Cephalosporins

General adverse effects and adverse reactions

Reactions that parallel those observed with penicillins include local reactions to parenteral administration, epileptogenicity, effects on sodium and potassium balance, autoimmune hemolytic anemia, neutropenia, thrombocytopenia, and altered platelet function.

More specifically associated with cephalosporins are false-positive Coombs’ tests (also seen with clavulanic acid and imipenem + cilastatin), impaired vitamin K-dependent clotting factor synthesis with cephalosporins that contain the N -methylthiotetrazole side chain, biliary sludge formation with ceftriaxone, tubular nephrotoxicity of some older compounds (cefaloridine, cefaloglycin, and cefalotin), and disulfiram-like interactions with alcohol. Anaphylactic shock and other IgE antibody-mediated reactions are rare, but analogous to those experienced with the penicillins. Sufficiently reliable tests to predict or prove these reactions are still lacking for the cephalosporins. Other hypersensitivity reactions include acute interstitial nephritis, the majority of drug-inducible mucocutaneous manifestations, and various combinations of symptoms often referred to as “serum sickness-like reactions.”

Cardiovascular

Angina and myocardial infarction can occur in the absence of angiographically stenosed coronary arteries, because of arterial vasospasm during a drug-induced allergic reaction. This rare condition is called the Kounis syndrome, and it has been reported in a 70-year-old woman after intravenous cefuroxime [ ]. The authors suggested that individuals in whom there is increased mast cell degranulation may be more susceptible to this effect. In isolated cases, cefalotin [ ] and cefaclor [ ] have been suspected to cause hypersensitivity myocarditis.

Respiratory

Diffuse pulmonary inflammation, as documented by gallium scanning in one case, was possibly caused by ceftriaxone [ ]. Cefotiam and in another case cefotiam followed by ceftazidime have been suspected to have caused pulmonary hypersensitivity [ , ].

Cefotetan-induced hiccup recurred after each cefotetan infusion and disappeared immediately after withdrawal; it did not recur after administration of another antibiotic [ ]. Intractable hiccups in a boy were attributed to ceftriaxone-induced pseudolithiasis [ ].

Nervous system

Since penicillin G-induced convulsions were observed in 1945 [ ], many investigators have studied the convulsive effects of the beta-lactams, the mechanism(s) of action, and structure-activity relations. The convulsive effects of seven different cephalosporins have been studied both in vivo and in vitro, by intracerebroventricular administration in mice, labelled ³ H-muscimol binding in mouse brain synaptosomes, and inhibition assays in Xenopus oocytes [ ]. The rank orders of convulsive effects were cefazolin > cefoselis > cefotiam > cefpirome > cefepime > ceftazidime > cefozopran. The authors suggested that the strong correlation between this effect and affinity for muscimol binding sites implies that most cephalosporins inhibit GABA-mediated transmission by binding to some specific subunits of the GABA receptors. They speculated that cefazolin and cefoselis might recognize a different molecular motif on GABA receptors from that detected by other cephalosporins. However, they also emphasized that while these results are suggestive, they do not completely clarify the convulsive risk of these cephalosporins and that intensive pharmacokinetic and pharmacodynamic studies will be required to predict the potential convulsive risk of these antibiotics.

In rats, intracerebroventricular injection of various cephalosporins produced markedly different responses in epileptogenic potential [ ], later confirmed with a total of 15 compounds [ ]. Compounds with two heterocyclic rings at both position 3 and position 7 of the cephalosporin molecule, for example ceftriaxone, cefoperazone, and ceftazidime, were even more epileptogenic than benzylpenicillin, while others, with only one heterocyclic ring at position 7, for example cefotaxime and cefonicid, were less potent. Cefazolin, a tetrazole derivative, similar to the convulsant phenyltetrazole, was most potent.

The convulsive effects of the cephalosporins may be caused by suppression of inhibitory neurotransmission via modulation of GABA _A receptors [ ]. Furthermore, radioligand binding studies show that cephalosporins inhibit GABA binding [ ]. Consistent with this hypothesis, positive modulators of these receptors, such as benzodiazepines and barbiturates, can prevent or treat cephalosporin-induced convulsions.

Clinical reports [ , ] and experimental reports [ ] continue to appear. The following two case reports can be taken as brief reminders

• A 60-year-old man with diabetes mellitus and end-stage renal disease on hemodialysis was given cefepime 2 g/day for a supposed pneumonia [ ]. Five days later he became confused and agitated and had visual and auditory hallucinations. His symptoms did not improve with further dialysis over 2 days, and cefepime was withdrawn. Within 1 day he started to improve, and 2 days later had regained his baseline mental status. He had had hallucinations and confusion after taking ceftazidime a year before.

• A 66-year-old woman with acute myeloid leukemia had a fever on third day of the initial chemotherapy cycle [ ]. She was given empirical antibiotic treatment with cefepime 2 g every 8 hours and 10 days later developed acute renal insufficiency and altered consciousness (Glasgow coma scale 6). An electroencephalogram showed generalized spike and sharp wave activity compatible with non-convulsive status. Cefepime was withdrawn and the epileptiform activity disappeared with clonazepam. She regained consciousness 48 hours after cefepime withdrawal.

The authors emphasized that neurotoxic symptoms are not uncommon in patients receiving cephalosporins and that non-convulsive status epilepticus is often underdiagnosed.

Neurotoxicity has been reported with intracerebroventricular cefazolin [ ] and with systemic cefazolin [ ], cefepime [ ], cefotaxime [ ], ceftazidime [ , ], and cefuroxime [ ]. Ceftazidime also caused truncal asterixis [ ] and absence status and toxic hallucinations [ ]. Even the least epileptogenic of 15 cephalosporins, namely cefonicid [ ], caused seizures [ ], although this effect was disputed [ ]. As expected, seizures after systemic treatment were predominant in uremic patients, and neurotoxicity has been associated with intraperitoneal ceftazidime therapy in a patient undergoing CAPD [ ]. Of practical interest was a patient treated with intravenous cefmetazole in whom the CSF concentration was twice as high as the corresponding blood concentration (236 versus 103 μg/ml) [ ]. Uremia may have contributed to this unusual distribution pattern.

• A 66-year-old woman had several episodes of recurrent aseptic meningitis associated with cefalexin, cefazolin, and ceftazidime [ ]. Intrathecal ceftazidime-specific IgG antibodies were isolated and a skin test with cefazolin provoked recurrence of the aseptic meningitis.

Two patients developed status epilepticus during treatment with cefepime for Pseudomonas aeruginosa sepsis [ ].

• A 44-year-old man, who had previously had bilateral lung transplantation and who was on hemodialysis for chronic renal insufficiency, was given cefepime 2 g/day. Within 24 hours he started to become confused and developed diffuse hyper-reflexia. Two days later an electroencephalogram showed nearly continuous, generalized sharp-wave/slow-wave activity. After lorazepam 2 mg the status epilepticus resolved, but he remained confused. A follow-up electroencephalogram showed recurrence of generalized sharp-wave activity. Cefepime was withdrawn, and within hours he rapidly recovered his mental status. An electroencephalogram showed absence of epileptiform discharges.

• A 28-year-old woman with a thoracic spina bifida was given cefepime 1 g bd for an infection with P. aeruginosa . After a time (not stated) an electroencephalogram showed a continuous generalized spike and wave pattern. She was given lorazepam 2 mg, which resulted in resolution. Cefepime was withdrawn and she promptly recovered.

In the first case the dose was inappropriate for the degree of renal impairment and in the second case the dose was inappropriate for the patient’s body weight. The authors underlined the importance of giving cefepime with great care, especially to patients with renal impairment and low body weight.

Five patients developed severe symptoms after receiving cefepime [ ]. The patients, three men and two women, aged 16–75 years, received 2 g/day (n = 3) 4 g/day (n = 1) or 9 g/day (n = 1). The symptoms started 12–16 days after the start of therapy. In all cases, the initial neurological symptoms (disorientation, confusion, and reduced consciousness) were progressive and were attributed to the infection. Facial or multifocal myoclonic movements occurred subsequently and were rapidly followed by convulsive or non-convulsive status epilepticus. The dose of cefipime had not been adjusted for renal function in any of the patients. Cefepime serum concentrations were measured in three cases, and were 72, 73, and 134 μg/ml. All the patients underwent hemodialysis, and the serum concentrations of cefepime fell to 4.3, 21, and 25 μg/ml respectively. In the other two patients, the serum concentrations after dialysis were 14 and 54 μg/ml, suggesting high concentrations before dialysis. There was complete recovery in four of the patients. One, a 73-year-old woman, died of multiorgan failure with refractory status epilepticus and coma. The authors referred to four other reports of cefepime-induced generalized seizures. They seriously questioned whether the actual frequency of this complication might not be underestimated, owing to insufficient knowledge, underreporting, and/or lack of specificity of clinical features.

• An 82-year-old man on chronic hemodialysis had pneumonia, for which he was given intravenous cefepime 1 g/day [ ]. After 4 days he developed a seizure and cefepime was withdrawn. Hemodialysis was started and his conscious level improved. On the next day, after a second hemodialysis, he recovered completely.

There have been many other reports of neurotoxicity and neuropsychiatric adverse effects of cefepime in patients with impaired kidney function [ ]. It might be wise to follow a recommendation given in a recent review: “Since reports of neurotoxic effects and of an increased mortality have created some concerns regarding its safety… caution in the use of cefepime should be adopted until new evidence on (its) safety is available” [ ].

Seven patients developed reversible cefepime-induced encephalopathy with a peculiar electroencephalographic pattern, characterized by semiperiodic diffuse triphasic waves [ ]. Abnormal electroencephalography was also found in a US patient [ ]. Most often, these types of adverse effects occur in patents with reduced renal function [ ], but they can occur in patients with normal renal function [ ]. In a 79-year-old patient with normal renal function subtle mental status changes during cefepime therapy were shown by electroencephalography to be due to non-convulsive status epilepticus [ ]. In three other patients non-convulsive status epilepticus due to cefepime was associated with varying degrees of renal impairment [ ]. Cefepime toxicity should be suspected whenever a patient taking the drug has a change in mental status or myoclonus.

Pseudotumor cerebri has been attributed to ceftriaxone [ ].

Psychological, psychiatric

It has long been known that intramuscular procaine penicillin can cause some peculiar psychological adverse reactions, and that other penicillin derivatives, such as amoxicillin, can cause psychiatric reactions, such as hallucinations [ ]. In a report from the Netherlands, neuropsychiatric symptoms occurred in six patients who received cefepime for febrile neutropenia [ ]. The patients, two men and four women, aged 32–75 years, received 6 g/day (n = 5) or 3 g/day (n = 1). The symptoms started 1–5 days after the first dose and varied from nightmares, anxiety, agitation, and visual and auditory hallucinations to coma and seizures. After withdrawal of cefepime, they recovered within 1–5 days. The causality between their neuropsychiatric symptoms and cefepime was considered as probable (WHO criteria) because of the temporal relation, lack of other causal neurological explanations, and positive rechallenge in five patients.

The mechanisms of these adverse effects are unknown, although it might be of value to take a closer look at the theory that drug-induced limbic kindling may be the principal pathogenic factor [ ].

Metabolism

Although possible interference with the metabolism of carnitine by pivaloylmethyl-esterified beta-lactams is a matter of concern [ ], new similar prodrug derivatives of cephalosporins continue to be marketed, as do reports that they can be given to healthy volunteers without concern [ ].

However, taking a closer look at the data, it is evident that healthy volunteers lost around 10% of their body stores of carnitine within 2 weeks of being given antibiotics containing pivalic acid [ ]. The authors emphasized that prolonged used of such drugs might result in profound carnitine depletion and that this depletion might be associated with clinical sequelae.

Valproate also causes urinary loss of carnitine, most probably by a different mechanism than pivalic acid [ ]. However, the combination can rapidly cause serious adverse effects [ ].

• A 72-year-old woman taking valproate as monotherapy for her epilepsy developed a urinary tract infection and was given pivmecillinam 600 mg/day. During the next few days she became stuporose; her serum ammonia concentration was high (113 mmol/l) but liver function was normal. Pivmecillinam and valproate were withdrawn and she recovered rapidly.

The authors recommended caution when treating patients taking valproate with pivmecillinam because of the risk of hyperammonemic encephalopathy. It seems reasonable to assume that this caution should include all beta-lactams that incorporate pivalic acid.

However, there may be another mechanism by which cephalosporins can interfere with carnitine metabolism. Cephalosporins with a quaternary nitrogen (cefepime, cefluprenam, cefoselide, and cefaloridine) compete with carnitine for renal reabsorption due to OCNT2, a major member of the family of organic cationic transporters [ ]. Mutations in the OCNT2 gene are responsible for the genetic disorder primary systemic carnitine deficiency [ , ]. Since carnitine and the cephalosporins mentioned above compete for the same substrate-binding site on OCTN2, it is likely that such mutations will interfere with the pharmacokinetics of these drugs. Consequently these cephalosporins should not be given to patients with such mutations.

Nutrition

Pivoxil is used as a component of prodrugs for its ability to increase drug absorption from the gastrointestinal tract. However, it can cause carnitine depletion, as illustrated in a report from Japan where three different pivoxil-containing cephalosporins are marketed [ ].

• A 1-year-old boy was given pivoxil-containing cephalosporins for recurrent otitis media and upper respiratory tract inflammation. He developed a tremor in his hands and feet, which led to a generalized convulsion. His blood carnitine concentration of was about 1/10 of normal.

Hematologic

Since the days when chloramphenicol was more commonly used, it has been recognized that many antimicrobial drug are associated with severe blood dyscrasias, such as aplastic anemia, neutropenia, agranulocytosis, thrombocytopenia, and hemolytic anemia. Information on this association has come predominantly from case series and hospital surveys [ ]. Some evidence can be extracted from population-based studies that have focused on aplastic anemia and agranulocytosis and their association with many drugs, including antimicrobial drugs [ , ]. The incidence rates of blood dyscrasias in the general population have been estimated in a cohort study with a nested case–control analysis, using data from a General Practice Research Database in Spain [ ]. The study population consisted of 822 048 patients aged 5–69 years who received at least one prescription (in all 1 507 307 prescriptions) for an antimicrobial drug during January 1994 to September 1998. The main outcome measure was a diagnosis of neutropenia, agranulocytosis, hemolytic anemia, thrombocytopenia, pancytopenia, or aplastic anemia. The incidence was 3.3 per 100 000 person-years in the general population. Users of antimicrobial drugs had a relative risk (RR), adjusted for age and sex, of 4.4, and patients who took more than one class of antimicrobial drug had a relative risk of 29. Among individual antimicrobial drugs, the greatest risk was with cephalosporins (RR = 14), followed by the sulfonamides (RR = 7.6) and penicillins (RR = 3.1).