Penicillins

Use in non-infective conditions

In spite of the fact that most trials of antibiotics in pregnancy have shown that antibiotic administration prolongs pregnancy, the mechanism is unclear. However, it is well established that several antibiotics can alter intracellular calcium concentrations [ ] or inhibit some enzymes, including various phospholipases [ ]. It is also well established that bacterial products, such as phospholipases and endotoxins, can stimulate prostaglandin biosynthesis and release by the human amnion [ ]. Therefore, because prostaglandin biosynthesis depends on the action of phospholipase A2, a calcium-dependent enzyme [ ], it has been hypothesized that antibiotics that interfere with phospholipase A2 might affect prostaglandin biosynthesis and release by the amnion. This hypothesis has been tested by evaluating the effect of ampicillin on the release of prostaglandin E from human amnion [ ]. The results were clear: ampicillin dose-dependently inhibited the release of prostaglandin E from human amnion in vitro. Moreover, ampicillin reversibly counteracted the rise in prostaglandin E induced by arachidonic acid or oxytocin. The authors concluded that inhibition of prostaglandin E release from amnion is a mechanism whereby ampicillin might prevent some cases of premature delivery, even in the absence of infection.

General adverse effects and adverse reactions

The major limitation of these substances is their propensity to cause allergic reactions; otherwise they rarely cause adverse reactions, even when they are given in an extended range of dosages. Non-allergic reactions to penicillins occur mainly at high doses or are related to renal insufficiency. They include convulsions and electrolyte disturbances, with hyperkalemia or sodium retention. The penicillinase-resistant and broad-spectrum penicillins can cause specific adverse reactions. Leukopenia, agranulocytosis, liver damage, and some cases of nephropathy are considered to be due to toxic rather than to allergic mechanisms. Diarrhea is a common complication, whereas severe antibiotic-associated colitis is rare. Hypersensitivity reactions are of great importance and are dealt with in the monograph on beta-lactam antibiotics. They range from mostly harmless skin reactions to life-threatening immediate reactions, including anaphylactic shock, acute bronchial obstruction, and severe skin reactions. Tumor-inducing effects have not been described.

Comparative studies

Respiratory

Bronchospasm may be a consequence of penicillin allergy [ ]. Acute severe dyspnea with cyanosis has also been observed without symptoms of bronchial obstruction or pulmonary edema [ ]. Specific mechanisms for such cases have yet to be identified.

Allergic pneumonitis and transient eosinophilic pulmonary infiltrate (Loeffler’s syndrome) are rare. These syndromes have also been observed with penicillin hypersensitivity [ ]. In one case, an alveolar allergic reaction, probably due to ampicillin, showed features of an adult respiratory distress syndrome [ ].

Nervous system

High doses of penicillins, in the order of several million units/day of penicillin G, can produce myoclonic jerks, hyper-reflexia, seizures, or coma. Drowsiness and hallucinations can occur occasionally [ ]. Such reactions are due to a direct toxic effect and are more likely with high concentrations, as seen with intravenous administration [ , ] and with cardiopulmonary bypass in open-heart surgery [ , ].

Myasthenia gravis can be aggravated by ampicillin [ ], a reaction that is well described with aminoglycosides and some other antibiotics.

Intrathecal instillation of more than 10 000 units of penicillin and the topical application of high concentrations of penicillin to the nervous system, especially the brain, during surgery have produced comparable reactions [ ]. All penicillin formulations can produce this kind of reaction.

Benign intracranial hypertension is an extremely rare reaction to penicillins, possibly allergic [ ].

Acute seizures are well known adverse reactions to many beta-lactam antibiotics. Tardive seizures in psychiatric patients undergoing electroconvulsive therapy and receiving a beta-lactam are rare, but two cases from the same hospital have been reported [ ].

• A 62-year-old man undergoing ECT developed pneumonia and was given piperacillin 2 g/day + tazobactam. After 5 days, and after his third ECT session, he had generalized tonic–clonic convulsions. Electroencephalography showed no focal abnormalities and other examinations, including MRI scans, laboratory tests, and cerebrospinal fluid examination, were all negative. Piperacillin was withdrawn. He had recurrent seizures during the next 2 days and gradually improved over the next weeks.

• A 24-year-old man undergoing ECT developed a urinary tract infection and was given cefotiam 2 g/day intravenously for 5 days. One day later and after his third ECT session, he had recurrent attacks of generalized tonic–clonic seizure. Electroencephalography showed no focal seizure activity and MRI and laboratory findings were normal. ECT was stopped and he gradually improved. Four weeks later he had ECT again without subsequent seizures.

Reviewing the literature, the authors found a case of seizures in a patient receiving ECT who was given ciprofloxacin [ ]. The epileptogenic effect of ciprofloxacin is thought to be mediated through suppression of the inhibitory function of GABA, as is that of some beta-lactams. In mice piperacillin and cefotiam inhibit GABA receptor function, inducing convulsions [ ].

Metabolism

Lipoatrophy can occur after the injection of some drugs, including penicillin [ ].

• A 2-year-old boy developed a non-tender, hypopigmented, atrophic patch measuring about 2 × 6 cm on his right buttock. He had been well until 5 months before, when he had received an injection of penicillin into the right buttock.

The incidence of this adverse reaction is unknown, as is the mechanism.

In six healthy subjects, ampicillin caused an increase in urinary uric acid excretion; this effect was attributed to competition for active renal tubular reabsorption of urate [ ].

Electrolyte balance

Potassium penicillin G (benzylpenicillin) can significantly alter potassium balance when given in very high doses; 20 million units of the potassium salt contains about 30 mmol of potassium, and in patients with renal insufficiency this amount can decisively aggravate potentially lethal hyperkalemia. Similarly, large doses of sodium penicillin G, carbenicillin, or ticarcillin can cause hypernatremia [ , ].

High doses of sodium penicillin can cause urinary potassium loss, presumably by acting as a non-absorbable anion in the distal tubule [ ]. Apparently by analogous mechanisms a variety of semisynthetic penicillins, including carbenicillin, cloxacillin, mezlocillin, nafcillin, piperacillin, and ticarcillin, caused hypokalemia, mainly in severely ill patients [ ].

Urinary loss of potassium and interstitial nephritis are well-recognized adverse effects of piperacillin. Since patients in ICU may have increased risks of renal complications, serum electrolyte concentrations have been measured in 43 patients before and after piperacillin administration and in 40 patients who were given other antibiotics [ ]. The groups were comparable in regard to age and severity of disease and all had normal serum creatinine concentrations before the study. Serum concentrations of magnesium, potassium, and, to a lesser degree, calcium fell significantly 36 hours after the start of therapy in patients who were given piperacillin, but not in patients who were given other antibiotics. The fall was most pronounced in the subgroup of patients who were also given furosemide. The authors concluded that treatment with piperacillin can cause or aggravate electrolyte disorders and tubular dysfunction in ICU patients, even when serum creatinine is normal and that the mechanism is probably exacerbation of pre-existing tubular dysfunction. Serum concentrations of electrolytes, including magnesium, should be regularly monitored and, if necessary, supplements should be given to patients in ICU who are receiving piperacillin. This may hold true for all patients receiving piperacillin.

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).

An immunologically induced hemolytic anemia due to penicillin or its congeners occurs but is rare [ ]. It typically occurs during treatment with high doses (over 10 million units/day) of penicillin for more than 2 weeks [ , , ]. The dose- and time-dependence of this reaction appear to be explained by the underlying mechanism. During penicillin treatment the erythrocytes are normally coated with penicillin, thereby forming a penicilloyl bond on their surface [ ]. A drug-specific IgG antibody is directed against the complete antigen, that is the penicillin–erythrocyte complex, and can be shown in direct and indirect Coombs’ tests. Clinical hemolysis therefore requires both sufficient coating of erythrocytes and high anti-penicilloyl IgG titers.

Besides this “hapten” or “penicillin-type” of drug-induced hemolysis, a second less frequent mechanism, the so-called “innocent bystander” mechanism can occur [ , , ]. Penicillin–antibody complexes are only loosely bound to erythrocytes and activate complement, which can be detected on the erythrocyte surface with the complement antiglobulin test (“complement” or “non-gamma” type). This mechanism plays a part in immune hemolytic anemias due to various drugs other than penicillins. The hemolytic reaction can continue for weeks after withdrawal of penicillin, that is as long as sufficient penicillin-coated erythrocytes and specific antibodies remain in circulation.

That any penicillin derivative can cause hemolytic anemia is emphasized by the following case [ ].

• A 34-year-old woman with cystic fibrosis took piperacillin 6 g tds for respiratory distress. She had no known allergies, although she had previously had pruritus while taking ceftazidime and tingling in her hands with azlocillin. She had completed courses of amoxicillin and flucloxacillin without adverse effects. After about 2 weeks she complained of headache and nausea and passed pink urine. A diagnosis of hemolytic anemia was established and piperacillin was withdrawn. She was given a blood transfusion, prednisone, and folic acid, with good effect.

Various antibiotics, including azlocillin, aztreonam, cefuroxime, ceftazidime, chloramphenicol, colistin, flucloxacillin, gentamicin, imipenem, meropenem, piperacillin, tazobactam, temocillin, and ticarcillin, were incubated with this patient’s serum. Only piperacillin and piperacillin + tazobactam caused agglutination in an indirect agglutination test. The authors concluded that the hemolytic anemia had been caused by piperacillin.

Penicillin has been rarely suspected to cause hemolytic–uremic syndrome [ ].

Agranulocytosis and leukopenia are discussed in the monograph on beta-lactam antibiotics. Over the years, several cases of neutropenia after treatment with piperacillin with or without tazobactam have been described, especially in children [ ].

• A 77-year-old man with chronic obstructive lung disease and pneumonia received piperacillin 4 g + tazobactam 0.5 g every 6 hours [ ]. The neutrophil count gradually fell to zero after 24 days. Piperacillin + tazobactam was withdrawn and lenograstim was given. Within 4 days, the number of neutrophils started to increase. Lenograstim was withdrawn, and the number of neutrophils returned to normal within a week. He made a full recovery.

Whether the rate of hematological reactions effects is higher for piperacillin + tazobactam than for other penicillins is unclear, as is the question of whether neutropenia is more frequent in children than in adults or more frequent in patients with cystic fibrosis than in patients with other conditions [ ]. It would anyway be wise to follow patients treated with piperacillin, either alone or in combination with tazobactam, with particular attention.

Thrombocytopenia with penicillins has very rarely been reported [ ]. In two cases with mezlocillin [ ] and piperacillin + azobactam [ ] antibodies became attached to the platelets in the presence of the incriminated drug. The second of these cases is of particular interest, since drug-dependent antibodies were found in the presence of piperacillin but not tazobactam.

• A young woman developed microangiopathic hemolysis and thrombocytopenia in temporal relation to three separate courses of penicillin or ampicillin [ ].

Bleeding disorders with penicillins are discussed in the monograph on beta-lactam antibiotics.

Disseminated intravascular coagulation has been reported during long-term administration of piperacillin [ ].

• A 51-year-old man was given piperacillin 2 g bd for osteomyelitis. After close to 4 weeks he developed acute renal insufficiency and superior mesenteric venous thrombosis. His coagulation profile showed disseminated intravascular coagulation. Withdrawal of piperacillin and anticoagulation therapy resulted in clinical improvement and normalization of the laboratory data.

Piperacillin + tazobactam has been associated with neutropenia [ ].

• A 19-year-old man had an attack of idiopathic acute pancreatitis and developed a large pseudocyst in the body and tail of the pancreas. He had an endoscopic cystogastrotomy, and 2 weeks later developed a high fever and a leukocyte count of 9.3 × 10 ⁹ /l. Blockage of the stent and infection in the cyst was suspected. Pus from the cyst showed a mixed growth dominated by Pseudomonas aeruginosa , susceptible to piperacillin, and he was given 8 g/day. His fever responded within 3 days, but 2 weeks later he again developed a fever and was given piperacillin + tazobactam 13.6 g/day. He became afebrile after 2 days. However, after 5 days he developed a neutropenia (lowest value 0.58 × 10 ⁹ /l) and thrombocytopenia (72 × 10 ⁹ /l). The antibiotics were withdrawn and his blood count returned to normal within 6 days.

The authors referred to several other cases of bone marrow suppression after therapy with piperacillin and/or piperacillin + tazobactam. Bone marrow suppression occurred in patients who had received a cumulative dose of piperacillin + tazobactam of 4929 mg/kg, i.e. 4372 mg/kg of piperacillin. Their patient had received a cumulative dose of piperacillin of 3547 mg/kg.

Teeth

Effects on the mineralization of teeth in children are usually associated with tetracyclines. The possibility that other antibiotics may also be involved has been investigated [ ]. The authors investigated molar incisor hypomineralization in 141 schoolchildren and recorded the use of antibiotics before 4 years of age. There was molar incisor hypomineralization in 16%, most commonly in those who had taken amoxicillin during their first year of life (OR = 2.06; 95% CI = 1.01, 4.17) compared with children who had not used antibiotics. In mouse E18 cells exposed to amoxicillin there was an altered pattern of mineralization.

Gastrointestinal

Antibiotic-induced colitis and diarrhea and non-specific gastrointestinal symptoms are discussed in the monograph on beta-lactam antibiotics.

Liver

Penicillin-induced hepatotoxicity may not be as uncommon as has been thought. There have been three reviews. The first was a comparison of the assessment of drug-induced liver injury obtained by two different methods, the Council for International Organizations of Medical Sciences (CIOMS) scale and the Maria & Victorino (M&V) clinical scale [ ]. Three independent experts evaluated 215 cases of hepatotoxicity reported using a structured reporting form. There was absolute agreement between the two scales in 18% of cases, but there was no agreement in cases of fulminant hepatitis or death. The authors concluded that the CIOMS instrument is more likely to lead to a conclusion compatible with the specialist’s empirical approach.

In the second review some syndromes of drug-induced cholestasis were outlined, with lists of typical examples of which drugs cause what [ ]. The authors stated that the treatment of drug-induced cholestasis is largely supportive and that the offending drug should be withdrawn immediately.

In the third review the authors’ intention was to give new insights into basic mechanism of bile secretion and cholestasis [ ]. Some drug-induced forms of cholestasis appear to be associated with certain HLA class II haplotypes in patients taking co-amoxiclav [ , ]. Whether or not this holds true for hepatotoxicity due to other beta-lactam antibiotics is not known.

In a study in Southwest England over 66 months during 1998–2004, 800 patients presented to a jaundice referral system serving a community of 400 000 [ ]. Of these, 28 cases were related to drugs (mean age 69 years, 17 men), most often antimicrobial drugs (n = 21). Co-amoxiclav (n = 9) and flucloxacillin (n = 7) were the main culprits, with incidence rates per 100 000 prescriptions of 9.91 and 3.60 respectively. Jaundice due to co-amoxiclav was more common in elderly men (age 65 years; M:F = 7:2). The authors suggested that an alternative to co-amoxiclav should be used if possible in men over the age of 60 years.