriaxone in a pediatric patient. J Pediatr Pharmacol Ther. 2018;23(2):168–71 [A]. Fernández-Torre JL, Paramio-Paz A, López-Delgado A, et al. De novo absence status epilepticus of late onset (DNASLO) precipitated by oral treatment with cefuroxime: description of an ambulatory case. Epileptic Disord. 2018;20(1):73–6 [A]. Randhawa A, Ngu I, Bilsland D. Doxycycline photosensitivity. QJM. 2018;111(4):259–60 [A]. Judge MS, Miller M, Lyons M. Green bone: minocycline-induced discoloration of bone rarely reported in foot and ankle. J Foot Ankle Surg. 2018;57(4):801–7 [A]. Toffoli A, Gamain R, Lazerges C, et al. Black pigmentation of both forearm bones after chronic minocycline antibiotic therapy for septic nonunion. A case report and literature review. Hand Surg Rehabil. 2018;38(1):71–3 [A]. Arshad J, Sayegh R. Scleral discoloration from minocycline treatment. N Engl J Med. 2018;378(16):1537 [A]. Kang MK, Gupta RK, Srinivasan J. Peripheral vasculitic neuropathy associated with minocycline use. J Clin Neuromuscul Dis. 2018;19(3):138–41 [A]. Duran FY, Yildirim H, Sen EM. A lesser known side effect of tigecycline: hypofibrinogenemia. Turk J Hematol. 2018;35(1): 83–84 [A]. Buckler RA, Mitchell MT, Peahota MM, et al. Beta-lactams and tetracyclines. In: Ray SD, editor. Side Effects of Drugs Annual: A Worldwide Yearly Survey of New Data in Adverse Drug Reactions. 40:Elsevier; 2018. p. 297–309 [chapter 24]. [R].